Effects of Ionizing Radiation UNSCEAR 20061 PDF

EFFECTS OF
IONIZING RADIATION
United Nations Scientific Committee on the Effects of Atomic Radiation
UNSCEAR 2006 Report
Volume II
Scientific Annexes C, D and E
EFFECTS OF IONIZING RADIATION
United Nations Scientific Committee on the
Effects of Atomic Radiation
UNSCEAR 2006
Report to the General Assembly
with Scientific Annexes
VOLUME II
Scientific Annexes C, D and E
UNITED NATIONS
New York, 2009
NOTE
The report of the Committee without its annexes appears as Official Records of the General
Assembly, Sixty-first Session, Supplement No. 46 and corrigendum (A/61/46 and Corr. 1). The
report reproduced here includes the corrections of the corrigendum.
The designation employed and the presentation of material in this publication do not imply the
expression of any opinion whatsoever on the part of the Secretariat of the United Nations con-
cerning the legal status of any country, territory, city or area, or of its authorities, or concerning
the delimitation of its frontiers or boundaries.
The country names used in this document are, in most cases, those that were in use at the time the
data were collected or the text prepared. In other cases, however, the names have been updated,
where this was possible and appropriate, to reflect political changes.
UNITED NATIONS PUBLICATION

Sales No. E.09.IX.5
ISBN 978-92-1-142270-2
CONTENTS
Page
VOLUME I
Report of the United Nations Scientific Committee on the Effects of Atomic Radiation
to the General Assembly
Scientific Annexes
Annex A. Epidemiological studies of radiation and cancer
Annex B. Epidemiological evaluation of cardiovascular disease and other non-cancer
diseases following radiation exposure
VOLUME II
Annex C. Non-targeted and delayed effects of exposure to ionizing radiation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Annex D. Effects of ionizing radiation on the immune system. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Annex E. Sources-to-effects assessment for radon in homes and workplaces. . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
iii
ANNEX C
Non-targeted and delayed effects of exposure to ionizing radiation
Contents
Page
INTRODUCTION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
I. RADIATION-INDUCED GENOMIC INSTABILITY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

A. Radiation-induced genomic instability in vitro . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
B. Induced genomic instability after in vivo irradiation followed by in vitro analysis. . . . . . . . . . . . . . . . . . . . . . 12
C. Induced genomic instability after in vitro irradiation followed by in vivo analysis. . . . . . . . . . . . . . . . . . . . . . 12
D. Radiation-induced genomic instability in vivo. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
1. Mouse models for radiation-induced genomic instability in vivo. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
2. Human studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
E. Genomic instability and radiation-induced leukaemia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
1. Mouse models. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
2. Human studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
F. Role of telomeres and telomerase in radiation-induced genomic instability. . . . . . . . . . . . . . . . . . . . . . . . . . 21
G. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
II. BYSTANDER EFFECTS AND RADIATION EXPOSURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

A. Bystander effects in vitro. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
1. Bystander effects after cytoplasmic irradiation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
2. Bystander effects after low fluences of alpha particle irradiation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
3. Bystander effects after irradiation with a charged-particle microbeam. . . . . . . . . . . . . . . . . . . . . . . . . . 27
4. Bystander effects after transfer of medium from irradiated cells. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
B. Bystander effects in vivo. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
III. Relationship between Radiation-Induced Genomic Instability and Bystander Effects. . . . . . . . . . 37

A. Relationship between radiation hypersensitivity at low doses and bystander effects . . . . . . . . . . . . . . . . . . 37
B. Relationship between radiation adaptive response and bystander effects. . . . . . . . . . . . . . . . . . . . . . . . . . . 38
C. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
IV. ABSCOPAL EFFECTS OF RADIATION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

A. Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
B. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
V. CLASTOGENIC FACTORS INDUCED BY IONIZING RADIATION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

A. Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
B. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
VI. IMPACT OF NON-TARGETED AND DELAYED EFFECTS OF RADIATION ON FUTURE GENERATIONS . . . . . . . . . . . . 45

A. Studies in non-mammalian species. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
B. Mouse studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
1. Irradiation of the mouse zygote. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
1
Page
2. Pre-implantation embryo chimera assay. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
3. Mouse mutation assays. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
4. Alterations in tandem repeat DNA sequences. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
5. Tumour induction in the offspring of irradiated parents. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
C. Malformation induction in the offspring of irradiated parents. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
D. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
E. Cancer incidence in the offspring of irradiated humans. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
F. Pregnancy outcomes in the offspring of irradiated humans. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
G. Genetic damage and malformation induction in the offspring of irradiated parents. . . . . . . . . . . . . . . . . . . . 52
H. Impact of non-targeted and delayed effects of radiation on future generations. . . . . . . . . . . . . . . . . . . . . . . 52
VII. IMPLICATIONS OF NON-TARGETED AND DELAYED EFFECTS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
CONCLUDING REMARKS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
2
INTRODUCTION
1. The goal of this annex is to summarize the evidence that can manifest across generations. This annex considers
for non-targeted and delayed effects of exposure to ionizing whether these effects pose new challenges to evaluating risks
radiation in vitro and in vivo. Currently, human health risk associated with radiation exposure, understanding radiation-
estimates for effects associated with radiation exposures are induced carcinogenesis and interpreting epidemiological
based primarily on the view that the detrimental effects of data on radiation exposure.
irradiation occur only in irradiated cells. Over the years, a
number of non-targeted effects of radiation exposure have 2. A central tenet in the radiation sciences has been that the
been described that challenge this concept. These non- energy from radiation must be deposited in the cell nucleus
targeted effects include genomic instability occurring in the to elicit a mutagenic and/or clastogenic effect and thus be rel-
progeny of an irradiated cell, bystander effects, clastogenic evant for its potential to cause damage (figureI). It is implicit
factors produced in plasma from irradiated individuals that in this tenet that the biological consequences of cellular irra-
can cause chromosome damage when cultured with non- diation affect only the irradiated cell and that non-irradiated
irradiated cells, and heritable effects of parental irradiation cells do not share the legacy of the radiation exposure.
Figure I. Prevailing paradigm for the biological effects of cellular exposure to ionizing radiation.
Ionizing radiation deposits energy in the nucleus of the cell. DNA damage is induced, and cellular responses to that damage can affect the fate
of the irradiated cell. The damage can be removed and the genetic material restored by high-fidelity DNA repair. DNA repair systems may also
eliminate the damage, but error-prone processing can result in gene mutations and clastogenic effects leading to chromosomal rearrange-
ments. Depending upon the cell type, various cellular processes may be initiated that result in carcinogenesis in somatic cells, heritable genetic
effects in germ line cells and developmental defects in foetal cells which may or may not be derived from mutational or clastogenic effects.
DNA damage might activate cell cycle checkpoint control and cause the damaged cell to go into a protracted senescent state. Alternatively,
if the damage is substantial, cell death may occur via a number of cellular pathways.
Radiation
High-fidelity Senescence
DNA damage
DNA repair
Death
- Apoptosis
- Necrosis
Mutations and/or - Mitosis-linked
chromosome rearrangements
Somatic Germ line Foetal
Carcinogenesis Heritable Developmental

genetic effects
effects
3
4 UNSCEAR 2006 REPORT: VOLUME II
3. When ionizing radiation is absorbed in biological mate- dose-rate exposures. In addition, inherent in many models
rial, excitations and ionizations occur that are non-randomly of radiation risk is that only those cells or tissues actually
distributed along localized tracks. The spatial distribution irradiated are burdened by the legacy of the radiation expo-
of these ionization/excitation events produced by different sure. A number of non-targeted delayed effects of radiation
particles varies considerably depending on the quality of exposure have been described; the purpose of this annex is
radiation. The term linear energy transfer (LET) is used to summarize the evidence for these effects and indicate
to classify radiation quality according to the average energy present hypotheses on how they may affect the assessment
transferred per unit length of the track. For the purposes of of health hazards associated with radiation exposure and
this annex, X- and gamma rays are considered to be low- radiation-induced carcinogenesis.
LET radiation, protons and neutrons are considered to be
intermediate LET radiation, and alpha particles and heavy 5. For the purposes of this annex, non-targeted effects
ions are considered to be high-LET radiation. refers to radiation-induced effects manifesting in cells
whose nucleus was not subject to a direct hit by the radia-
4. In contrast to the risks associated with exposures to tion, i.e. no ionization events due to cellular irradiation
low doses of ionizing radiation (less than about 200mSv, were deposited within the volume of that nucleus. In such
UNSCEAR 2000 Report [U2]), the risks of cancer after high instances the radiation may have hit the cytoplasm, or neigh-
and moderate doses of radiation are relatively well under- bouring cells, tissues or organs, or even cells in another
stood. This understanding is based on data from detailed culture vessel, and a response is communicated from these
epidemiological studies of the survivors of the atomic irradiated cells to non-irradiated cells to elicit an effect. It
bombings in Japan and other exposed groups, e.g. clinically must be stressed at this stage that the non-targeted effects
irradiated populations and those exposed as a result of the of ionizing radiation described in this annex do not imply
Chernobyl accident (UNSCEAR 2000 Report, annex I). that the well-documented targeted effects of radiation are
However, risks at low doses are generally extrapolated from irrelevant or unimportant, or that the concept of dose
the high-dose data, applying dose and dose-rate effective- needs to be revised. That is not the case. Rather, the goal
ness factors. Estimating risk is further complicated because of this annex is to summarize the literature on non-targeted
environmental exposures are predominantly protracted, low- effects associated with exposure to ionizing radiation and,
dose, low-dose-rate exposures, or high-dose-rate exposures where possible, to evaluate how such effects may affect
delivered in small fractions (see annex A, Epidemiological risks associated with radiation exposure, the understanding
studies of radiation and cancer). This contrasts with the of radiation-induced carcinogenesis, and the mechanistic
majority of laboratory studies and clinical exposure situa- basis for interpreting epidemiological data on radiation
tions, where exposures are usually acute, high-dose, high- effects.
I. RADIATION-INDUCED GENOMIC INSTABILITY
A. Radiation-induced genomic instability in vitro microsatellite (short tandem repeat) instabilities and/or
decreased plating efficiency (summarized in table1), and
6. Genomic instability is an all-embracing term to has been the subject of a number of reviews [K17, L14,
describe the increased rate of acquisition of alterations in M11, M12, M14, M48, W12]. These observed delayed
the genome. As compared with the direct effects of radia- effects can persist in unstable clones over time, and in
tion, i.e. those effects directly induced as a consequence of some instances mimic those effects seen in tumour cells.
energy deposition, radiation-induced instability is observed There are likely to be multiple pathways for initiating and
in cells at delayed times after irradiation and manifests in perpetuating induced instability [K8, L11], and the rela-
the progeny of exposed cells multiple generations after tive contributions of the different pathways involved prob-
the initial insult (figure II). Instability is measured as ably depend on the genetic background of the target cell or
chromosomal alterations, changes in ploidy, micronucleus organism [P3, W1] and on environmental factors (reviewed
formation, gene mutations and amplifications, mini- and in references [K4, M32, M33]).
Figure II. Radiation-induced genomic instability.

A single cell survives irradiation and is clonally expanded. During clonal expansion, a number of the progeny of that irradiated cell die (through
lethal mutations or delayed reproductive cell death), which results in a persistently reduced plating efficiency in this clone. Alternatively, or as a
consequence of the presence of these dead and dying cells, instability events can occur in the progeny of the irradiated cell. These may result
in chromosomal rearrangements, aberrations or gaps, micronuclei, mutations, gene amplifications and/or a failure of the cells to correctly
separate their chromosomes at mitosis, resulting in aneuploid cells.
Ionizing radiation
First
instability
event
Cell death occurs
-Lethal mutation
-Delayed reproductive
cell death Second
instability
event
occurs
Aneuploidy
Multiple subpopulations appear within a colony

clonally expanded from a single irradiated cell
5
Table 1 In vitro studies of radiation-induced genomic instability
Year End point Cell type Radiation typea Comments Reference
1991 Plating efficiency Chinese hamster ovary cells X-rays [C13]
1992 Chromosomal aberrations Murine haemopoietic stem cells Alpha particles [K3]
1992 Mutation frequency Chinese hamster ovary cells X-rays [C12]
1992 Plating efficiency Chinese hamster ovary cells X-rays [C12]
1993 Chromosomal instability Human skin fibroblasts Heavy ions: neon, argon Dose response [M30]
1993 Chromosomal aberrations Human lymphocytes X-rays [H7]
1993 Chromosomal aberrations GM10115 humanhamster hybrid cells X-rays [M2]
1993 Neoplastic transformation HeLa skin fibroblast human hybrid cells Gamma radiation [M31]
1993 Plating efficiency HeLa cells X-rays Dose response [F8]
1993 Plating efficiency GM10115 humanhamster hybrid cells X-rays [M2]
1994 Chromosomal aberrations HeLa cells X-rays [B20]
1994 Chromosomal aberrations Human haemopoietic stem cells Alpha particles [K1]
1994 Giant cell formation HeLa cells X-rays [B20]
1994 Plating efficiency HeLa cells X-rays [B20]
1994 Plating efficiency Human keratinocyte cells Gamma radiation; [O5]

alpha particles
1995 Chromosomal aberrations Human lymphocytes X-rays [H8]
1995 Chromosomal aberrations Murine haemopoietic stem cells Alpha particles; X-rays [K2]
1995 Delayed TP53 mutation Murine epithelial cells Gamma rays [S11]
1995 Plating efficiency Murine haemopoietic stem cells Alpha particles; X-rays [K2]
1996 Apoptosis V79 Chinese hamster ovary cells X-rays Dose response up [J5]
(112Gy) to 34Gy
1996 Apoptosis Human keratinocyte cells; CHOK hamster Gamma rays Dose response [L34]
cells
1996 Chromosomal aberrations Human epithelial cells X-rays; alpha particles [D18]
1996 Chromosomal aberrations TK6 human lymphoblasts X-rays [G8]
1996 Chromosomal aberrations V79 Chinese hamster ovary cells X-rays Dose response up [J5]
to 34Gy
(112Gy)
1996 Chromosomal aberrations Human lymphocytes Alpha particles [K5]
1996 Micronucleus frequency V79 Chinese hamster ovary cells X-rays Dose response up [J5]
(112Gy) to 5 Gy
1996 Morphological abnormalities Human keratinocyte cells; CHOK hamster Gamma rays Dose response [L34]
cells
1996 Mutation frequency TK6 human lymphoblastoid cells X-rays [G8]
1996 Plating efficiency Human epithelial cells X-rays; alpha particles [D18]
1997 Chromosomal aberrations GM10115 humanhamster hybrid cells X-rays; gamma rays; 56Fe Dose response [L30, L31]
ions; neutrons; gold ions
1997 Chromosomal aberrations V79 Chinese hamster ovary cells Alpha particles; X-rays Dose response [M28]
1997 Chromosomal aberrations Murine haemopoietic stem cells Gamma rays [P9, P15]
ANNEX C: NON-TARGETED AND DELAYED EFFECTS OF EXPOSURE TO IONIZING RADIATION 7
1997 Micronucleus frequency V79 Chinese hamster cells Alpha particles; X-rays Dose response [M28]
1997 Mutation frequency Murine haemopoietic stem cells X-rays; alpha particles; [H12]
neutrons
1997 Mutation frequency Chinese hamster ovary cells X-rays; alpha particles [L29]
1997 Plating efficiency V79 Chinese hamster cells Alpha particles; X-rays Dose response [M28]
1998 Chromosomal aberrations Human fibroblasts X-rays; neutrons; [K18]

alpha particles
1998 Chromosomal aberrations Human epithelial cells Gamma rays; neutrons [U20]
1998 Chromosomal aberrations GM10115 humanhamster hybrid cells X-rays [D1]
1998 Chromosomal aberrations Human lymphocytes Gamma rays [H9]
1998 Chromosomal aberrations Murine haemopoietic stem cells Alpha particles; X-rays [K18]
1998 Chromosomal aberrations GM10115 humanhamster hybrid cells 125

I [K9]
1998 Chromosomal aberrations Human lymphocytes Gamma rays [L32]
1998 Chromosomal aberrations GM10115 humanhamster hybrid cells X-rays; gamma rays; 56Fe Dose response [L9]
1998 Chromosomal aberrations Murine haemopoietic stem cells Alpha particles [L20]
1998 Chromosomal aberrations GM10115 humanhamster hybrid cells X-rays; gamma rays; 56Fe Dose response [P14]
1998 Chromosomal aberrations V79 Chinese hamster ovary cells X-rays [T3]
1998 Plating efficiency GM10115 humanhamster hybrid cells X-rays [D1]
1998 Plating efficiency Murine haemopoietic stem cells Alpha particles; X-rays [K18]
1998 Plating efficiency Murine haemopoietic stem cells Alpha particles [L24]
1999 Apoptosis; micronucleus AGO l522B primary human fibroblasts X-rays; alpha particles Dose response [B22]
frequency
1999 Micronucleus frequency Human SCL-II squamous carcinoma cells X-rays Dose response [K20]
1999 Plating efficiency AGO 1522B primary human fibroblasts X-rays; alpha particles Dose response [B22]
1999 Plating efficiency Human keratinocyte cells Gamma rays; [C14]

alpha particles
1999 Plating efficiency Human SCL-II squamous carcinoma cells X-rays Dose response [K20]
2000 Chromosomal aberrations HPV-G and HaCaT human keratinocyte cells Gamma rays; [M29]
alpha particles
2000 Chromosomal HF19 human fibroblasts No instability [G25]

rearrangements observed
2000 Chromosomal aberrations Human lymphocytes Alpha particles; X-rays [A6]
2000 Chromosomal aberrations GM10115 humanhamster hybrid cells X-rays; gamma rays; Fe 56
Dose response [L12]
2000 Plating efficiency HPV-G and HaCaT human keratinocyte cells Gamma radiation; alpha [M29]
particles
2001 Apoptosis WTKI human lymphoblastoid cells Fe ions; 137Cs gamma rays
56
[S8]
2001 Chromosomal aberrations TK6 human lymphoblasts Fe ions; gamma rays

56
[E14]
2001 Chromosomal aberrations Human lymphocytes Gamma rays [B11]

2001 Chromosomal aberrations Human lymphocytes Fe ions

56
[G9]
2001 Chromosomal aberrations Human lymphocytes Alpha particles [K19]
2001 Chromosomal aberrations WTK1 human lymphocytes Fe ions; 137Cs gamma rays
56
[S8]
2001 Microsatellite instability; BEP2D human bronchial epithelial cells Alpha particles; 56Fe ions [P16]
gene amplifications
2001 Minisatellite instability 4T1 murine mammary adenocarcinoma cells Gamma rays [L33]
2001 Mutation frequency Saccharomyces cerevisiae Gamma rays Dose response [B19]
2001 Mutation frequency TK6 human lymphoblasts Fe ions; gamma rays

56
[E14]
2001 Mutation frequency Human lymphoid cells Gamma rays [G9]

(12Gy)
2001 Mutation frequency 4T1 murine mammary adenocarcinoma cells Gamma rays [L33]
(12Gy)
2001 Plating efficiency Saccharomyces cerevisiae Gamma rays Dose response [B19]
2001 Plating efficiency Human lymphoid cells Fe ions

56
[G9]
2001 Recombination frequency Saccharomyces cerevisiae Gamma rays Dose response [B19]
2001 Telomere shortening WTKI human lymphoblastoid cells Fe ions; 137Cs gamma rays
56
[S8]
2002 Apoptosis Mouse fibroblast clones; V79 Chinese X-rays [C11]

hamster ovary cells
2002 Chromosomal aberrations Human fibroblasts Gamma rays [B21]
2002 Chromosomal aberrations Murine haemopoietic stem cells Gamma rays [B23]
2002 Chromosomal aberrations Mouse fibroblast clones; V79 Chinese X-rays [C11]
hamster ovary cells
2002 Chromosomal aberrations TK6 human lymphoblasts Fe ions; gamma rays

56
[E13]
and response to second
irradiation

56
[E13]
2003 Chromosomal aberrations Normal diploid human fibroblasts Low- and high-LET radiation No instability [D17]
observed
2003 Chromosomal aberrations TK6 human lymphoblasts Gamma rays [E15]
2003 Global gene expression Primary human lymphocytes Gamma rays [F16]
2003 Chromosomal instability and Haemopoietic stem cells Gamma rays Independent of [M27]
radiation-induced delayed (R-M26/2-1) TP53 status
reproductive death
2003 Delayed lethality and micro- Human osteoblast cells Depleted uranium [M57]
nucleus formation
2003 Chromosomal aberrations TK6 and NH32 human lymphoblasts Gamma rays Dose response up [S9]
to 5Gy
2003 Micronucleus frequency Human peripheral blood lymphocytes Gamma rays Dose response [J8]
2003 Chromosomal aberrations Murine haemopoietic stem cells Gamma rays [M27]
2003 Delayed TP53 activation HTI 080 human fibrosarcoma cells X-rays; gamma rays [S24]

56
[E15]
2003 Plating efficiency Murine haemopoietic stem cells Gamma rays [M27]
2004 DNA damage; comet assay Chinese hamster ovary cells X-rays Low dose [G23]
2004 GFP-based protein assay for Human RKO cells X-rays [H24]
homologous recombination
2004 Cell viability; apoptosis; Human lymphoblast cells X-rays [R13]

changes in MAP and ERK
signalling
2004 Gene expression analysis GM10115 humanhamster hybrid cells X-rays [S59]
2004 ROS production Mouse m5S derived cl. 2011-14 cells X-rays Cell killing related [T6]
to time after
irradiation
2004 Lethal sectoring; HeLa S3-9IV cells X-rays; alpha particles [S47]
division delay
2004 Chromosomal aberrations Scid mouse cells X-rays [U26]
2004 Mutagenic radicals Humanhamster hybrid A (L) cells X-rays High-LET [W20]
2005 Chromosomal aberrations Peripheral blood lymphocytes Gamma irradiation [B33]
2005 HPRT frequency; apoptosis; Lymphoblastoid TK6 cells [C20]

cell survival
2005 H2AX phosphorylation Human fibroblasts Si and Fe ions High-LET [D26]
2005 Global gene expression Human skin fibroblasts X-rays 2cGy and 4Gy [D27]
profile
2005 Chromatid and chromosomal Haemopoietic stem cells Gamma rays [G22]
aberrations
2005 Micronuclei; chromosomal Human peripheral blood lymphocytes Co gamma rays

60
04Gy [J9]
aberrations
2005 Genomic patterns of Mouse genomic BACs [M55]

aberrations; radiation-induced
mouse lymphomas
2005 Delayed apoptosis CGL1 (HeLa fibroblast) hybrid cells X-rays 7Gy [M56]
2005 Chromosomal TK6 cells and clones with differing TP53 Gamma rays 2Gy [M54]
rearrangements status
2005 Delayed apoptosis GM10115 humanhamster hybrid cells X-rays [N29]
2005 Cell killing V79 cells X-rays Low dose [S65]
2005 Microarray analysis of Humanhamster hybrid cells X-rays [S61]

isogenic clones to assay for
gene expression
2005 Gene expression influenced TK6; NH32; WTK1 Gamma rays 10Gy at different [T7]
by TP53 status times
a It is not possible to include the range of doses used, as many studies used different doses, dose rates and radiation types within a single study. The reader is referred to the
original study for information on the range of doses used.
7. Of the multitude of end points associated with chromosomal rearrangements, particularly chromosomal trans-
radiation-induced instability, chromosomal changes are the locations, duplications and partial trisomies [G8, M2, S8],
best described. While some investigators describe chromosome which appear to involve amplification and recombination of
gaps [S11, U20] or breaks [K3, L24] as the primary aber- large chromosomal regions by a currently unknown mechanism
rations observed, it is unlikely that these contribute to long- [D1, M16]. An example of chromosomal instability in human
term instability, as gaps have no known phenotype and breaks hamster hybrid GM10115 cells clonally expanded from a single
are generally lethal [C2, C3]. Of more significance are gross cell surviving X-irradiation is presented in figureIII.
Figure III. Metaphase spreads from humanhamster hybrid GM10115 cells clonally expanded from a single cell surviving
exposure to 5Gy of X-rays.
A: Metaphase chromosomes from non-irradiated GM10115 cells. Using fluorescence in situ hybridization, the human chromosome 4 in these
humanhamster hybrid cells is painted green, and the hamster chromosomes are stained red. BH: Representative metaphase cells showing
the chromosomal rearrangements observed in one colony of cells clonally expanded from a single cell. Radiation-induced instability stimulated
the dynamic rearrangement of the genetic material, resulting in multiple subpopulations of cytogenetically rearranged cells within the clonally
expanded population. Such cytogenetic rearrangements in GM10115 cells have been used by Morgan and colleagues [K9, L6, L9, L30, L31,
M2] as a measure of genomic instability induced by both high- and low-LET radiation.
8. Instability is a frequent event in colonies of surviving a dose response at lower doses that tends to saturate at higher
cells. Kadhim et al. [K3] reported karyotypic abnormalities doses, and a few investigators have observed consistent dose-
in 4060% of murine stem cells exposed to doses of alpha related effects. These data are summarized in table1 and are
particles that would produce about one hit per cell. Sabatier reviewed in references [L6, M32]. Furthermore, radiation-
and colleagues [S44] observed late passage non-random chro- induced instability appears independent of dose rate, although
mosomal instability in >50% of metaphase cells from human this has not been extensively investigated to date [L6]. In addi-
dermal fibroblasts irradiated with a wide range of high-LET tion, there does not appear to be a significant LET effect for
radiations (386 to 13,600keV/m). Likewise, Limoli et al. radiation-induced genomic instability, with both high- and
[L6] observed that X-rays induced chromosomal instabil- low-LET radiations being effective [H2, K34, L12].
ity in ~3% of surviving humanhamster hybrid GM10115
clones per gray of radiation. This increased to ~4% Gy1 11. Many of the genomic changes described under the
after high-LET iron ion exposure [L12, L13]. This observed title of induced instability are changes of the same type as
frequency of instability is grossly in excess of the reported observed in human tumours. Radiation-induced cancers have
frequency for gene mutations at similar doses. Therefore it no known molecular signature, and continued investigation
is unlikely that mutation in a single gene or gene family is aimed at understanding the processes and pathways by which
responsible for the unstable phenotype in unstable clones. radiation induces genomic alterations in the progeny of irra-
Instead it is reasonable to suppose that factors contributing diated cells should provide insights into the mechanisms of
to maintaining genomic instability over time include critical radiation-induced transformation and carcinogenesis [M62].
pathways in DNA damage and repair [C10, H11, M48, Y3], Kennedy et al. [K10] demonstrated replication dependence
chromosomal replication [B32], cellular homeostasis [B3, of radiation-induced transformation of C3H 10T cells.
B6, M24, M48] and alterations in gene expression [S59, A similar replication dependence was also reported for
S60, S61, S62]. radiation-induced mammary cancers in rats, in which expres-
sion of epigenetic initiation required replication of irradiated
9. The high frequency of induced instability observed in mammary stem cells in the tissue microenvironment [K7].
different systems raises the intriguing question as to what is
really being measured and of the significance of these obser- 12. While the multiple phenotypes associated with
vations. While the numerous in vitro studies summarized in radiation-induced genomic instability are relatively well
table1 have established the occurrence of radiation-induced characterized, the molecular, biochemical and cellular events
genomic instability, many of the cell lines used were not that initiate and perpetuate instability remain unknown.
normal initially, and in many cases they involved tumour- Directly induced DNA damage, e.g. induced DNA double-
derived cell lines. Dugan and Bedford [D17] have pointed out strand breaks, is probably not causative [M13]. Instead,
that instability is sometimes not observed in apparently nor- deficiencies in cellular responses to DNA damage [C10,
mal cells after irradiation. However, there are many reports Y3], changes in gene expression [B6] or perturbations in
of instability in the progeny of irradiated normal human and cellular homeostasis [B3] are more likely to be involved,
murine bone marrow cells [K1, K2] and in cultured human and provide a rational explanation as to why the unstable
lymphocytes [B11, H7, H8, H9]. Some of this confusion phenotype can persist. In the GM10115 cell system, clones
may relate to the role of a functional TP53 tumour suppres- of unstable cells continue to show the dynamic production
sor gene. Both TP53-dependent [S9] and TP53-independent of novel chromosomal rearrangements for over four years
pathways have been proposed [K5, L8], and Moore et al. post-irradiation [N1]. Attempts to define the target for
[M54] showed that genomic instability might differ both induced instability indicate that, while the nucleus may be
quantitatively and qualitatively as a consequence of altered the ultimate target [B6, K9], there is evidence for a persist-
TP53 expression. Furthermore, differences in cellular prolif- ent increase in reactive oxygen species (ROS) in cultures of
eration patterns and susceptibility to mutation between cells cells showing radiation-induced genomic instability. A role
and cell lines might also influence the reported results [C19]. for enhanced oxidative stress in perpetuating the unstable
Because the majority of reports indicate that irradiated normal phenotype was first described by Clutton et al. [C5], and was
primary cells readily demonstrate the instability phenotype later confirmed in studies by Limoli et al. [L7, L9, L10] and
(table 1), this implicates ionizing radiation as the causative Redpath and Gutierrez [R3]. A persistent induction of ROS
agent. It also establishes induced instability as a phenotype has also been shown to cause delayed reinduction of TP53
associated with radiation exposure. As always, however, in normal human fibroblasts [R6]. A study by Roy et al. [R5]
caution should be exercised when extrapolating from in vitro revealed that hypoxia (2% oxygen) significantly reduced
cell culture systems to the human situation in vivo. X-ray-induced delayed effects, specifically cell death, giant
cell formation and chromosomal aberrations, compared with
10. When cells or tissues are directly exposed to ionizing cells cultured under their normal 20% oxygen conditions.
radiation, biological effects are generally induced in a dose- The role of ROS in radiation-induced genomic instability has
dependent manner. One perplexing feature of radiation- been reviewed in detail by Mikhailov and colleagues [B45,
induced genomic instability, and of non-targeted effects in M48]. It should be noted that oxygen tension in normal
general, is the lack of a well-defined dose response profile. tissue shows a typical Gaussian distribution of values with
Most investigators report that non-targeted effects are inde- a median between 40 and 60mm Hg, and no values below
pendent of dose. However, some investigators have observed 10 mm Hg [A13]. Tumours, on the other hand, invariably
show a distribution with much lower oxygen tension [B44]. followed by analysis in vitro. They reported structural and
As will be described later, a role for ROS in non-targeted numerical chromosomal anomalies as well as micronuclei
radiation-induced bystander effects has also been described, at the first, second and third mitosis after in vivo irradiation
suggesting a potential commonality in processes involved in of one- or two-cell mouse embryos with X-rays or neutrons
these delayed effects of exposure to ionizing radiation. [W6, W7]. These observations were extended by Ullrich
and Davis [U18], who irradiated inbred BALB/c mice and
13. It is well known that most mammalian cells do not at varying intervals after irradiation removed and cultured
divide indefinitely in vitro or in vivo, owing to a process the mammary glands in vitro. Cytogenetic analysis indicated
termed replicative senescence. In human cells, replica- that instability could develop and persist in situ in a mature,
tive senescence can be caused by telomere shortening, but fully differentiated tissue after in vivo irradiation. Further-
murine cells senesce despite having long, stable telomeres. more, there was a dose-dependent increase in the frequency
Parrinello et al. [P19] showed that the phenotypes of senes- of delayed aberrations at low doses (0.11Gy) that reached
cent human fibroblasts and mouse embryonic fibroblasts a plateau at higher doses [U18].
(MEFs) differ under standard culture conditions that include
20% oxygen. The MEFs did not senesce in physiological 16. Cellular studies on radiation-induced murine mam-
(3%) oxygen levels, but underwent a spontaneous event that mary cancer demonstrated strain-dependent differences
allowed indefinite proliferation in 20% oxygen. The prolifer- in susceptibility, presumably resulting from differences in
ation and cytogenetic profiles of DNA repair-deficient MEFs sensitivity to neoplastic initiation [U17]. Similar strain sus-
suggested that DNA damage limits MEF proliferation in 20% ceptibility is apparent for in vivo irradiation followed by
oxygen. Indeed, MEFs accumulated more DNA damage in invitro analysis of induced instability. Mammary cells from
20% oxygen than in 3% oxygen, and more damage than BALB/c mice are more susceptible to radiation-induced
human fibroblasts in 20% oxygen. These results identify genomic instability than those from C57BL/6 or F1 hybrid
oxygen sensitivity as a critical difference between mouse crosses of C57BL/6 and BALB/c mice [P9, U20]. Studies
and human cells, explaining their proliferative differences in of DNA repair in the radiosensitive BALB/c mouse revealed
culture, and possibly their different rates of cancer induction inefficient end-joining of gamma-ray-induced double-strand
and ageing. Furthermore, they may contribute to explaining breaks in DNA. This is apparently due to reduced expression
some of the differences between mouse and human studies of the DNA-PKcs protein and lowered DNA-PK activity in
described later in this annex. these mice. This may impair the animals ability to appro-
priately respond to induced damage and may thus account
14. There is emerging evidence implicating a role for for the increased instability [O4, Y3]. Most DNA repair pro
extranuclear and even extracellular events in initiating and cesses have evolved to prevent genomic instability induced
perpetuating radiation-induced chromosomal instability. by endogenous lesions [L49] and induced DNA damage (for
Kadhim et al. [K3] analysed chromosomal instability in a comprehensive discussion, see the BEIR VII [C23] and
murine haemopoietic stem cells following alpha particle irra- French Academies [T8] reports).
diation. Many of the surviving cells were those that were not
traversed by an alpha particle during irradiation. Expanding
these studies, Wright and colleagues used a protective metal
grid to shield regions of the cell culture flask and lethally C. Induced genomic instability after in vitro
irradiated the non-shielded regions of the flask. They then irradiation followed by in vivo analysis
cultured the non-irradiated, shielded cells and examined the
clonal progeny for induced chromosomal instability. A high 17. Conversely, instability induced in vitro can be trans-
frequency of instability was observed in the progeny of cells mitted in vivo following transplantation of irradiated cells
that were not directly hit by radiation [L24]. Clearly, induced into recipient animals. Paquette and Little [P3] irradi-
instability has an extracellular component, and signals from ated C3H 10T cells and cultured half in cell culture in
irradiated cells can stimulate chromosomal rearrangements vitro; the other half was transplanted into syngeneic and
in non-targeted cells within the radiation environment non-immunosuppressed C3H mice. Interestingly, a higher
(reviewed in reference [M10]). These observations have frequency of minisatellite instability was observed in those
implications for the fate of cells surviving radiation exposure irradiated cells injected into mice than those cultured in
in that some of these surviving cells may develop genomic vitro. Watson et al. [W3] reported the induction and long-
instability. These observations also indicate that even cells term persistence of chromosomal instability after murine
outside the radiation field can manifest phenotypes similar bone marrow cells were irradiated in vitro and then trans-
to those of irradiated cells. planted into female CBA/H mice that had received 10Gy of
X-irradiation less than two hours before to eradicate the host
bone marrow. These studies were later extended to demon-
B. Induced genomic instability after in vivo strate that instability induced by X-ray or neutron irradiation
irradiation followed by in vitro analysis in vitro can be transmitted in vivo [W4]. A recent analysis
of a series of radiation-induced sarcomas [G10] showed a
15. Weissenborn and Streffer were the first to describe prevalence (53%) of somatic TP53 mutations, which was
induction of genomic instability after irradiation in vivo significantly higher than that for sporadic sarcomas (16.8%).
The mutations were inactivating and associated with the and secretion of soluble factors. These secreted factors
loss of the other TP53 allele. This loss of heterozygosity [S39] might include extracellular cytokine-like factors [L2,
was due to the loss of a large fragment of the chromosome N8] that are able to increase intracellular levels of ROS
or of the whole chromosome, probably indicating a more in non-irradiated cells [L23, M10, M16]. Lorimore et al.
general chromosomal instability similar to that previously recently proposed a potential mechanism for these in vivo
described [L1]. radiation-induced bystander effects [L22]. They found per-
sistent macrophage activation combined with neutrophil
18. Watson et al. [W2] have provided convincing evidence infiltration following 4Gy whole-body irradiation of mice.
that the induction of genomic instability following in vitro The inflammatory nature of the observed responses may
irradiation and in vivo expression can result from a non- provide a mechanism for the long-term production of
targeted bystander-like effect. That is, rather than resulting genetic damage by a bystander effect, ultimately con-
from the direct effect of radiation exposure being passed tributing to radiation-induced instability and potentially
on to the progeny of that irradiated cell, instability might leukaemogenesis. This will be discussed in more detail in
also result from soluble signals being passed from irradi- the section on radiation-induced genomic instability and
ated cells to non-irradiated cells. When non-irradiated cells bystander effects.
were mixed with cells irradiated with 0.5Gy of neutrons at
0.04 Gy/min and then transplanted into recipient CBA/H
mice, instability was observed in the non-irradiated cell
population [W2]. An elegantly conceived chromosomal
marker system allowed the investigators to distinguish D. Radiation-induced genomic instability in vivo
between the irradiated and non-irradiated transplanted cells
and cells derived from the host mouse. Irradiated and non- 20. In reviewing the literature on in vivo non-targeted
irradiated cells were distinguished by using marrow from effects of ionizing radiation, it becomes obvious when
CBA/H mice (40XY cells) and the congenic CBA/H strain considering the mouse studies that many of the observed
(40XY6T6 cells) homozygous for the stable T6 recipro- effects are highly dependent upon the mouse strain used
cal translocation between chromosomes 14 and 15. Using and the sex of the animal studied [M58]. Consequently,
this system, unambiguous evidence for non-clonal chro- there has been an effort throughout this annex to identify
mosomal aberrations was observed in clonal populations the mouse strain used when comparing conflicting data. It
derived in vitro from neutron-irradiated bone marrow cells. is also apparent that even the same mouse strain can vary
Furthermore, after transplantation with neutron-irradiated significantly when bred in different colonies in differ-
cells, translocations and deletions were observed for ent laboratories. Differences due to sex might also exist,
a period of 313 months. Significantly, there was also a but not all of the studies provide adequate details on the
higher frequency of unstable aberrations in the bone marrow sex of the animals used. While much has been learned
of the recipient mouse. These results implicate an in vivo from animal models [F7], caution should be exercised
bystander-like mechanism in the induction of chromosomal when extrapolating from the animal studies to the human
instability, and suggest that the instability observed in the situation.
non-irradiated cells is not an artefact of clonal selection.
This result was confirmed by Xue et al. [X2], who injected 21. The reports of radiation-induced genomic instability
nude mice with a mixture of human colon LS174T adeno- in vivo are summarized in table2, which also lists the end
carcinoma cells and LS174T-cells prelabelled with lethal point used to assay instability, the model system, the type of
doses of DNA-incorporated 5-[125I]iodo-2-deoxyuridine radiation used and whether or not genomic instability was
(125IUdR). A distinct inhibitory effect on the growth of the observed. In this section the methods of analysing instabil-
unlabelled LS174T tumour cells was observed. Because ity in vivo will be highlighted along with potential areas of
125
IUdR is incorporated into DNA, almost all the electrons conflict and associated caveats.
emitted during radioactive decay have a subcellular range
of <0.5m. This led the authors to conclude that the inhibi- 22. Nowell [N19] first proposed that genomic instabil-
tory result was due to a bystander effect generated in vivo ity might be a driving force in tumorigenesis and a hall-
by factors present within and/or released by the 125IUdR- mark of many cancers [C7, L3]. There is accumulating
labelled cells. However, it is also possible that debris and evidence suggesting that instability may represent a criti-
breakdown products from the heavily irradiated cells might cal step in the genesis of certain radiation-induced cancers
affect bystander cells, and these non-labelled cells might [L14, S3, U20]. Implicit in this annex is the hypothesis that
even incorporate 125I released from dying cells. radiation-induced genomic instability provides relevant
underlying mechanistic contributions to some radiation-
19. Currently the mechanisms underlying the induction induced cancers. While the precise relationship between
and persistence of instability are not understood. The induc- radiation-induced genomic instability and radiation car-
tion of chromosomal aberrations in vivo by a bystander-like cinogenesis remains to be determined, understanding the
mechanism might provide insights into the mechanisms as mechanisms of induced instability might provide valuable
well as link instability to bystander effects. Bystander effects insights into health risks associated with radiation exposure
can be mediated by cell-to-cell gap junction communication and the carcinogenesis process in general.
Table 2 In vivo studies of radiation-induced genomic instability (RIGI) and transgenerational effects
Year End point Cellular system Radiation type RIGIa Reference
1976 Graft versus host reactions; non-specific (PVGc Wistar) F1 hybrids; PVGc spleen X-rays + [J10]
bystander activity cells
1979 Chromosomal aberrations Haemopoietic cells in atomic bombing Neutrons; gamma rays [K21]
survivors
1979 Tumour induction Mouse localized exposures X-rays; neutrons + [U19]
1980 Tumour induction Mouse localized exposures X-rays; neutrons + [U16]
1982 Foetal deaths, malformations in F1 mice Mouse whole-body irradiation X-rays + [K13]
1982 Tumour induction in F1 Mouse whole-body irradiation X-rays + [N17]
1984 Foetal deaths, malformations in F1 mice Mouse whole-body irradiation X-rays + [K12]
1985 Tumour induction Mouse whole-body irradiation X-rays + [C6]
1988 Chromosomal aberrations Skin fibroblasts (mouse zygotes irradiated) X-rays; neutrons + [P1]
1988 Chromosomal aberrations Mouse embryo X-rays; neutrons + [W14]
1988 Congenital abnormalities Skin fibroblasts (mouse zygotes irradiated) X-rays; neutrons + [P1]
1988 Micronucleus frequency Mouse embryo X-rays + [W14]
1989 Cell proliferation in F1 and F2 generations Mouse whole-body irradiation Gamma rays + [O2]
1989 Chromosomal aberrations Mouse zygotes X-rays + [P17]
1989 Chromosomal aberrations Mouse embryo X-rays + [W6]
1989 Micronucleus frequency Mouse zygotes X-rays + [P17]
1990 Cancer prevalence Children of nuclear plant workers X-rays; gamma rays + [G2]
1990 Foetal deaths, malformations Mouse embryos X-rays + [M26]
1991 Chromosomal aberrations Blood lymphocytes of uranium miners after Alpha particles [M34]
whole-body irradiation
1991 Sister chromatid exchanges Blood lymphocytes of uranium miners after Alpha particles [M34]
1993 Chromosomal aberrations Skin fibroblasts in atomic bombing survivors Neutrons; gamma rays [H13]
1993 Microsatellite instability in F0, F1 and F2 Mice after whole-body irradiation Neutrons; X-rays; + [D10]
generations gamma rays
1994 Cancer prevalence Children of nuclear plant workers X-rays; gamma rays [D6]
1994 Microsatellite instability in F0, F1 and F2 Mice after whole-body irradiation Neutrons; X-rays; + [S1]
1994 Minisatellite instability C3H 10T murine cells (irradiated in vitro, X-rays + [P3]
then injected into mice)
1995 Cancer prevalence Progeny of cancer patients who had under- X-rays [H4]
gone radiation therapy
1995 Microsatellite instability in F0, F1 and F2 Mice after whole-body irradiation Neutrons; X-rays; + [F2]
1995 Tumour induction in F1 Mouse whole-body irradiation X-rays [C4]
1996 Chromosomal aberrations Murine bone marrow (in vitro irradiation) Alpha particles + [W3]
1996 Minisatellite instability Chernobyl survivors after whole-body Gamma rays + [D11]
irradiation
1996 Minisatellite instability Haemopoietic cells in atomic bombing Neutrons; gamma rays +/ [S5]
survivors
1996 Neoplastic transformation Epithelial cells of whole-body-irradiated mice X-rays + [U17]
1997 Cancer prevalence Children of nuclear plant workers X-rays; gamma rays [D7]
1997 Cell proliferation in F1 and F2 generations Mouse whole-body irradiation Gamma rays + [W10]
irradiation
1997 Mutation frequencies in F1 Mice after whole-body irradiation Gamma rays + [L25]
1998 Chromosomal aberrations Human lymphocytes after whole-body Gamma rays [S2]
irradiation
1998 Chromosomal aberrations Lymphocytes from uranium miners Alpha particles (radon) +/ [S25]
1998 Chromosomal aberrations Blood lymphocytes from plutonium workers Gamma rays [W9]
1998 Micronucleus frequency Rat lung cells after partial-volume irradiation Gamma rays + [K11]
1998 Micronucleus frequency Lymphocytes from uranium miners Alpha particles (radon) + [S25]
1998 Tumour induction in F1 Mouse whole-body irradiation Gamma rays + [L20]
1999 Chromosomal aberrations Lymphocytes of Chernobyl survivors after Gamma rays + [G3]
1999 Chromosomal aberrations Lymphocytes of Chernobyl recovery opera- Gamma rays +/ [L36]
tions workers and workers from the nuclear
power plant
1999 Chromosomal aberrations Haemopoietic cells in atomic bombing Neutrons; gamma rays [N6]
survivors
1999 Chromosomal aberrations Mouse epithelial cells after whole-body X-rays + [U18]
irradiation
1999 Chromosomal aberrations Mouse bone marrow cells after whole-body X-rays + [X1]
irradiation
1999 Prenatal mortality; developmental and Mouse zygotes X-rays + [P7]

skeletal defects in F2 mice
1999 Sister chromatid exchanges Lymphocytes of Chernobyl recovery opera- Gamma rays + [L36]
tions workers and workers from the nuclear
power plant
1999 Minisatellite instability Children of Chernobyl recovery operations Gamma rays +/ [L18]
workers
2000 Chromosomal aberrations Foetal haemopoietic cells of mice after Gamma rays + [D3]
foetal irradiation
2000 Chromosomal aberrations C57BL/6 mice after whole-body irradiation Gamma rays + [S20]
2000 Chromosomal aberrations Blood lymphocytes of patients after whole- X-rays [T2]
body irradiation for radiotherapy
2000 Chromosomal aberrations Mixture of irradiated and non-irradiated Neutrons + [W2]

murine bone marrow cells
2000 Micronucleus frequency CBA mice after prenatal irradiation Gamma rays [A1]
2000 Tumour induction in F1 Pregnant mice Gamma rays + [U21]
2000 Minisatellite instability Sperm from three seminoma patients X-rays [M5]
2001 Chromosomal aberrations Mouse bone marrow cells after whole-body Alpha particles (224Ra); [B12]
irradiation X-rays
2001 Chromosomal aberrations Mouse bone marrow cells after whole-body X-rays + [M1]
irradiation
2001 Chromosomal aberrations Blood lymphocytes of uranium miners after Alpha particles [M35]
2001 Chromosomal aberrations Blood lymphocytes of cancer patients after Gamma rays [V1]
2001 Chromosomal aberrations Murine bone marrow; irradiated cells or X-rays; alpha particles; + [W4]
whole-body irradiation neutrons
2001 Chromosomal aberrations Blood lymphocytes from plutonium workers Gamma rays [W8]
2001 Ductal dysplasia Epithelial cells of ATM+/- mice X-rays + [W15]
2001 Minisatellite instability Children of Chernobyl recovery operations Gamma rays [L17]
workers
2001 Minisatellite instability Haemopoietic cells in atomic bombing Neutrons; gamma rays +/ [N7]
survivors
2001 Minisatellite instability Children of Chernobyl recovery operations Gamma rays + [W5]
workers
2001 Mutation frequencies in F1 Mice after whole-body irradiation Gamma rays + [N14]
2001 Signal kinase activity in F3 Mouse whole-body irradiation Gamma rays + [B4]
2001 Sister chromatid exchanges Blood lymphocytes of uranium miners after Alpha particles [M35]
2002 APRT, HPRT mutation frequency Mouse T-lymphocytes after whole-body X-rays + [L35]
irradiation
2002 Cancer prevalence Progeny of radiation workers X-rays; gamma rays + [D20]
2002 Cell proliferation in F1 and F2 Mouse whole-body irradiation Gamma rays + [B5]
2002 Chromosomal aberrations Mouse T-lymphocytes after whole-body X-rays + [L35]

irradiation
2002 Microsatellite instability in F0, F1 and F2 Mice after whole-body irradiation Neutrons; X-rays; gamma + [B2]
generations rays
2002 Microsatellite instability in F0, F1 and F2 Mice after whole-body irradiation Neutrons; X-rays; gamma + [D9]
generations rays
irradiation
2002 Minisatellite instability Children living in Semipalatinsk I, 90Sr and 137Cs

131
+ [D8]
2002 Mutation frequencies in F1 Mice after whole-body irradiation Gamma rays + [S26]
2002 Signal kinase activity in F3 Mouse whole-body irradiation Gamma rays + [V2]
2003 ROS content; state of DNA structure Bone marrow cells of male mice after X-rays (1.5Gy) + [M58]
2003 Minisatellite instability Children of Chernobyl recovery operations Gamma rays [K37]
workers
2004 DNA double-strand breaks; morula and Oryzias latipes F3 embryos derived from Gamma rays + [A18]
gastrula formation male founders
2004 Epigenetic global genomic DNA methylation Male and female mouse whole-body Low-dose X-rays + [K30]
changes irradiation
2004 Latency of cancer risk Cohorts of underground miners exposed to Radon [L41]
radon
2004 Chromosomal aberrations; transformation Mouse embryonic fibroblasts from mice + [H26]
frequency; cell killing; DNA damage deficient in Hsp70.1 and Hsp70.3
2004 Epigenetic global genomic DNA methylation Male and female mouse whole-body High-dose X-rays + [P21]
changes irradiation (5Gy)
2004 Somatic mutation assay F1 and F2 progeny of Oryzias latipes Gamma rays + [S42]
2004 Destruction of haematopoietic progenitor and Mice after sublethal irradiation + [Z8]
stem cells in F1
2004 Chromosomal aberrations; tumour incidence; Pregnant mice; mice foetal liver and spleen 1Gy irradiation + [U22]
blood counts cells
2004 Apoptosis; cell proliferation and differentiation Mouse limb bud cells 0.3 and 5Gy + [W21]
2004 Micronuclei; number of ovules; male fertility Pea plant seedlings for two generations Gamma rays + [Z8]
2004 Mini- and microsatellite instability Children of Chernobyl recovery operations Gamma rays [S55]
workers
2005 Chromosomal aberrations Pregnant Swiss albino mice Gamma rays + [U23]
(11.5Gy)
2005 Initiation of intestinal adenoma Apc mice X-irradiation [E20]
2005 Locus-specific mutations Oryzias latipes spermatogonial stem cells Gamma rays + [S43]
(0.03cGy/min and
95cGy/min)
2005 Chromosomal instability Congenic haematopoietic cells into irradi- Gamma rays + [L47]
ated mouse host
2005 Chromatid aberrations; chromosomal Prostrate patients with prostatic hyperplasia Ionizing radiation + [H25]
radiosensitivity
2005 Clonogenic survival; apoptosis Bladder explants from C57BL6 and CBA/Ca Low-dose irradiation (0.5Gy) + [H25]
mice after whole-body irradiation
2005 Chromosomal aberrations Clonal T-cells from atomic bombing survivors Gamma rays [K29]
2005 Chromosomal instability Haemopoietic stem cells Gamma rays + [L47]
2005 Tumour formation Female B6C3 F1 mice Gamma rays (1.9Gy) + [S66]
2005 Microsatellite instability Children of Chernobyl recovery operations Gamma rays [F15]
workers
a +: genomic instability was observed; : genomic instability was not detected.
1. Mouse models for radiation-induced protracted whole-body gamma irradiation of prenatal CBA-
genomic instability in vivo Ca mice at either 44, 99 or 265mGy/day (to a total dose of
0.7, 1.6 or 4.2Gy) did not induce damage in erythroid stem
23. As described above, transmissible genomic instabil- cells that could be detected as persistent or delayed chromo-
ity has been observed after irradiation in vivo followed by somal aberrations as measured by micronucleated erythro-
culture in vitro and vice versa. The picture following irra- cytes at 35days after irradiation [A1]. Bouffler et al. [B12]
diation in vivo and subsequent expression of instability in also failed to find evidence of transmissible chromosomal
vivo is less clear and more controversial. Following irradia- instability 50 or 100days after in vivo exposure of CBA/H
tion of bone marrow cells from 12 week-old CBA/H mice mice either to alpha particles from the bone-seeking radio
with 0.5Gy of alpha particles, Watson et al. [W3] observed nuclide 224Ra or to X-rays. Likewise, chromosomal instabil-
a constant frequency (1013.4%) of cells with stable chro- ity was not detected in peripheral blood lymphocytes from
mosomal aberrations for up to 17 months. This increased C57BL/6 mice for up to 30days after whole-body gamma
to 49.8% at 24months in pooled samples from three CBA/H radiation [S21] or up to 21months [S20]. These last results
mice. They noted significant variation between individuals, are consistent with in vitro studies indicating that induced
with a few animals exhibiting little or no induced instability instability was not observed in C57BL/6 mice [P9, W1].
despite CBA/H being an inbred mouse strain. In contrast, Furthermore, no instability was reported in bone marrow
cells from Swiss mice up to 100 days after exposure to stromal microenvironment and experiments replacing irradi-
3Gy of X-rays [X1]. These results were initially presumed ated cells with irradiated cell-conditioned medium revealed
to indicate that the Swiss mouse strain, like the C57BL/6 the source of the in vivo bystander effect to be the descend-
mouse strain, is refractory to radiation-induced instability. ants of irradiated cells rather than the irradiated cells them-
However, this does not appear to be the case. When Swiss selves. Lorimore et al. [L47] speculated that it is possible
albino mice were exposed to 0.251.5Gy of gamma radia- that a radiation-induced genomic instability phenotype in
tion on day 14 or 17 of gestation, significant dose-dependent vivo need not necessarily be a reflection of intrinsically
increases in chromosomal aberrations, micronuclei and/ unstable cells but the response to ongoing production of
or changes in ploidy were observed in the bone marrow at inflammatory-type damaging signals [L22] as a long-term
12 months of age [D3]. The investigators concluded that unexpected consequence of the initial radiation.
radiation-induced genomic instability in the foetal haemo-
poietic cells of the mouse persisted post-natally [D3]. These 27. While the literature is replete with apparently contradic-
data are summarized in table2. tory reports of radiation-induced instability in mouse model
systems, these results clearly indicate that genetic factors can
24. Although not designed to specifically investigate play a major role in the instability phenotype and that analy-
radiation-induced genomic instability, a number of studies sis of radiation-induced genomic instability in vivo is signifi-
have examined the persistence of cytogenetic rearrangements cantly more complicated than in vitro. Critical analysis of
in animals at delayed times after irradiation. Hande et al. radiation-induced genomic instability in vivo is not a trivial
[H18, H19, H20, H21] used female Swiss mice to study the undertaking. In any animal model there is likely to be some
induction and persistence of dicentrics and translocations in inherent genomic instability that complicates the selection of
splenocytes up to 112days after exposure to 2Gy of whole- appropriate control populations. Such experiments generally
body X irradiation. The frequencies of dicentrics decreased involve inbred strains of mice, and even in radiation-sensitive
exponentially with time, while the frequencies of transloca- populations only a small percentage, generally <50%, will
tions were constant in the period 07days and then decreased exhibit an instability phenotype. Furthermore, extrapolating
linearly or exponentially. No new chromosomal rearrange- such results to other mouse strains or outbred populations is
ments were observed, suggesting that there was no delayed difficult at best. Until a careful study involving sound and
cytogenetic instability in these animals. Similar studies using relevant controls as well as statistically relevant numbers
other mouse models have reported similar results [T5]. of animals exposed to a homogeneous quality of radiation
is carried out, the induction of radiation-induced genomic
25. In attempting to reconcile the apparently conflicting instability in vivo will remain controversial.
results described above, Bouffler et al. [B12] have noted
the sensitivity of mouse bone marrow cells to perturbations
through transplantation and culture, and emphasized the 2. Human studies
need for sound control experiments to be performed con-
currently. For instance, some of the radiation-induced trans- 28. Radiation therapy has improved over recent years, and
missible chromosomal instability reported by Watson et al. many of the cancer patients treated with radiation are surviv-
[W3] could be attributed to the low background frequency of ing longer than did those in the past. Second cancers occur-
aberrations observed in the control repopulating cells. This ring in the irradiated field have been reported in some of these
is in contrast to the higher background described by Bouffler patients, suggesting a direct role of the radiation exposure
et al. [B12]. It is also possible that the disparate literature [B37, B38]. Data on second cancers occurring in children
on radiation-induced genomic instability in vivo reflects the irradiated for cancer indicate that some genetic predisposi-
inherent variability between the inbred mouse strains used tion to cancer may also predispose them to radiotherapy-
and differences due to sex within the animal strains used. related second cancers [D22, E19, F14]. Nevertheless,
it is still difficult to identify the radiation-induced lesions
26. To investigate the in vivo non-targeted effects of low- initiating the second malignancy. At the time of diagnosis,
LET radiation, Lorimore et al. [L47] used the same congenic multiple genomic alterations are present in the tumours, and
sex-mismatch bone marrow transplantation protocol as used the majority are likely to represent secondary events occur-
by Watson et al. [W2] to repopulate the haemopoietic system ring during tumour evolution and subsequent selection.
from a mixture of gamma-irradiated and non-irradiated hae- This underscores that caution must be applied to analysis of
mopoietic stem cells such that host-, irradiated donor- and radiation-induced genomic instability and its role in human
non-irradiated donor-derived cells could be distinguished. carcinogenesis. The subsequent discussion in this section
Chromosomal instability in the progeny of irradiated haemo- highlights the controversies and contradictions inherent in
poietic stem cells accompanied by a reduction in their contri- the human studies. To this end it is reasonable to expect that
bution to the repopulated haemopoietic system was observed analysis of normal, healthy populations of individuals would
and is consistent with a delayed genomic instability pheno- not provide evidence of instability regardless of the individu-
type being expressed in vivo. However, chromosomal insta- als radiation history. Indeed, the majority of studies inves-
bility was also shown in the progeny of the non-irradiated tigating instability in radiation-exposed populations have
haemopoietic stem cells, implicating a bystander-like analysed samples from normal, healthy individuals and did
mechanism. Studies of the influence of irradiated recipient not find evidence of instability [T2, T4]. It is also reasonable
to expect that analysis of instability in individuals manifest- genomic instability in the bone marrow of radiation workers
ing phenotypic effects of radiation exposure, e.g. cancer or with internal deposits of plutonium [W8]. Likewise, clonally
leukaemia, might well show evidence of induced instabil- expanded T-cell lymphocyte populations did not demonstrate
ity. Once again, limited studies indicate that this is the case increased chromosomal instability using either G-band anal-
[N6, N7]. Whether or not the observed instability is a direct ysis or multicolour fluorescence in situ hybridization [K29].
or non-targeted effect of radiation exposure, or a secondary
selective effect of disease evolution, cannot be definitively 31. The long-term effect of radiation exposure on uranium
determined at present. Furthermore, this question is unlikely miners employed by the Wismut uranium mining company
to be resolved in the foreseeable future. This caveat should in the former German Democratic Republic was investigated
be kept in mind in the following discussion. by scoring the frequency and percentage of micronuclei with
and without a centromere. Kryscio et al. [K38] reported
29. As has been described utilizing the mouse as a model that genomic instability had occurred in the lymphocytes of
system, both induction and lack of induction of transmissi- miners, especially those with cancer.
ble radiation-induced genomic instability have been reported
in humans, and once again genetic factors appear to play 32. A number of investigators have studied the alpha radia-
a role in the observed instability [K4]. Induced chromo- tion risks in patients who received injections of Thorotrast,
somal instability has been described in long-term cultures an X-ray contrast medium used in Europe, Japan and the
of human lymphocytes following irradiation and culture in United States from the late 1920s to 1955. Thorotrast was
vitro [H9]. Using the same lymphocyte culture protocol, composed of thorium dioxide and contained 232Th, a natu-
chromosomal instability was reported in blood samples rally occurring radionuclide. Because the physical half-life
from individuals exposed during the radiation accident in of 232Th is 14 billion years and Thorotrast is not appreci-
Estonia in 1994 [S2]. Radiation exposure was variable, pro- ably eliminated from the body, the tissues in which it was
tracted and not precisely determined. Furthermore, blood deposited are irradiated by alpha rays for the entire lifetime
samples were taken well after radiation exposure. No dose of the subject. The major causes of death among the Thoro-
response was apparent, and contrary to previous studies trast patients are liver cancer, liver cirrhosis, leukaemia and
from the Lambert laboratory, chromosomal instability was other cancers. Mutation analyses of the TP53 gene and loss
also observed in long-term cultures from non-exposed con- of heterozygosity (LOH) studies at the 17p locus were per-
trols [S2]. In contrast, cytogenetic analysis of 18 individu- formed by Ishikawa et al. [I2] to characterize the genetic
als who had received between 35 and 80Gy of fractionated changes in Thorotrast-induced liver tumours. LOH was not
radiation therapy for different cancers showed no increase frequent; most mutations were transitions, suggesting that
in aberrant cell types as a function of time after complet- genetic changes in Thorotrast-induced cancers were mainly
ing therapy. Thus no cytogenetic evidence that fractionated delayed mutations and not the result of the direct effects of
radiotherapy induced a persistent or late-manifesting state radiation.
of genomic instability was found [T2]. It should be stressed
that the majority of patients treated for different malignan- 33. Likewise Iwamoto et al. [I3] analysed mutations in
cies received localized, partial-body irradiation with empha- TP53 from 20 Thorotrast recipients who developed can-
sis on minimizing damage to normal tissue. Consequently, cer, mostly of hepatic bile duct and blood vessel origin. Of
different proportions of bone marrow stem cell populations the 20 cases, 19 had TP53 point mutations. Moreover, the
and peripheral blood lymphocytes would have been exposed accompanying non-tumour tissues from these patients also
to the radiation. It is likely that more cells than the number had TP53 mutations, albeit at lower frequency. The distri-
actually analysed (<200 per patient), would have to be inter- bution pattern of the point mutations was significantly dif-
rogated before evidence of persistent transmissible chromo- ferent between the non-tumour and tumour tissues, with
somal instability would be observed in these individuals, if it most mutations in malignant tissues located in the highly
indeed existed [T2]. conserved domains of the TP53 gene. These results support
the idea that TP53 mutations are important in the genesis of
30. The availability of cultured lymphocyte preparations Thorotrast-induced tumours but that these point mutations
from radiation workers with internal deposits of plutonium are a secondary outcome of genomic instability induced by
has provided the opportunity to examine whether protracted the irradiation. A similar result was reported by Kamikawa
irradiation of bone marrow cells had induced a transmissi- et al. [K24], who investigated mutations of the RAS and the
ble genomic instability in descendant cells in the peripheral TP53 genes in archival sections of liver cancers induced by
blood [W8]. Bone marrow dose calculations provided indi- Thorotrast. These investigators were unable to rule out the
vidual cumulative estimates at the time of sampling ranging possibility that genetic insults occurred indirectly in the pro-
up to 1.8Sv. Chromosome analysis revealed no significant liferating cells adjacent to the necrosis rather than being a
differences, either in comparisons between the total group direct effect of alpha particles.
of plutonium workers and controls for comparable periods
or when the comparisons were restricted to a group of plu- 34. Wada et al. [W17] also investigated genetic changes
tonium workers with initial bone marrow plutonium doses in the TP53 gene in 19 autopsy cases of liver malignan-
of greater than 0.25 Sv. There was therefore no evidence cies. LOH at the 17p13 locus and mutations in TP53 were
from this study for the induction of persistent transmissible analysed. A number of cases were informative: four cases
showed LOH and eight contained mutations. The direct stem cells survived exposures to alpha particle radiation that
action of alpha particles was thought to result in relatively induced complex genomic alterations. Increased frequen-
large deletions, such as those detected by LOH. Therefore cies of GPA mutations were observed, demonstrating that
the low frequency of such changes (27%) compared with genomic damage was also induced in erythroid progenitors.
point mutations (47%) suggests that the genetic changes in Despite the relatively severe burden of somatic cell damage
the TP53 gene in the liver tumours related to Thorotrast were induced by 40years of internal alpha particle irradiation, the
not caused mainly by direct actions of alpha particles but patient remained free of any serious illness. Furthermore,
rather by indirect effects that may have been due to cycles of these results provided no in vivo evidence for the contin-
necrosis and regeneration. This study was recently expanded ued expression of genomic instability. A similar observation
to compare Thorotrast-induced liver cancers to those not was reported by Hande et al. [H3], using a fluorescence in
associated with Thorotrast exposure. LOH at 37 loci was situ hybridization technique that made possible the detec-
investigated. Liu et al. [L46] found frequent LOH at micro tion of intrachromosomal rearrangements and deletions.
satellite markers D4S1538, D16S2624 and D17S1303 to be They described the quantification of stable intrachromo-
common to all the subtypes of liver cancer, independent of somal aberrations in lymphocytes of healthy former nuclear
the specific carcinogenic agent. In contrast, LOH at marker weapons workers who were exposed to plutonium. Even
D4S1652 was generally not observed in Thorotrast-induced many years after occupational exposure, more than half
cancers. LOH analysis revealed that Thorotrast-induced can- the blood cells of the healthy plutonium workers contained
cers share some LOH features with cancers not induced by large (>6Mb) intrachromosomal rearrangements. The yield
Thorotrast, and Liu and colleagues concluded that induced of these aberrations was highly correlated with plutonium
LOH is not simply due to direct insult to DNA by alpha par- dose to the bone marrow. It is significant that, despite the
ticles, but can occur through complex mechanisms, includ- relatively high frequency of intrachromosomal aberrations,
ing bystander effects [L46]. Such a conclusion is reasonable there was no evidence of transmissible chromosomal insta-
given the analysis of Goto et al. [G18], who used imaging bility and no obvious detrimental health consequences in the
plate autoradiography to examine the microdistribution populations sampled.
of alpha particles in pathological sections of tissues from
Thorotrast patients. They found that the amount of thorium 37. Nevertheless, a role for radiation-induced genomic
deposited in tumour tissue was correlated with that in non- instability has been described for solid tumours develop-
tumour tissue, and that Thorotrast deposition was not asso- ing after radiotherapy for bilateral retinoblastoma [L1].
ciated with DNA damage determined by histochemistry. Genome alterations of second tumours (five osteosarcomas,
Goto et al. [G18] concluded that radioactive thorium always one malignant peripheral sheath nerve tumour, one leio-
migrates in macrophages within the deposited organs, and myosarcoma) occurring in the field of irradiation of seven
that the organs are evenly exposed to alpha particles. patients treated for bilateral retinoblastoma were studied.
Because of a germ line mutation in the retinoblastoma gene
35. In an evaluation of Thorotrast-induced genomic insta- (RB1), these patients were predisposed to develop radiation-
bility, Liu et al. [L45] analysed microsatellite instability in induced tumours. In all radiation-induced tumours ana-
Thorotrast-induced liver cancers. The frequency of micro- lysed, the normal RB1 allele was lost, whereas the germ line
satellite instability cases was 62.5% in Thorotrast-induced mutated allele was retained and the two TP53 alleles were
cancers, whereas it was 22.7% in non-Thorotrast induced inactivated. A comparison of these tumours with the non-
cancers. Liu and colleagues suggested that microsatellite radiation-induced tumours led Lefevre et al. [L1] to conclude
instability induced by exposure to Thorotrast mainly reflects that this loss was due to the radiation-induced chromosomal
clonal expansion of cancer cells and is partly due to inactiva- instability rather than a direct effect of ionizing radiation. A
tion of the DNA mismatch repair gene hMLH1 by hyper- similar observation was reported by Ryabchenko and col-
methylation. A recent finding also suggests that methylation leagues [R12] after analysis of chromosomal aberrations
changes in DNA can be associated with radiation-induced in peripheral lymphocytes taken from Hodgkins disease
genomic instability [K35]. patients after prolonged (up to 31years) remission periods.
The mean frequency and patterns of aberrations in remission
36. Littlefield et al. [L16] examined the cumulative genetic patients were significantly different from comparison groups
damage in a 72-year-old man who was treated with a 32mL (healthy donors and primary Hodgkins disease patients).
bolus of Thorotrast during cerebral angiography performed New cancer cases were diagnosed in a number of the remis-
more than 40years earlier. Peripheral T-lymphocytes were sion patients, leading the investigators to suggest that the
cultured to quantify the frequencies and cellular distribu- tumorigenic potential of radiochemotherapy is mediated via
tions of asymmetrical and symmetrical types of chromo- induction of genomic instability in exposed cells. Long after
somal aberrations. Assays of glycophorin A (GPA) muta- the therapy, the instability may become an initiating event
tions in red blood cells were also performed. Their results in the development of new malignancies in affected tissues,
revealed that approximately 30% of the lymphocytes in this whereas the instability induced in haemopoietic stem cells
patient contained one or more chromosomal aberrations, may reveal itself in peripheral lymphocytes derived from
the majority of which were of the stable type. About one previously exposed precursor cells. The caveat, of course,
third of the lymphocytes with chromosome damage carried is that these individuals were cancer patients and may have
multiple aberrations, suggesting that significant numbers of been inherently predisposed to second cancers.
E. Genomic instability and radiation-induced leukaemia by studies demonstrating high frequencies of microsatellite
instability in those bombing survivors with acute myelo-
1. Mouse models cytic leukaemia and a history of high exposure [N7]. These
investigators concluded that this persistent instability might
38. Plumb et al. [P8] have reviewed the relationship between strongly influence the development of leukaemia in humans
radiation-induced genomic instability and radiation-induced exposed to ionizing radiation. This study stimulated two
leukaemia. They presented evidence that genomic instabil- letters to the editor of the journal in which it was published.
ity plays a role during radiation leukaemogenesis. How- The first, by Little [L40], claimed that although there was
ever, with the exception of a high incidence of non-clonal evidence that the microsatellite instability rate was higher
chromatid-type cytogenetic aberrations in neutron-induced in the AML cases among the bombing survivors than in the
acute myeloid leukaemia in mice [B26], the genetic lesions control group, the evidence that this higher rate was related to
described (including non-clonal chromosomal aberrations, the radiation dose these cases received was weak. Little went
LOH and minisatellite/microsatellite mutations) were sim- on to show that the number of loci for which microsatellite
ilar to those detected in de novo leukaemias and cancers. mutation data were not detectable was higher in the bombing
This damage was not transmissible and the authors inter- survivor cases than in the control group. The second letter,
preted these observations as evidence of apoptosis or other by Cox and Edwards [C15], raised the issue of the statistical
cell death. Nevertheless, this radiation-induced damage in strength of the dose-related association between expression
vivo was indistinguishable from de novo multistage leu- of genomic instability in AML and the probability of causa-
kaemogenesis. Thus it is not yet possible to define a type of tion by radiation. In response to these letters, Plumb [P18]
genomic instability in radiation-induced leukaemias in mice pointed out that, from a biological perspective, the striking
that demonstrates a specific characteristic of immediate or similarities in the leukaemias that arose in the bombing sur-
delayed effects of the initiating exposure to ionizing radiation. vivors and in therapy patients indicated that a significant
Evidence for radiation-induced genomic instability in mouse proportion of the AML cases among the bombing survivors
leukaemia and haemopoietic stem cells led M acDonald etal. described by Nakanishi et al. [N6, N7] could indeed have
[M1] to conclude that the induced instability contributed sig- been induced by the radiation. Reconciling mathematical
nificantly to the induced leukaemia. A similar conclusion was models [L40] and statistical analysis [C15] with the biologi-
reached by Ban et al. [B1], who suggested that loss of TP53 cal observations will always be difficult, however, particu-
function triggers the tumorigenic process leading to stem cell larly with the small number of AMLs observed in this unique
leukaemia through the induction of chromosomal instability. population.
These authors also pointed out that the aetiology of stem cell
leukaemia is likely to differ from that of myeloid leukaemia, 41. Mazurik and colleagues [M63] investigated molec-
because different results were observed in acute myeloid ular, biochemical and cytogenetic parameters in blood
leukaemia (AML) [B1]. samples from 17 radiation accident victims who between
1.7 and 43.8years previously had suffered acute radiation
39. Interestingly, however, susceptibility to radiation- sickness ranging in severity from grade I to grade IV. All
induced leukaemia is genetically separable from sensitivity patients showed ~2530% reduction in oxidative status and
to radiation-induced genomic instability [B13]. A series of increased levels of both stable and unstable chromosomal
matings, backcrosses and intercrosses between CBA/H mice aberrations that correlated with the severity of the acute
susceptible to radiation-induced acute myeloid leukaemia radiation sickness. These data were interpreted as evidence
and radiation-resistant C57BL/6 mice was carried out, and for delayed genomic instability in these radiation exposed
acute myeloid leukaemia and thymic lymphoma susceptibil- individuals.
ity was analysed. No simple genetic relationship between
susceptibility to radiation-induced leukaemia and the sensi-
tivity of the haemopoietic stem cells to induced instability F. Role of telomeres and telomerase in
was found. radiation-induced genomic instability
42. Telomeres are specialized DNAprotein complexes at

2. Human studies the ends of linear chromosomes. They are composed of a
repetitive DNA sequence and associated proteins. Telomere
40. Cytogenetic analysis of leukaemia patients among the alterations, caused by replication-mediated shortening,
survivors of the atomic bombings in Japan revealed that direct damage or defective telomere-associated proteins, can
patients exposed to >2 Gy exhibited a higher incidence of generate chromosomal instability, which can be observed
chromosomal aberrations and more complex chromosomal in senescence and during the immortalization process
rearrangements than did patients exposed to lower radiation (reviewed in reference [M47]). Telomeres are essential for
doses or unexposed patients [T1]. A more recent cytogenetic proper maintenance of chromosomes and may play a role in
analysis of the heavily exposed patients with acute myelo- ageing and cancer [G13, G14]. Telomere length can be main-
cytic leukaemia or myelodysplastic syndrome in the cohort of tained by telomerase [B25], or by the alternative mechanism
bombing survivors indicated persistent chromosomal insta- of telomere lengthening which is telomerase-independent
bility [N6]. These cytogenetic observations are supported [M7, S50]. Telomere length abnormalities observed in
radiosensitive cells suggest that, in some human cells, short Sabatier et al. [S44] in high-LET-irradiated human fibrob-
telomeres might correlate with radiation sensitivity [M49]. lasts. They demonstrated that instability acquired by human
This may or may not be the case in mouse cells, as both chromosomes recurrently involved telomeric associations.
hypersensitivity [G19] and the absence of an effect have This was not due to drastic telomere shortening [S45]. A
been described [M49]. To complicate the matter further, role for recombination involving interstitial telomere-like
long but dysfunctional telomeres have been found to corre- repeat sequences in inducing chromosomal instability was
late with chromosomal radiosensitivity in a mouse AML cell later demonstrated by Day et al. [D1] in an in vitro Chinese
line 7926 [F13]. humanhamster hybrid model system. In this instance it
was apparent that rearrangements involving unstable chro-
43. Another role for telomerase appears to be the de novo mosomes occurred preferentially at the sites of interstitial
formation of telomeres, or chromosome healing to stabilize telomere sequences rather than at the true terminal telo
broken chromosomes [M41, S35]. Telomere loss results in meres as observed by Sabatier [S45]. This difference is
sister chromatid fusion and prolonged breakagefusion likely to be due to the telomeres on transformed hamster
bridge cycles leading to extensive DNA amplification and chromosomes being very small relative to human telomeres
large deletions (reviewed in reference [M37]). Significantly, [S56]. Ojima et al. [O6] have reported that telomeres are
the loss of a single telomere can result in the instability of destabilized several generations after X-irradiation in nor-
multiple chromosomes [S46] and generate many of the types mal human fibroblasts. Their data suggest X-irradiation
of cytogenetic rearrangements commonly associated with might not affect telomeres directly, but rather by inducing
human cancer. Telomere dysfunction can also trigger exten- a delayed instability.
sive DNA fragmentation and the evolution of complex chro-
mosomal abnormalities in tumours in mice [A10] and humans 47. Initially it was thought that an interstitial telomere-like
[G11, M37]. This also appears to involve repeated cycles of repeat sequence on chromosome 2 played an important role
dicentric chromosome formation, anaphase bridging, subse- in the deletions in somatic haemopoietic cells that charac-
quent breakage and refusion events [G12]. In addition, telo terized the earliest phases of radiation-induced AML in the
mere dysfunction can result in increased mutation rates and CBA/H mouse [B28]. Subsequent detailed molecular analy-
genomic instability (reviewed in references [F9, M37]). sis of break points suggested that, while telomere sequences
were located close to regions frequently involved, break
44. It is noteworthy that exposure to ionizing radiation can points were not exactly coincident with telomere sequences
induce telomerase activity both in vitro [H23, N27] and in [F10]. The regions of frequent breakage appeared to have
vivo [H22]. This appears to be TP53-dependent [N26] and properties expected of matrix/scaffold attachment regions
has been suggested as a measure for monitoring the radio- [F10]. At this stage one can only speculate on whether telo-
curability of tumour cells [S49]. Radiation-induced telom- meric changes are a cause, an effect or a combination of both
erase activation depends on dose rate, is not related to cell in contributing to genomic instability independent of radia-
cycle redistribution or to the induction of cell death, and is tion exposure.
likely to be the consequence of specific regulatory responses
to ionizing radiation [P20].
45. Telomere repeat-like sequences are also seen as dis- G. Conclusions

crete bands at distinct intrachromosomal sites in a number
of vertebrate species [M42]. These interstitial telomere sites 48. Radiation-induced genomic instability is now well
probably represent ancestral telomere fusion events or ampli- established in a number of normal and transformed cell
fication of the repeat sequences in ancestral karyotypes as lines in vitro. Instability can manifest as multiple dif-
latent telomeres [L39, M42]. There is compelling evidence ferent end points and can result from both targeted and
that some of these interstitial telomere sites may be hot spots non-targeted events. The results of studies of induced
for both spontaneous [A11, H15] and radiation-induced instability in vivo are more complex and contradictory. In
chromosome damage [A9, B27, S36, S57, S58]. While it is mice, observation of the instability phenotype appears to
clear that interstitial telomere sequences can influence the be dependent upon the mouse strain used and the power
radiation sensitivity of chromosomes, many of these studies of the investigation in terms of the numbers of animals
were performed in hamster cells where the interstitial telo investigated. The evidence for induced instability in
meres are located at or near pericentromeric heterochroma- exposed human populations is controversial, with both
tin. Analyses of radiation sensitivity in a naturally occurring positive and negative effects being reported. It is possi-
short interstitial telomere in a human chromosome (2q31, ble that radiation-induced genomic instability provides
[A16]) and of a transfected 800bp telomeric repeat in human the impetus for those genomic alterations associated with
chromosome 4q indicate that human interstitial telomere radiation carcinogenesis. This view should be tempered
sequences might not be prone to spontaneous [D24] or by the high frequency with which instability is observed
radiation-induced [D25] breakage. both in vitro and in vivo, and the general lack of a dose
response curve. Overall, a specific role for induced insta-
46. The involvement of telomeric repeats in radiation- bility in the genesis of radiation-induced cancers has yet
induced chromosomal instability was first described by to be definitively demonstrated.
II. BYSTANDER EFFECTS AND RADIATION EXPOSURE
49. There has been a resurgence of interest in radiation- [M50]. This underscores the critical role of adequate and
induced bystander effects, largely because of the develop- appropriate controls. A historical perspective describing key
ment of single-cell charged-particle irradiators. The term events in the study of radiation-induced bystander effects
bystander effect was adopted from the gene therapy lit- has been presented by Mothersill and Seymour [M45].
erature, where it usually refers to the killing of several sub-
populations of tumour cells by targeting only one type of
cell within a heterogeneous population [F6]. For the pur-
poses of this annex, the definition proposed by Djordjevic A. Bystander effects in vitro
will be used [D5]. That is, bystander effect describes the
ability of cells affected by an agent to convey manifestations 50. Radiation-induced bystander effects in vitro embrace a
of damage to other cells not directly targeted by the agent number of different non-targeted experimental effects, some
or not necessarily susceptible to it per se. Thus radiation- of which are likely to be detrimental to the cell, whereas
induced bystander effects are effects manifesting in cells others are not. Different effects are observed in differ-
that were non-irradiated neighbours of irradiated cells or ent cell types, and depend on the cell type producing the
that received factors secreted or shed by irradiated cells. It is bystander signal after irradiation and the cell type receiving
implicit in this review that in vitro bystander effects are the the bystander signal (summarized in table3). Consequently,
result of a signal generated by an irradiated cell interacting no rigid rules can be applied to the multitude of responses
with a non-irradiated cell [C22] and are not the result of radi- occurring in cells not targeted by radiation. For convenience,
ation-induced changes in the culture medium [Z2], or due to bystander effects have been divided into four, not necessarily
experimental variables such as the cell culture environment mutually exclusive, subcategories.
Table 3 In vitro studies of the bystander effect
Year Origin of bystander effect End point Cell type Radiation type Reference
1992 Low-fluence alpha particle Sister chromatid exchanges Human fibroblasts and epithelial Alpha particles [N4]
irradiation cells
1996 Low-fluence alpha particle Sister chromatid exchanges Human lung fibroblasts Alpha particles [D2]
irradiation
1997 Medium transfer Sister chromatid exchanges Human lung fibroblasts Alpha particles [L2]
1997 Medium transfer Clonogenic survival Human epithelial cells; human Gamma rays [M18]
fibroblasts
1997 Medium transfer Clonogenic survival Human keratinocytes Gamma rays [S12]
1997 Microbeam irradiation Si- mutants induced AL humanhamster hybrid cells Alpha particles [H14]
1998 Low-fluence alpha particle p53, p21, MDM2, CDC2, RAD5 1 Human fibroblasts Alpha particles [A3]
irradiation protein levels
1998 Low-fluence alpha particle Plating efficiency; chromosomal Murine bone marrow cells Alpha particles [L24]
irradiation aberrations
1998 Medium transfer Clonogenic survival Human keratinocytes Gamma rays [M22]
1998 Microbeam irradiation Micronucleus frequency; apoptosis Human fibroblasts Alpha particles [P10]
1999 Cytoplasmic irradiation by Clonogenic survival; CD59 mutation AL humanhamster hybrid cells Alpha particles [W13]
microbeam frequency
1999 Low-fluence alpha particle HPRT mutations Chinese hamster ovary cells Alpha particles [N5]
irradiation
23
2000 Cytoplasmic irradiation by Clonogenic survival; CD59 mutation AL humanhamster hybrid cells Alpha particles [Z1]
microbeam frequency
2000 Low-fluence alpha particle Gl checkpoint Human fibroblasts Alpha particles [A8]
irradiation
2000 Medium transfer Clonogenic survival; AP-endonuclease; Human lung fibroblasts (HFL-l) Alpha particles [I10]
TP53; ROS
2000 Medium transfer Clonogenic survival; intracellular cal- Human keratinocytes Gamma rays [L28]
cium levels; mitochondrial membrane
potential; ROS levels
2000 Medium transfer Clonogenic survival Human keratinocytes Gamma rays [S13]
2001 Co-culture Clonogenic survival V79 Chinese hamster cells (3-D H beta particles
3
[B24]
tissue culture model)
2001 Co-culture p53, HSP72 protein levels A-172 human glioblastoma cells X-rays [M3]
2001 Co-culture Enhanced plating efficiency; Human salivary gland cells X-rays or carbon [S30]
micronucleus frequency beam
2001 Low-fluence alpha particle Changes in gene expression; induction Human fibroblasts and epithelial Alpha particles [A4]
irradiation of DNA damage cells
2001 Medium transfer Clonogenic survival; apoptosis; trans- CGLI human HeLa skin fibroblast X-rays [L5]
formation frequency hybrid cells
2001 Medium transfer Clonogenic survival; intracellular cal- Human keratinocytes Gamma rays [L38]
2001 Medium transfer Clonogenic survival Human urothelium cells Gamma rays [M39]
2001 Microbeam irradiation Micronucleus frequency Primary human fibroblasts Alpha particles [B9]
2001 Microbeam irradiation Transformation frequency C3H 10T murine fibroblasts Alpha particles [S6]
2001 Microbeam irradiation Clonogenic survival C3H l0T murine fibroblasts Alpha particles [A7]
2002 Co-culture Enhanced plating efficiency and Human salivary gland cells Carbon beam [S15]
proliferation
2002 Co-culture on double Mylar dishes Clonogenic survival; CD59 mutation AL humanhamster hybrid cells Alpha particles [Z4]
frequency
2002 Low-fluence alpha particle Micronucleus frequency Human fibroblasts Alpha particles [L43]
irradiation
2002 Low-fluence alpha particle HPRT mutations; sister chromatid Human fibroblasts and epithelial Alpha particles [L37]
irradiation exchanges cells
2002 Low-fluence alpha particle Chromosomal aberrations Chinese hamster ovary cells Alpha particles [N3]
irradiation
2002 Low-fluence alpha particle HPRT mutations; sister chromatid Chinese hamster ovary cells Alpha particles [N21]
irradiation exchanges
2002 Medium transfer Clonogenic survival; AP-endonuclease; Human lung fibroblasts (HFL-l) Alpha particles [I1, I5]
TP53; ROS
2002 Medium transfer Clonogenic survival; intracellular cal- Human keratinocytes Gamma rays [L26, L27]
2002 Medium transfer Clonogenic survival Thirteen cell lines: human epithelial Gamma rays [M21,
carcinoma cells, SW48 human M38]
colon carcinoma cells
2002 Microbeam irradiation Micronucleus frequency; apoptosis Sections of human and porcine Alpha particles [B7]
ureter
2002 Microbeam irradiation Clonogenic survival V79 Chinese hamster cells Alpha particles [S27]
2003 Co-culture Micronucleus frequency Human fibroblasts Carbon-ion beam: [S28]

beta particles
2003 Co-culture Enhanced plating efficiency and Human salivary gland cells Carbon beams [S29]
proliferation
2003 Low-fluence alpha particle HPRT mutations Chinese hamster ovary cells Alpha particles [N20]
irradiation
2003 Medium transfer Clonogenic survival Human keratinocytes Gamma rays [M27]
2003 Microbeam irradiation Micronucleus frequency; apoptosis Sections of human and porcine Alpha particles [B8]
ureter
2003 Medium transfer Apoptosis; micronuclei Humanhamster hybrid cells X-rays [N1, N2]
(GM10115; Fe10-3; LS12)
2003 Carbon ion beam Micronuclei; gap junctions; ROS Human fibroblasts Carbon ion beam [S28]
2003 Helium ion microbeam Micronuclei; nitric oxide T98G cell nuclei from human Helium ion beam [S16]
glioblastoma
2003 Microbeam irradiation AL cell mutagenic assay AL cells Charged particle [Z6]
microbeam; alpha
particles; X-rays
2004 Medium transfer RPA expression Primary human fibroblasts Gamma irradiation [B42]
2004 Medium transfer Micronucleus frequency Chinese hamster ovary cells Ultrasoft X-ray [K31]
microprobe
2004 Medium transfer Transformation frequency HeLa skin fibroblast hybrid cells Low-dose X-rays [K32]
2004 Co-culture Cell proliferation using 3H-TdR Antigen presenting cells (J774A.1) Low-dose irradiation [L44]
incorporation and T-lymphocytes
(EL-4)
2004 Chronic and acute irradiation iNOS accumulation WTP53 cells Chronic gamma [M59]
rays; acute X-rays
2004 Co-culture and medium transfer Oncogenic transformation frequency C3H 10T cells High- and low-dose [M51]
X-rays
2004 Cellcell contact during irradiation Oncogenic transformation frequency C3H 10T cells X-rays [M43]
2004 Co-culture and medium transfer Cloning efficiency; cell numbers Repair-deficient human cell lines Gamma rays [M44]
2004 Co-culture Chromosomal instability Human fibroblast BJ1-htert Alpha irradiation [P22]
2004 Co-culture Apoptosis; necrosis LY (L5178Y) suspension cells; Carbon ions; X-rays [S31]
human salivary gland cells
2004 Co-culture Micronuclei; nitric oxide Glioma cells; primary human He ion particles [S32]
fibroblasts
2004 Co-culture AL cell mutagenic assay AL cells Low-dose X-rays [Z10]
2004 Microbeam irradiation Micronuclei and cell cycle delays Human fibroblasts 90 keV/m alpha [P6]
particles
2005 Co-culture Transposition of chromosomal loci Human lymphocytes X-rays (10cGy) [T4]
2005 Medium transfer Micronucleus frequency; apoptosis X-rays [K33]
2005 Medium transfer Mutation and deletion in mitochondrial Human keratinocytes (HPV-G) Gamma irradiation [M60]
DNA
2005 Medium transfer Micronucleus frequency; HPRT GM10115 humanhamster hybrid X-rays [N30]
mutation frequency cells
2005 Co-culture Sister chromatid exchanges and Hamster cell lines (V3 and irs3) Low-fluence alpha [N25]
chromosomal aberrations particles
2005 Co-culture Micronuclei; nitric oxide; ROS Glioma cells (T98G) and fibroblasts Helium particles [S23]
(AG01522)
2005 Medium transfer Micronuclei; induction of p21waf1 Human fibroblasts X-rays [Y5]
protein; gamma H2AX foci; ROS;
clonogenic survival
2005 Bystander assay COX-2 signalling involving mitogen- Charged particle [Z5]
activated protein kinases beam
2005 Co-culture Micronuclei; apoptosis Mouse embryonic stem cells Alpha particles [Z7]
2006 Apoptosis from bystander effect Iodine incorporation for apoptosis; gap Non-small-cell lung cancer Ionizing radiation [Z9]
junctions; connexin-43 expression
1. Bystander effects after cytoplasmic irradiation probability of cell killing increases, whereas after cytoplas-
mic irradiation the increased mutagenicity occurs where
51. The most convincing demonstration of the bystander there is negligible killing of the irradiated cells [W13].
effect has come from studies using charged-particle micro
beams [F3, F4, F5, R1]. The microbeam is capable of putting
an exact number of particles through a specific subcellular 2. Bystander effects after low fluences
compartment of a defined number of cells in a particular of alpha particle irradiation
radiation environment.
53. It is implicit in the evaluation of bystander effects that
52. Using the microbeam at the Radiological Research bystander cells were not hit by the radiation but received
Accelerator Facility of Columbia University in the United signals from an irradiated cell that generated a response in
States [R1], Wu et al. [W13] targeted and irradiated the the bystander cell. Broad-beam irradiation with low fluences
cytoplasm of humanhamster (AL) cells. They observed a of alpha particles does not traverse every cell in the radia-
significant increase in mutations at the CD59 (S1) nuclear tion environment, and data suggest that a sizeable portion of
gene locus while causing minimal cytotoxicity. Cytoplasmic the damage observed after exposure to low fluences of alpha
irradiation with a single alpha particle doubled the spontane- particles results from responses occurring in cells that were
ous mutation frequency, while a two- to threefold increase not actually traversed by an alpha particle.
was observed after four cytoplasmic traversals. The muta-
tion spectrum was similar to the spontaneous, non-irradiated 54. Nagasawa and Little [N4] observed small increases
mutation spectrum, but different from that observed after in sister chromatid exchange frequency in ~30% of cells
targeted nuclear irradiation. The addition of the free radi- analysed, even though <1% of the cell nuclei were actu-
cal scavenger dimethyl sulphoxide or the intracellular glu- ally traversed by an alpha particle. This observation was
tathione inhibitor buthionine-S-R-sulfoximine indicated that later confirmed and extended by Lehnert and co-workers
the mutagenicity of cytoplasmic irradiation depended on the [D2, L2]. The induced sister chromatid exchanges could
generation of ROS (figure IV). Shao et al. [S32] also used be inhibited by superoxide dismutase, once again indi-
a charged-particle microbeam, at the Gray Cancer Institute cating a role for ROS [L2, N8, N9]. The alpha-particle-
in the United Kingdom, to target individual glioma cells induced increase in ROS appears to be temporally linked
cultured alone or in co-culture with primary human fibro to enhanced production of tumour necrosis factor alpha
blasts. They found that even when only a single cell within and interleukin 1, which in turn operate in an autocrine
the glioma cell population was precisely traversed through manner to up-regulate interleukin 8 [N9]. Low fluences
its cytoplasm with one helium ion, bystander responses were of alpha particles can also increase mutation yield [N5]
induced in the neighbouring non-irradiated glioma cells or and cause accumulation of the tumour suppressor protein
fibroblasts. Significantly, the yield of bystander-induced TP53 in a higher percentage of the exposed population than
micronuclei was similar when the cytoplasm or nucleus of calculated to receive a nuclear traversal by one or more
a cell was targeted, indicating that direct DNA damage is alpha particles [H5]. Whether or not mutation induction or
not required for switching on cell-signalling mechanisms induced gene expression is mediated by ROS is uncertain,
after low-dose irradiation. Two important conclusions can but whatever the mechanism, it involves gap-junction-
be reached from these experiments. First, because bystander mediated intercellular communication in the transmission
effects are observed after cytoplasmic irradiation, the target of damage signals from irradiated to non-irradiated cells
for genetic effects of radiation is larger than the nucleus. (figure V[A]). By examining changes in gene expression
Secondly, cytoplasmic traversal by alpha particles may be after low-fluence alpha particle irradiation, Azzam et al.
more deleterious in the long term than nuclear traversal. This [A3, A4] demonstrated the involvement of connexin-43-
is because, as the number of nuclear traversals increases, the mediated intercellular communication in the transmission
of damage signals to non-irradiated cells. In gap-junction- correlated with the induction of micronuclei as a measure
competent cells, induction of p21Waf1 protein far exceeded of DNA damage as well as with increased Ser-15 phospho-
the fraction of cells whose nuclei had been traversed, and rylation of TP53 (reviewed in reference [A5]).
Figure IV. Induced S1 mutations in humanhamster AL cells per 105 survivors.

AL cells were irradiated with four alpha particles through the nucleus (1) or the cytoplasm (2). Dimethyl sulphoxide (8%) from 10minutes
before until 10 minutes after cytoplasmic irradiation with four alpha particles significantly suppressed mutation yield (3). Treatment with
d-dimethyl sulphoxide alone did not increase mutation frequency (4). In contrast, pretreatment of AL cells with a 10M dose of buthionine-
S-R-sulfoximine for 18hours, which reduced the intracellular glutathione content to <5% of control levels, increased the mutagenicity of
cytoplasmic irradiation with four alpha particles by four- to fivefold (5). Treatment with buthionine-S-R-sulfoximine alone had no significant
effect on mutation frequency (6). These data strongly implicate ROS as being the mediator of the mutagenic response of cytoplasmic irradia-
tion (adapted from reference [W13]). The insert represents a schematic of the irradiation protocol.
700
600
ROS
S1 MUTATIONS PER 105 SURVIVORS
500
-particle irradiation
400
300
200
100
0
1 2 3 4 5 6
TREATMENT
Figure V. Bystander effects are those effects occurring in cells that were not directly subjected to the deposition of energy
by radiation but were in contact with irradiated cells or received a signal from an irradiated cell.
A cell is irradiated through the nucleus with an alpha particle (vertical arrow). This irradiated cell then communicates a signal to a non-
irradiated bystander cell by intercellular cell-to-cell gap junction communication (A) or the transmission of soluble factors from the irradiated
cell to the non-irradiated cell via the cell medium (B).
A. B.
Gap junction
communication Soluble factors
Alpha particle
55. A bystander effect for chromosomal aberrations Figure VI. CD59 mutants per 105 surviving AL cells.
induced by low fluences of alpha particles in wild-type (1) Non-irradiated cells. (2) Observed mutation yield when 20% of
and repair-deficient (xrs-5) Chinese hamster ovary cells AL cells were exposed to a lethal dose of 20 alpha particles per cell.
has been described [N3]. Gross chromosomal aberrations (All cells irradiated with 20 alpha particles should have been killed.)
are generally associated with DNA double-strand breaks (3) Expected mutation yield when 20% of AL cells were exposed to
[M15], suggesting that the factors responsible for the a lethal dose of 20 alpha particles per cell. (4) Effect of two hours of
bystander effect are also ultimately capable of cleaving the pretreatment and 72hours of post-treatment with 40M Lindane
double helix. As an explanation of their data, Nagasawa when 20% of AL cells were exposed to a lethal dose of 20 alpha
and Little [N3] proposed that the relatively small bystander particles per cell. (5) Effect of 40M Lindane alone on AL cells
effect in wild-type cells was due to proficient double-strand (adapted from reference [Z1]).
break repair as compared with the significantly enhanced
bystander effect, manifesting as dramatic increases in aber- 250
ration yields in repair-deficient xrs-5 cells. This study was
expanded to examine potential bystander effects for sister
chromatid exchanges and chromosomal aberrations in ham-
200
ster cell lines deficient in either DNA-PKcs (V3 cells, defi-
cient in non-homologous DNA end joining) or RAD51C
MUTANTS/105 SURVIVING CELLS

(irs3 cells, deficient in homologous recombination). Cells
were irradiated with very low fluences of alpha particles 150
such that <1% of the nuclei were traversed by an alpha
particle. Wild-type cells showed a prominent bystander
response for sister chromatid exchange induction; an even
100
greater effect was observed in V3 cells. On the other hand,
no significant induction of sister chromatid exchanges was
observed in the irs3 RAD51C-deficient bystander cells. In
contrast, a marked bystander effect for chromosomal aber- 50
rations occurred in V3 cells, and the induction of chro-
mosomal aberrations in irs3 bystander cells was minimal
and similar to that of wild-type cells. On the basis of these
0
findings, Nagasawa et al. [N25] hypothesized that homolo- 1 2 3 4 5
gous recombination is essential for the induction of sister
TREATMENT
chromatid exchange in bystander cells; but homologous
recombination is unable to repair the damage induced in
non-homologous end-joining-deficient bystander cells that
leads to either sister chromatid exchange or chromosomal 57. Unlike cytoplasmic irradiation [W13] or the bystander
aberrations. effect reported by Lehnert et al. after low fluences of alpha
particle irradiation [L2, N8, N9], the bystander effect
described by Zhou et al. [Z1] was not modulated by addition
of the free radical scavenger dimethyl sulphoxide. Instead,
when AL cells were treated with the cell-to-cell gap junction
communication inhibitor Lindane, the bystander effect was
3. Bystander effects after irradiation with significantly reduced but not eliminated (figureVI).
a charged-particle microbeam
58. In a subsequent study, Zhou et al. [Z3] used the Colum-
56. Using humanhamster hybrid AL cells, Zhou et al. bia University microbeam to deliver exactly one alpha
[Z1] located all cells in the radiation environment and particle through the nuclei of 5%, 10%, 20% or 100% of
exposed 20% of these to 20 alpha particles using the Colum- the AL cells. Their results indicated that the frequencies of
bia University microbeam. This dose of radiation allowed induced mutations and chromosomal changes in populations
less than 1% of the irradiated cells to survive. They then where known fractions of nuclei were hit were consistent
assayed surviving cells for mutations in the target human with non-hit cells contributing significantly to the response.
chromosome and found a mutation frequency four times that When 10% of a confluent mammalian cell population was
of background (figure VI). Since the irradiated cells were irradiated with a single alpha particle, the mutation yield
exposed to lethal doses of radiation, these mutations must was similar to that observed when 100% of the cells were
have arisen in non-exposed bystander cells. Furthermore, irradiated. This effect was significantly reduced in cells pre-
the mutation spectrum observed in bystander cells was sig- treated with octanol, which inhibits gap-junction-mediated
nificantly different from the spontaneous spectrum and from intercellular communication, or in cells carrying a domi-
that observed after cytoplasmic irradiation, suggesting that nant negative connexin-43 vector. These results indicate
different mutagenic mechanisms were involved in the two that a single alpha particle can induce genomic damage in
processes [Z1]. cells that were not irradiated. Since a cell cannot receive a
lower dose of radiation after exposure to alpha particles than transformation that cell-to-cell gap junction communica-
a single traversal, these data suggest that at the very low- tion is the most important mediator of the bystander effect
est radiation dose of alpha particles, i.e. a single particle, in C3H 10T cells after microbeam irradiation [M43].
the genotoxic risk for high-LET radiation may be underes-
timated. It should be noted that traversal of a single alpha 60. Related studies using microbeam-generated alpha
particle results in a dose of 0.0740.17Gy, depending upon particles have important implications for evaluating poten-
the nuclear cross-sections of a given cell type and assuming tial hazards associated with radiation exposure [M6]. One
an average LET of 90keV/m [R1]. alpha particle per nucleus, the lowest possible dose of high-
LET radiation, effectively elicits a bystander response in
59. The precision of intracellular irradiation and the high different cell types [B9, Z3]. By comparing the biologi-
throughput available at the microbeam facility at Colum- cal effectiveness of exposure to exactly one alpha particle
bia University have also enabled studies of oncogenic per cell with that expected from normal broad-beam irra-
transformation to be carried out. Sawant et al. [S6] utilized diation similar to that used in the experiments described
sparsely populated monolayers of mouse C3H 10T cells above (using a mean of one particle per cell), it is clear
and irradiated the nucleus of every cell, or every tenth cell that exactly one particle per cell is less biologically effec-
at random, with either two or four alpha particles. The tive than a mean of one particle per cell. Miller et al. [M6]
yield of transformed foci was determined morphologically, found that the transformation frequency after irradiation
and the frequency of transformation was similar whether with exactly one alpha particle per nucleus did not dif-
100% or only 10% of the cells were irradiated (figure VII). fer significantly from that observed in non-irradiated cells
(figure VIII). This suggested that the increased transfor-
mation frequency observed after broad-beam alpha irradi-
ation, where a mean of one alpha particle traversal per cell
Figure VII. Transformation frequency in C3H 10T cells
results in a Poisson distribution of particles per cell, is a
in vitro.
consequence of the minority of cells subjected to multiple
(1) Non-irradiated controls. (2) 10% of the cells received two alpha
(2) alpha particle traversals.
particles. (3) 100% of the cells received two alpha particles. (4)
10% of the cells received four alpha particles. (5) 100% of the cells
received four alpha particles. (6) 10% of the cells received eight
alpha particles. (7) 100% of the cells received eight alpha particles Figure VIII. Transformation frequency in C3H 10T cells
(adapted from reference [S6]). in vitro.
(1) Non-irradiated controls for the microbeam experiment. (2) Cells
20 receiving exactly one alpha particle per nucleus from the Columbia
TRANSFORMATION FREQUENCY/104 SURVIVING CELLS
University microbeam. (3) Non-irradiated controls for the broad-

beam experiment. (4) Cells receiving a mean of one alpha particle
per nucleus after broad-beam irradiation. Note that the transfor-
15 mation frequency in cells receiving exactly one alpha particle per
nucleus is only slightly different from that in the non-irradiated
controls (adapted from reference [M6]).
10 3
TRANSFORMATION FREQUENCY/104 SURVIVING CELLS
2.5
5
0
1 2 3 4 5 6 7 1.5
TREATMENT
1
Furthermore, Lindane (the cell-to-cell communication

gap junction inhibitor) reduced but did not eliminate this 0.5
bystander effect. In subsequent studies from the Colum-
bia University group, a role for secreted factors or fac-
tors released from irradiated cells into the culture medium 0
has also been identified. However, it is clear from stud- 1 2 3 4
ies of bystander-induced cell killing and oncogenic TREATMENT
61. An important advantage of using low fluences of alpha thus eliminating potential cell-to-cell gap junction commu-
particles or a charged-particle irradiator is that it represents nication [B9, P10]. This indicates that radiation-induced
environmentally relevant exposure conditions, where most soluble factors may be released into the culture medium and
cells in a tissue would not be traversed by an alpha particle. affect non-irradiated cells (figure V[B]), and suggests that
It should be stressed, however, that to irradiate cells in vitro there are at least two different types of bystander effect, those
with a high-energy alpha particle, target cells must be grown effects mediated by cell-to-cell gap junction communica-
as monolayers on a Mylar substrate. Under these culture tion and those induced by secreted soluble factors (figure V).
conditions, cells by necessity are more flattened and more Alternatively, there are at least two mechanisms for the same
elongated that would reasonably be expected in a three- biological effect. Intriguing data from Sawant et al. [S7] indi-
dimensional in vivo situation. Consequently, the energy cated that, as the number of alpha particles through a fixed
deposited per traversal is much less biologically effective. (10%) number of cells increases, more bystander-induced
To address this issue, three-dimensional model tissue culture cell killing occurs (figure IX). These observations suggested
systems are being developed. Any evaluation of potential that increasing induced damage in 10% of the cells in the cul-
hazards associated with these types of high-LET radiation ture produced more cell-to-cell gap junction communication
must consider these unique cell culture conditions. and/or increased secretion of cytotoxic substances into the
culture environment. A strategy combining medium transfer
62. There is also a microbeam at the Gray Cancer Institute, experiments and gap junction inhibitor studies would enable
where 3He ions with an LET of 100keV/m have been used investigators to determine the relative contributions of these
for targeted cellular irradiation [F5]. In addition, the Gray bystander-mediated cytotoxic effects and ultimately this
Cancer Institute microbeam has recently been adapted so that would aid in identification of the secreted factors.
the effects of ultrasoft X-rays can also be investigated [F3].
Using this microbeam, evidence for a bystander effect in pri- 63. Interestingly, some novel insights into the mechanisms
mary human fibroblasts, as measured by micronucleus forma- of radiation-induced bystander effects in vitro have been
tion and cell killing, revealed significantly more damage than revealed using the single-cell microbeam at the Gray Can-
expected on the basis of direct effects of radiation [B7, B8, cer Institute. When human glioblastoma T98G cell nuclei
B9, P11, P12]. The bystander effects observed using the Gray were individually irradiated with an exact number of helium
Cancer Institute microbeam can occur when cells are consid- ions, it was found that, when only one cell in a population
erable distances apart from one another and not in contact, of approximately 1,200 cells was targeted, cellular damage
Figure IX. Bystander effect for cell survival.

Ten per cent of the cells, selected randomly, were exposed to increasing numbers of alpha particles from 2 to 12, and the percentage of cell
survival was determined by reduction in plating efficiency. Open bars: experimentally determined survival. Filled bars: expected survival if only
irradiated cells were killed (adapted from reference [S7]).
120
100
80
% CELL SURVIVAL
60
40
20
0
0 1 2 4 6 8 10 12
NUMBER OF ALPHA PARTICLES IN 10% OF CELLS
measured as induced micronuclei was increased by 20% exposure to alpha particles. All populations, when confluent,
[S16]. When the percentage of cells individually targeted demonstrated a dose-independent bystander effect with respect
was increased from 1% to 20%, the yield of micronuclei in to cell killing and apoptosis. Minimal alpha particle induction
the population greatly exceeded that predicted on the basis of micronuclei in bystander cells was observed, except for the
of the yield when all of the cells were targeted assuming no Rad9-/- mutant, where a significant increase above background
bystander effect. However, when 2-(4-carboxyphenyl)-4, 4, 5, was detected. Therefore the Rad9 null mutation selectively
5-tetramethylimidazoline-1-oxyl-3-oxide (c-PTIO), a nitric- sensitizes mouse embryonic stem cells to spontaneous and
oxide-specific scavenger, was present in the culture medium, high-LET-radiation-induced bystander apoptosis and micro-
the micronucleus yields decreased to the predicted values. nucleus formation, but it has much less impact on cell killing
This indicates that nitric oxide contributed to the bystander by direct or bystander alpha particle exposure.
effect. Moreover, the medium harvested from cells targeted
with helium ions showed a cytotoxic effect by inducing 66. At present there is no detailed information on potential
micronuclei in non-irradiated T98G cells, and this bystander bystander effects occurring after cellular exposure to low-
response was also inhibited by c-PTIO treatment. The induc- LET radiation in non-irradiated cells subsequently cultured
tion of micronuclei in the population could also be decreased in the same physical proximity. This is because the develop-
by c-PTIO treatment when 100% of cells were individually ment of focused low-LET radiation sources has lagged well
targeted by one or two helium ions, indicating a complex behind that of high-LET charged particle microbeams, owing
interaction of direct irradiation and bystander signals. A role to practical and technical complications. Gamma rays inter-
for nitric oxide in the medium-mediated bystander effect has act with matter in a number of ways, including photoelectric
now been described in a number of studies [S15, S16, S31, absorption, Compton scattering and pair production. Since
S32]. Furthermore, the secretion of nitric oxide as a bystander the electrons will undergo scattering as they exit the vacuum
effect has been linked to the induction of radioresistance in system, it is not practical at present to irradiate single cells or
recipient cells [M3, M4]. However, it is not clear whether subcellular structures, as is possible with the charged parti-
nitric-oxide-mediated bystander effects occur in conjunction cle microbeams described above. However, by using pulsed
with, or independent of, increased levels of ROS, and how electron beams, a low-LET microbeam can be constructed
this might affect the characterization of subsequent radiation that will mimic many important aspects of the interaction
sensitivity. of gamma rays with cells. Such devices are currently avail-
able at the University of Maryland [S37] and Texas A&M
64. Microbeam experiments using high-Z elements University [W16] in the United States. Consequently, it is
(460MeV 40Ar, 1,260keV/m and 260MeV 20Ne, 380keV/ anticipated that in the foreseeable future many of the studies
m) have also been performed at the Japan Atomic Energy that have been performed with high-LET alpha particles or
Research Institute [S33]. Confluent normal human fibrob- intermediate-LET ultrasoft X-rays can be replicated using
lasts were targeted and the induced micronuclei evaluated these new low-LET microbeams. In addition, the ability to
after replating the cells. Even when only a single cell was experimentally vary the LET distribution by changing the
hit, a 1.4-fold increase in the frequency of micronuclei was incident beam energy will allow investigation of the rela-
observed, indicative of a bystander effect. The observed tive biological importance of various parts of the energetic
increase in micronucleus frequency saturated when four electrons track and hence evaluate how this might modulate
cells were targeted and could be suppressed when dimethyl bystander responses [S38].
sulphoxide (a scavenger of ROS) or PMA (an inhibitor of
gap junction communication) was present at the time of irra-
diation. Thus a role for nitric oxide, ROS and cell-to-cell gap 4. Bystander effects after transfer
junctions has been invoked in bystander responses. of medium from irradiated cells
65. It is likely, however, that there are multiple bystander 67. Mothersill and Seymour [M18] demonstrated a sig-
pathways. By using the Columbia University charged parti- nificant reduction in plating efficiency in non-irradiated
cle beam in conjunction with a strip dish design, Zhou et al. cultures of human epithelial cells (but not fibroblasts) that
[Z5] show that the cyclooxygenase-2 (COX-2, also known as received culture medium from irradiated cultures. These
prostaglandin endoperoxide synthase-2) signalling cascade observations indicated that irradiated cells secreted a toxic
plays an essential role in the bystander process. Treatment substance, a bystander factor, into the culture medium
of bystander cells with NS-398, which suppresses COX-2 that can kill non-irradiated cells (figureX). Medium irra-
activity, significantly reduced the bystander effect. This pro- diated in the absence of cells had no effect on survival
vided evidence that the COX-2-related pathway, which is when transferred to non-irradiated cells. Not all cells are
essential in mediating cellular inflammatory response, is a capable of producing the toxic bystander factor, nor are all
critical signalling link for the bystander phenomenon in this cells capable of receiving and responding to the secreted
assay system. Furthermore, any signalling pathway likely to signal [M17, M18, M22, M25]. The effect was depend-
be involved is complicated by the genotype of the exposed ent on the cell number at the time of irradiation, could be
organism. For example, Zhu et al. [Z7] examined the ability observed as early as 30minutes post-irradiation, and was
of mouse embryonic stem cells differing in the status of the still effective when medium transfer occurred 60 hours
DNA repair gene, Rad9, to express a bystander effect after after irradiation.
Figure X. Bystander effects in an immortalized human keratinocyte cell line as demonstrated by medium transfer
experiments.
Upper portion: schematic of the experimental protocol. A flask of cells is irradiated, and as a function of time post-irradiation, medium
is removed from the irradiated cells, filtered and transferred to non-irradiated cells. Clonogenic survival is then investigated in these non-
irradiated cells. Bystander effects are indicated by a reduction in plating efficiency in the non-irradiated cells that were cultured in medium
from the irradiated cells. Lower portion: plating efficiency expressed as percentage of survival after transfer of medium from cells exposed to
increasing doses of ionizing radiation (adapted from reference [S13]).
Filter
Transfer
medium
Determine plating efficiency in

Irradiated flask of cells non-irradiated cells
100
90
80
70
% CELL SURVIVAL
60
50
40
30
20
10
0
0 0.01 0.03 0.05 0.1 0.3 0.5 2.5 5
RADIATION DOSE (Gy)
68. Whether this is the same bystander phenomenon as the non-irradiated cells. Importantly, such factors had
described above for bystander effects after low fluences little effect on mutation induction, indicating that differ-
of alpha particles or irradiation with a charged particle ent bystander end points may involve different mechanisms
microbeam has yet to be determined. If it is not an identical with different cell types. This is supported by the study by
phenomenon, it is likely to be similar to those bystander Wang and Coderre [W18], who used a co-culture system to
effects defined above that involve the secretion of soluble examine bystander effects transmitted through the medium
factors [M43, S64, Z2]. However, one caveat in these stud- from the directly targeted cells to tumour cells growing
ies should be mentioned. When AL cells were plated on on an insert well beyond the range of the alpha particles.
either one or both sides of double Mylar dishes before irra- Alpha particle doses of 0.16.0Gy to the targeted cells on
diation, and one side (with or without cells) was irradiated the Mylar membrane, followed by a 2 hour co-incubation
with alpha particles, different effects on different cellular of the cells on the insert in the irradiated medium above the
end points were observed for both survival and mutation irradiated cells, all caused an approximately 50% increase
[Z2]. When the side with cells was irradiated, the surviv- in micronucleus formation in the non-targeted co-cultured
ing fraction among the non-irradiated cells was significantly cells. Addition of the radical scavenger dimethyl sulph
lower than that of the controls after 48 hours co-culture. oxide to the medium during the irradiation and the 2hour
However, such a change was not detected after 1hour co- post-irradiation incubation period completely blocked the
culture or when medium alone was irradiated. Furthermore, bystander effect, whereas addition of a nitric oxide scaven-
co-cultivation with irradiated cells had no significant effect ger had no effect.
on the spontaneous mutagenic yield of non-irradiated cells
collected from the other half of the double Mylar dishes. 69. Medium transfer experiments demonstrated that irra-
These results suggested that the irradiated cells released diation can lead to secretion of a factor or factors by irradi-
certain cytotoxic factors into the culture medium that killed ated cells that can reduce cloning efficiency, predominantly
by stimulating apoptosis [L26, L27, L28, S12], increasing irradiated cultures, Iyer and Lehnert [I4] have observed quite
neoplastic transformation [L5] or inducing genomic instabil- different cellular responses in human fibroblast cells cul-
ity [S12] in non-irradiated cells. The first detectable effect tured in supernatants from alpha-irradiated fibroblasts. They
on recipient cells after transfer of medium containing the observed decreases in basal levels of TP53 and CDKN1AQ
bystander factor from irradiated cells was a rapid calcium in non-irradiated cells, rather than increases as described by
pulse (12minutes) followed 30120minutes later by changes others (e.g. [A4, H5]). These decreases were accompanied
in mitochondrial membrane permeability and the induction by increases in proliferating cell nuclear antigen and CDC2,
of ROS [L28, L38, M24]. Cell-to-cell contact during irradia- apparently mediated by TGF-beta 1 and the induction of
tion was not required to induce killing of bystander cells, but intracellular ROS [N8]. In contrast to the detrimental effects
medium from cell cultures irradiated at high densities resulted on cell well-being characteristic of bystander effects so far
in the greatest amount of bystander-induced cell death [M22]. described, Iyer and Lehnert [I4] showed that their decreased
Furthermore, the use of apoptosis inhibitors or medium from TP53/CDKN1A bystander effect correlated with enhanced
lactate dehydrogenase or glucose-6-phosphate dehydrogenase cell proliferation.
mutant cells reduced or prevented the bystander effect [M24].
Treatment with the antioxidants L-lactate and L-deprenyl 73. Attempting to reconcile these conflicting results raises
prevented bystander-factor-associated cell killing [M24], sug- a number of questions. While the quality of radiation and
gesting that energy/redox metabolism may be involved in the the cell types under investigation are different, these stud-
medium-mediated bystander response. ies highlight the family of responses characterizing the
bystander effect. Mechanistically, factors transferred via
70. Mothersill and co-workers [M44] showed that repair- cell-to-cell gap junction communication or secreted into
deficient human cell lines produced a moderate to severe the culture medium may interact with those non-irradiated
amount of bystander-induced cell death after medium cells in an antagonistic manner, ultimately killing the non-
transfer to autologous cells or to a reporter cell line. Nor- irradiated cells (reviewed in reference [S39]), but the reasons
mal repair-proficient lines have much less severe, or no, why cultured cells should secrete cytotoxic factors and why
bystander-induced effects on cloning efficiency. These no such dramatic reduction in plating efficiency is observed
results are in agreement with the observations of Little and when populations of cells are irradiated with low doses of
colleagues [L42, N3]. Mothersill et al. [M44] interpreted low-LET radiation are not immediately obvious. Likewise,
these data as supporting the hypothesis that bystander effects the pro-mitogenic response reported by Lehnert et al. [L2,
play a protective role in biological systems by terminating L48] after medium transfer is contradictory to those direct
division in cells containing DNA damage. Thus the repair- effects observed in irradiated cells where irradiation can
deficient cells, irrespective of the actual repair defect, may inhibit cell growth. Cell proliferation following irradiation
respond to the occurrence of DNA damage in the population appears contrary to the long-term well-being of the cell,
by removing large numbers of cells from the proliferating tissue, organ or organism, whereas cell death would be likely
pool. It should be noted that repair-deficient cell lines tend to protect against the possibility of detrimental mutations,
to show an increased frequency of induced genomic insta- chromosomal rearrangements, and so on. Clearly bystander
bility, again suggesting a commonality in the mechanism of effects can modify cellular responses to radiation, and it
radiation-induced genomic instability and bystander effects. remains to be determined whether these effects character-
ized in non-irradiated cells in vitro have a major role in the
71. The majority of medium transfer experiments reported response of irradiated cells in vitro or in irradiated and non-
have utilized low-LET radiation to induce the bystander effect irradiated cells in vivo.
and have come primarily from a single laboratory (reviewed
in references [M19, M20]). A fascinating observation from
these studies, but one that is difficult to reconcile with those B. Bystander effects in vivo
of other studies, concerns the radiation doses required to elicit
a bystander response. In human keratinocytes, low-LET 60Co 74. Bystander effects have been observed predominantly
gamma ray doses of 0.010.5 Gy reduced clonogenic sur- by using single-cell in vitro systems that do not have real-
vival after transfer of irradiated medium. This was entirely istic multicellular morphology. Given that the bystander
due to bystander effects. The magnitude of cell killing was phenomenon must involve cell-to-cell interactions, the rele
relatively constant and appeared to saturate at doses in the vance of such single-cell in vitro studies is questionable.
range 0.030.05Gy [S13]. At doses of greater than 0.5Gy, However, Belyakov et al. [B36] have described bystander
cell killing was the result of the direct effects of radiation as responses in a three-dimensional, normal human tissue sys-
well as the dose-independent bystander effect [S13]. These tem. While not a true in vivo assay, this model skin system
observations are difficult to explain in terms of the classical does provide some semblance of multicellular interactions.
cell survival curve, where there is very little if any cell kill- End points were induction of micronucleated and apoptotic
ing observed at radiation doses of a few milligrays in directly cells. Non-irradiated cells up to 1 mm distant from irradi-
irradiated cells. ated cells showed a significant enhancement in the effect
over background levels, with an average increase in effect
72. In contrast to the cell-killing effects reported by of 1.7-fold for micronuclei and 2.8-fold for apoptosis. The
Mothersill and Seymour after medium transfer from gamma- surprisingly long range of bystander signals in a human
tissue model system suggests that bystander responses may specifically at non-targeted effects of radiation but for other
be important in extrapolating potential radiation effects from purposes, so that critically evaluating bystander effects in
epidemiologically relevant doses down to very low doses vivo is premature at present. It should be mentioned at this
(<200 mGy), where non-hit bystander cells would likely stage that investigators are beginning to move from single-
predominate [M36]. cell systems to multicellular systems using primary explant
techniques [B8, B36] as well as three-dimensional model
75. Compared with the number of in vitro studies on systems [P11]. Consequently, it is anticipated that as more
bystander effects, there are relatively few studies on bystander information from these model systems becomes available
effects in vivo, and these are summarized in table4. Many and more focused studies in vivo are undertaken, it will be
of these studies appear to have been performed not to look possible to critically re-evaluate bystander effects in vivo.
Table 4 In vivo studies of the bystander effect
End point Cellular system Radiation type Reference
Chromosomal aberrations Chinese hamster ovary and liver 239

PuO2 particles; [B16, B17, M40]
alpha particles
Mixture of irradiated and non-irradiated mice bone Neutrons [W2]

marrow cells
Micronucleus frequency Rat lung Gamma rays [K11, K22]
Calcium mobilization; alkaline phosphatase levels; Rat incisor, thyroid and abdomen X-rays [C8, H1]
embryonic development
Regenerative capacity Earthworm X-rays [M8]
Macrophage activation; respiratory burst; TP53-/- mice Gamma rays [L22]

NO activation; neutrophil infiltration
Growth of tumour Mixture of human colon LS174T adenocarcinoma cells I beta particles
125
[X2]
and 125I-labelled LS174T cells
C57BL/6 mice Gamma rays [C1]
76. Despite the caveats outlined above, there are stud- by an alpha particle [B16, B17]. Furthermore, these data
ies indicating a bystander effect in vivo. Chinese hamsters raise the intriguing possibility that the target for induced
were injected with different sized particles of the internally bystander effects may actually be limited to the specific organ
deposited alpha emitter plutonium. The radioactive particles irradiated and that adjacent non-irradiated organs are not tar-
concentrate in the liver and produce chronic low-dose radia- gets for bystander effects. It is certainly not unexpected that
tion exposure, with the dose and dose rate being highest to multicellular organs function in response to genotoxic stress
cells located closest to the largest particles. However, analy- in a coordinated fashion [G24], and recently Barcellos-Hoff
sis of induced chromosome damage in these livers revealed and Brooks have hypothesized that multicellular responses
increased cytogenetic damage that was not directly related through extracellular signalling are integral components
to the local dose distribution [B17]. These observations were of predicting cancer risk after radiation exposure [B3]. To
interpreted as indicating that all the cells in the liver were this end, there is evidence from in vivo studies of radiation-
at the same risk of induced chromosome damage despite induced genomic instability that delayed instability has a
only a small fraction of the total liver being exposed to the significant bystander component [W2, X2]. Nevertheless, a
radiation. The cumulative incidence of liver cancer as a recent report of the International Commission on Radiologi-
function of time after plutonium injection and total dose was cal Protection (ICRP) [I11] suggests that early initiating cel-
also determined. Neither the time of tumour onset nor the lular and molecular events are the major determinants of risk
tumour incidence varied with particle size, indicating that at low doses, rather than cell-, tissue- and host-modifying
the number of cells hit by alpha particles was not a factor in factors.
tumour induction in irradiated livers [B16].
78. The evidence for in vivo bystander effects has been
77. These two studies suggest that radiation-induced reviewed in detail [B43, K25] and shows that these effects
genetic damage and ultimately tumour induction are related probably involve a genetic component [M61]. In addition
to the total dose to the organ, i.e. the whole liver, rather than to damage directly induced by the deposition of energy
the dose to individual cells or the number of cells traversed in the irradiated cell, consideration must now be given to
these indirect effects of radiation, and a model quantifying [B43]. Thus, at the present state of our knowledge, it is
these considerations has been proposed [B14]. An irradi- reasonable to assume that any bystander effect induced in
ated cell can send out a signal and induce a response in a vivo is accounted for in models of organ risk evaluation.
cell whose nucleus was not hit by radiation. Thus a detri- As a result, it is unlikely that the resurgence of interest in
mental bystander effect, e.g. chromosomal aberrations, in these non-targeted radiation effects will substantially alter
essence modifies the biological effectiveness of a given risk estimates as discussed in detail in the BEIR VII report
radiation dose by increasing the number of cells that expe- [C23]. Nevertheless, it cannot be excluded that increasing
rience adverse effects over that directly exposed to the the knowledge basis for in vivo bystander effects at low
radiation. Significantly, these bystander effects appear to doses and low dose rates in specific organs may affect
be limited to the organ irradiated, i.e. are organ-specific current organ risk estimates.
III. Relationship between Radiation-Induced
Genomic Instability and Bystander Effects
79. The evidence for effects occurring in cells that them- GM10115 cells. This indicates that GM10115 cells either do
selves were not irradiated but are the progeny of irradiated not secrete a cytotoxic bystander factor or are not susceptible
cells (radiation-induced genomic instability), and non- to a bystander factor, and that the death-inducing effect is
targeted cellular effects usually associated with direct expo- not the same as the bystander effect described by Mothersill
sure to ionizing radiation occurring in non-irradiated cells and co-workers. Likewise, chromosomal instability was not
(bystander effects), has been reviewed in the previous para- detected in GM10115 cells after transferring medium from
graphs. Many of the end points associated with these two irradiated cells as described by Mothersill and Seymour
phenomena are the same: induced chromosomal rearrange- [M18, M21] for induced bystander effects.
ments, micronuclei, increased mutation, increased transfor-
mation and cell killing. So what is the relationship, if any, 81. It should be noted that Mothersill et al. [M44] have
between induced instability and bystander effects? Chromo- also reported that they do not find a bystander response
somal instability in haemopoietic cells can be induced by in some Chinese hamster cell lines after medium transfer.
an indirect, non-targeted bystander type of mechanism [K3, This implies that, like the humanhamster hybrid GM10115
L24]. Persistently increased levels of intracellular ROS have cell line, CHOK1 hamster cells may be deficient in produc-
been reported in chromosomally unstable cells [C5, L7, L8, ing a bystander signal or in responding to that signal. It is
L9, L10, R3, R6], and provide a plausible mechanism for interesting that when medium from irradiated CHOK1 cells
perpetuating instability over time (reviewed in references was added to either non-irradiated CHOK1 cells or repair-
[M10, M16]). Considerable experimental support for this deficient XR1 hamster cells, the plating efficiency actually
hypothesis comes from Wright and co-workers [L22, W2, increased rather than decreased [M44]. However, signifi-
W4], and this has recently been reviewed in detail [L23]. The cantly increased bystander effects after cellular exposure to
resultant intercellular signalling cascades, cytokine produc- low fluences of alpha particles have been described in repair-
tion, nitric oxide production and persistent free radicals all deficient Chinese hamster cells compared with wild-type
have the potential to mediate both instability and bystander hamster cells [N3, N20, N25].
effects (reviewed in references [L23, M10]).
82. Evidence increasingly suggests that induced instabil-
80. To critically evaluate the hypothesis that chromosomally ity and bystander effects are linked (reviewed in references
unstable GM10115 clones perpetuate instability by secreting [L23, M10, M16]), and it is likely, given the commonality of
a bystander-like factor into the culture medium, thus driv- the end points observed, that both phenomena could be mani
ing the delayed production of chromosomal rearrangements, festations of the same non-targeted processes [M10, M16].
Nagar et al. took medium from a chromosomally unstable Furthermore, a significant contribution from bystander-like
clone of GM10115 humanhamster hybrid cells, filtered it factors could help explain the high frequency of radiation-
and cultured non-irradiated GM10115 cells in this medium. induced instability reported, for example, in references [K3,
None of the non-irradiated GM10115 cells were able to sur- L6, M2].
vive and form colonies in medium from the unstable clone.
Nagar et al. called this novel effect, by which cells cultured in 83. The Committee continues to hold the view that mecha-
medium from chromosomally unstable GM10115 cells die, nistic information is important for its recommendations on
the death-inducing effect [N1]. The unstable clones showing radiation-induced health effects at doses of below ~200mSv
the death-inducing effect also showed increased numbers of and for risk assessment for individuals. The latter aspect is
apoptotic cells and elevated levels of intracellular ROS [N2], important because epidemiology always refers to popula-
either or both of which might contribute factors to the cul- tions, and genomic instability, for example, varies among
ture medium responsible for the death-inducing effect. Fur- individuals.
thermore, Nagar et al. [N1] have interpreted this observation
as indicating that unstable clones of cells do secrete factors
that, while generally not toxic to the unstable clone, most A. Relationship between radiation hypersensitivity
likely contribute to the perpetuation of the unstable pheno at low doses and bystander effects
type. It should be stressed that the death-inducing effect
is separate from the bystander effect observed after trans- 84. To date, investigation of the relationship between
ferring medium from irradiated cells. Nagar et al. did not radiation hypersensitivity at low doses and bystander
observe a reduction in plating efficiency when medium from effects has been limited to a single study. Joiner et al. [J4]
irradiated GM10115 cells was transferred to non-irradiated described radiation hypersensitivity at radiation doses where
37
the in vitro bystander effect would be expected to pre- cycle effects, types of radiation used, doses and dose rates,
dominate. Interestingly, an investigation into the relation- as well as time interval between irradiations [S54]. Current
ship between radiation-induced low-dose hypersensitivity uncertainties in interpreting experimental data from both
and the bystander effect indicated a weak inverse correla- adaptive response and bystander investigations do not per-
tion between these two low-dose phenomena. Specifically, mit any firm conclusions regarding the relationships between
those cells exhibiting a large bystander effect did not show these two low-dose phenomena to be reached at present.
radiation hypersensitivity [M23]. Should these results be
confirmed, they would suggest that, at very low radiation 87. Nevertheless, radiation-induced bystander effects can
doses, bystander effects might dominate the overall cellu- be considered a competing phenomenon with respect to
lar response. Furthermore, such bystander effects at doses an adaptive response [S7]. Using the Columbia University
of a few milligrays could have some bearing on the apparent charged particle microbeam and the AL cell mutagenic assay,
elimination of damaged cells and the absence of repair of Zhou et al. [Z6] showed that pretreatment of cells with a low
radiation-induced DNA double-strand breaks in the very low dose of X-rays four hours before alpha particle irradiation
dose range (1.2mGy) in X-irradiated normal human fibro significantly decreased this bystander mutagenic response.
blasts as reported by Rothkamm and Lobrich [R14]. Furthermore, bystander cells showed an increase in sensitiv-
ity after a subsequent challenging dose of X-rays. Using the
same irradiation system, Mitchell et al. [M51] found that an
B. Relationship between radiation adaptive adaptive dose of 2cGy of X-rays cancelled out the major-
response and bystander effects ity of the bystander effect produced by alpha particles. For
oncogenic transformation, but not cell survival, radioadapta-
85. The radiation adaptive response refers to the phe- tion could occur in non-irradiated cells via a transmissible
nomenon by which cells irradiated with a sublethal dose of signal.
ionizing radiation (an adaptive dose of a few centigrays)
become less susceptible to subsequent exposure to high doses
of radiation (a challenge dose of several grays). There is C. Conclusions
a vast literature on adaptive responses, and this section is
not intended to be an exhaustive literature review. Instead, 88. Ionizing-radiation-induced bystander effects are those
the goal is to provide examples of the main evidence for low effects occurring in cells that were not traversed by radiation
doses of radiation protecting against a subsequent high-dose but were induced by signals from irradiated cells. Mecha-
radiation challenge. The adaptive response to radiation was nistically, the signal is passed from cell to cell by gap junc-
first described as a reduction in chromosomal aberration fre- tion communication or is secreted into the culture medium
quency in stimulated human lymphocytes [O7]. Subsequent where it can be transferred to non-irradiated cells. Both
reported adaptive responses include reduction of cell killing positive effects for the cell (e.g. increased cell proliferation
[I6], micronucleus formation and sister chromatid exchange or an induced radioprotective adaptive response) and nega-
[I7, I8], mutation [K26, R11, U25] and transformation [A17, tive effects (e.g. cytogenetic damage or cytotoxic bystander
R8]. An adaptive response has also been described after responses) have been described. Bystander effects induced
clinical [M53], environmental [G16] or occupational [B34] by high-LET radiation have been described in a number of
exposures to radiation. The mechanism for this radioadapta- different cell types in studies using either low radiation flu-
tion is thought to be that low radiation doses enhance DNA ences of alpha particles or charged particle microbeams. A
repair ability and antioxidant activity, resulting in more pro- bystander effect induced by low-LET radiation is less well
ficient cellular responses to the subsequent challenge [G21, established and to date has only been demonstrated after
I9, S48]. medium transfer experiments. Experimental verification in
different laboratories and the use of newly developed low-
86. Reports of the adaptive response to radiation are con- LET microbeams will extend these observations. To date,
flicting, however, because radioadaptation is not consistently low-LET bystander effects appear to be a low-dose phenom-
a robust effect in all cell systems [A14, B35, B40, H16]. The enon, and reconciling low-dose bystander cytotoxicity with
variation among different studies could be related to a number the lack of directly induced cell killing at these same doses
of factors, including cell type [R7], cell culture conditions, cell is perplexing.
IV. ABSCOPAL EFFECTS OF RADIATION
A. Review and T241 tumour cells implanted into the midline dorsum
grew at a significantly slower rate when the leg of the animal
89. An abscopal effect may be defined as a significant was exposed to five 10Gy fractions of radiation compared
tissue response to irradiation in tissues definitively separate with sham-irradiated animals. This suggests that the absco-
from the region exposed to radiation. The response must pal effect is not tumour-specific. When the radiation dose to
be measurable, and the distance separating the responding the leg was reduced (12 2Gy), the inhibition of Lewis lung
tissues and the portal(s) of irradiation must be great enough carcinoma tumour growth was decreased, indicating a radia-
to rule out any possible effect of scattered radiation [N15]. tion dose dependency for the abscopal effect. In contrast,
Originally described by Mole [M52] in 1953, the word when the legs of TP53 null animals or wild-type TP53 mice
abscopal comes from the Latin ab (position away from) and treated with pifithrin-alpha (a TP53 blocker) were irradiated
scopus (mark or target). The mechanism of the abscopal (5 10 Gy), tumour growth was not delayed. These data
effect is unknown, although a variety of underlying biologi- implicate TP53 as a key mediator of the radiation-induced
cal events can be hypothesized, including a possible role for abscopal effect and suggest that pathways downstream of
the immune system [M46, U24]. TP53 are important in eliciting this response.
90. An example illustrating radiation-induced abscopal 92. Ionizing radiation can reduce tumour growth outside
effects is the study of early DNA damage induced in rat lung the field of radiation [A15, E16, K27, R9, R10], but this
cells following single-dose, partial-volume (lung base and abscopal effect remains a rare and poorly understood event.
lung apex) irradiation [K11]. When the lungs were removed Ionizing radiation generates inflammatory signals and in
at 1618 hours after whole-lung irradiation, an average of principle could provide both tumour-specific antigens from
~0.85 micronuclei per binucleate cell were observed in the dying cells and maturation stimuli that are necessary for den-
irradiated animals, compared with 0.02 micronuclei per dritic cells to activate tumour-specific T-cells. Demaria et al.
binucleate cell in the lungs from control animals. When only [D23] tested the hypothesis that the abscopal effect elicited
the lung base was irradiated, the frequency of micronuclei by radiation is immune-mediated. Mice bearing a syngeneic
in cells from the irradiated field was 0.85. However, non- mammary carcinoma, 67NR, in both flanks were treated with
irradiated cells from the out-of-field lung apex also showed a growth factor Flt3-Ligand daily for 10days after local radia-
significant increase in the frequency of micronuclei, 0.43 per tion therapy to only one of the two tumours at a single dose
binucleate cell, significantly higher than the non-irradiated of 2 or 6Gy. The second, non-irradiated tumour was used as
control value. Cells from the lungs of rats injected with indicator of the abscopal effect. Radiation alone led to growth
superoxide dismutase within one hour prior to irradiation delay exclusively of the irradiated 67NR tumour. However,
of the lung base and processed 1618 hours after irradia- growth of the non-irradiated tumour was also impaired by
tion showed a reduction in the number of micronuclei in the the combination of radiation and ligand. Importantly, the
shielded lung apex, indicating the potential involvement of abscopal effect was shown to be tumour-specific, because
oxygen radicals [K11]. growth of a non-irradiated A20 lymphoma in the same mice
containing a treated 67NR tumour was not affected. More
91. Ohba et al. [O3] described the case of a 76-year-old over, no growth delay of non-irradiated 67NR tumours was
Japanese man with hepatocellular carcinoma that regressed observed when T-cell-deficient (nude) mice were treated
after radiotherapy for thoracic vertebral bone metastasis. with the combination of radiation and ligand. These results
Serum levels of tumour necrosis factor alpha increased demonstrate that in this cell system the abscopal effect is
after radiotherapy, and the investigators suggested that in part immune-mediated and that T-cells are required to
such abscopal-related regression might be associated with mediate distant tumour inhibition induced by radiation.
host immune response, involving cytokines such as tumour
necrosis factor alpha. To understand the potential mecha- 93. Abscopal effects after partial-body irradiation have also
nisms, Camphausen et al. [C1] examined whether the absco- been described in earthworms [M8], White Leghorn cock-
pal effect was mediated through TP53. Non-tumour-bearing erels [M9] and rats [C8, H1]. Abscopal reactions have also
legs of C57BL/6 (wild-type TP53) and TP53 null B6.129S2- been described in patients with chronic leukaemias, wherein
Trp53(tm1Tyj) mice were irradiated to determine whether irradiation of an enlarged spleen or liver will induce a gen-
an abscopal effect could be observed against Lewis lung car- eralized remission with return of the bone marrow, white
cinoma and T241 (fibrosarcoma) implanted at a distant site. blood cell count and peripheral blood cells to normal ranges
In the TP53 wild-type mice, both the Lewis lung carcinoma [N15]. In fact, there are a number of well-recognized effects
39
described by radiation therapists that occur beyond the radia- B. Conclusions

tion field. Goldberg and Lehnert [G7] have recently reviewed
these bystander-like effects but concluded that the clinical 94. The few studies discussed in this section that describe
literature does not provide strong evidence for or against the the potential abscopal effects of ionizing radiation are gener-
existence of radiation bystander effects, and by extension ally descriptive in nature and provide little or no interpre-
abscopal effects, in vivo. They argue that many studies can tation in terms of the mechanism underlying the response.
be interpreted as suggesting non-targeted effects in vivo, and This together with the lack of confirmatory studies means
recommend that prospective clinical trials be carried out that that definitive conclusions on the impact of any poten-
involve detailed field and dose information combined with tial abscopal effects are not possible. Additional focused
well-documented patient risk factors in order to investigate research involving well-designed prospective clinical trials
potential bystander effects after radiation therapy [G7]. could clarify this issue.
V. CLASTOGENIC FACTORS INDUCED BY IONIZING RADIATION
A. Review factors capable of inducing detrimental effects in unex-

posed cells. These clastogenic factors (or clastogenic
95. Following whole-body irradiation, blood plasma from plasma factors) were first described by Parsons et al. [P5],
some animals and humans can contain factors that can cause who observed bone marrow damage in the sternum of chil-
chromosome damage, hence the name clastogenic factors. dren with chronic granulocytic leukaemia whose spleens
This indicates the persistence of soluble factors induced by had been irradiated. This report was corroborated by Souto
radiation that are capable of causing effects in non-irradiated [S19], who showed that rats injected with plasma from
cells. As such, clastogenic factors are not necessarily classi- irradiated animals developed mammary tumours at a sig-
cal bystander effect factors but are included here to support nificantly higher rate than rats exposed to plasma from non-
the concept of a role for secreted and released soluble fac- irradiated animals. A number of reports eventually followed
tors in delayed effects associated with radiation exposure. that demonstrated that culturing normal human peripheral
Strictly, under the definitions presented in this review, clas- blood lymphocytes in medium containing plasma obtained
togenic factors, like abscopal effects, could well be consid- from accidentally [G5] or therapeutically [H6, L15] irra-
ered bystander effects. However, for historical reasons, both diated individuals resulted in significantly more chromo-
abscopal effects and clastogenic factors are considered sepa- somal aberrations than culturing lymphocytes in medium
rately. In reality, however, no mechanistic distinctions are with plasma from non-irradiated individuals. These obser-
implied between these non-targeted effects of exposure to vations led to the suggestion that, after in vivo irradiation,
ionizing radiation. exposed individuals can possess clastogenic factors in their
blood plasma that, when transferred to cell cultures from
96. There is a large body of evidence demonstrating that unexposed individuals, can induce chromosome damage
plasma from irradiated animals and humans can contain (figureXI).
Figure XI. Theoretical schematic for identifying clastogenic factors.

Plasma isolated from blood from an irradiated mouse is mixed with blood from a non-irradiated mouse and cultured for cytogenetic analysis.
Clastogenic factors in the plasma from the irradiated mouse can cause chromosomal aberrations in the peripheral blood lymphocytes of the
non-irradiated mouse. A: metaphase chromosomes from a peripheral blood sample from a non-irradiated mouse cultured in media containing
isolated plasma from a non-irradiated mouse. No chromosomal aberrations are observed. B and C: metaphase chromosomes from a peripheral
blood sample from a non-irradiated mouse cultured in isolated plasma from an irradiated mouse (B: chromatid deletions (arrows); C: chromatid
exchange and deletion (arrows)).
Ionizing radiation
Blood sample Blood sample
Isolate plasma Peripheral blood lymphocytes
Culture for cytogenetic analysis
A B C
41
97. Clastogenic factors have been described in plasma is probably mediated by free radicals. Free radical scaven-
from survivors of the atomic bombings in Japan [P2], per- gers such as superoxide dismutase, penicillamine, cysteine
sonnel involved in salvage operations after the Chernobyl and various antioxidant plant extracts all reduce or elimi-
accident [E8, E10] and children exposed as a consequence of nate clastogenic factor activity [E1, E2, E3]. The molecu-
the Chernobyl accident [E11, G3]. In addition, clastogenic lar mechanisms for this effect and the specific nature of the
factors have been reported in human [G1, L19, S10] and rat factors capable of persisting, or of being regenerated over
blood plasma [F1] after in vitro irradiation. Clastogenic fac- protracted time intervals (>30 years in the case of some
tors can be induced within 15 minutes of irradiation [F1] of the atomic bombing survivors [P2]), remain unknown.
and appear to be very persistent or continuously regener- Nevertheless, it is tempting to speculate on the poten-
ated: times of 10weeks post-irradiation have been reported tial relationship between clastogenic factors and factors
for rats [F1], 710 years for irradiated humans [E8, G5, involved in the bystander effect. Both can be induced
G6] and >30years for the atomic bombing survivors [P2]. by ionizing radiation and the factors produced can cause
Clastogenic factors reflect neither radiation-induced deple- genetic damage in non-irradiated cells. Given the current
tion of protective factors nor radiation-induced changes in interest in bystander effects resulting from secreted fac-
normal plasma components, but rather represent products tors produced after cellular irradiation [S39], it may be an
secreted or excreted by cellular elements as a result of irradi- appropriate time to revisit clastogenic factors and evaluate
ation [F1]. In vitro induction of clastogenic factors does not the biological significance and nature of these radiation-
appear to be related to the dose [S10] or quality of radiation induced secreted factors.
[G1]; however, this might not be the case in vivo [E8].
101. At present, the biological significance of clastogenic
98. Emerit et al. [E8] investigated clastogenic factors in factors remains unclear [H11]. Furthermore, it would be
the plasma of 32 civil workers from Armenia who had been misleading to imply that clastogenic factors are unique to
engaged as emergency workers around the Chernobyl atomic radiation exposure. Transferable clastogenic effects have
power station in 1986. They also included 15 emergency been described in blood plasma after whole-body stresses
workers who had emigrated from the former Soviet Union as diverse as asbestos exposure [E7] and ischaemia reper-
to Israel. Reference plasma samples were obtained from 41 fusion injury [E6], and occur spontaneously in patients
blood donors from the Armenian Blood Center in Yerevan. with HIV-1 [E1], hepatitis C [E12], Crohns disease [E5]
The samples were tested for their clastogenic activity in and scleroderma [A2]. The reports of diffusible clastogenic
blood cultures from healthy donors. The samples from the factors induced by irradiation also resemble the reports of
first Armenian group, with the higher average radiation dose clastogenic activity in the plasma of patients with certain
(0.6 0.6Gy), were more clastogenic than those from the inherited disorders, including Blooms syndrome [E4],
second group, which had been exposed to 0.2 0.2Gy. The ataxia-telangiectasia [S14] and Fanconis anaemia [E9].
samples from the Israeli emergency workers also induced Individuals with these chromosome breakage syndromes
significantly increased aberration rates (14.0 3.9% aber- show an increased incidence of cancer, which begs the
rant cells). The clastogenic activity described above could be question as to the role of clastogenic factors in creating
inhibited by superoxide dismutase [E8], indicating that the a cellular environment predisposed to increased genomic
chromosome-damaging effects of radiation-induced clasto instability and ultimately neoplastic transformation [H11,
genic factors are exerted via the intermediation of super W11].
oxide radicals, as is known for clastogenic factors of different
origin [E18, F12]. 102. Emerit and colleagues have carried out many of the
studies investigating clastogenic factors. These investiga-
99. It should be stressed that there is variability between tors have described these factors in plasma from individu-
individuals in their ability to produce clastogenic factors als exposed to different types of radiation under a variety
[E11, G3], and not all irradiated individuals exhibit this of exposure conditions. In addition, Emerits group has
effect [L4]. Indeed it is difficult to evaluate how common is described clastogenic factors after exposure to other DNA-
the induction of clastogenic factors in the human population. damaging agents, as well as in individuals with a number of
On the one hand, blood samples from irradiated individuals medical conditions and various genetic diseases. It would be
are a valuable commodity, usually studied for more conven- misleading to imply that Emerit and colleagues are the only
tional biomarkers of radiation exposure. On the other hand, ones to describe clastogenic factors in various disease states.
it is perhaps not surprising that there are very few reports Reports from other laboratories lend support to these obser-
failing to detect clastogenic factors, as such negative results vations (e.g. [B10, G1, S14]), but the biological significance
are generally less likely to be published. and potential health hazards associated with clastogenic
factors remain to be determined.
100. The precise nature of clastogenic factors is unknown,
but endogenous viruses and compounds that interfere with 103. Nevertheless, the presence of clastogenic factors in
DNA repair and/or increase the production of free radi- peripheral blood samples from some irradiated individuals
cals have all been implicated [E1, E2, E3]. On the basis raises intriguing questions concerning the role of chromo-
of a number of inhibitor studies, the bulk of evidence sug- somal rearrangements as dosimeters of radiation exposure
gests that the mechanism of action of clastogenic factors [S10]. Cytogenetic analysis of first division metaphase
cells from irradiated individuals reveals both asymmetri- rearrangements in blood samples from irradiated individuals
cal (dicentric and polycentric chromosomes as well as ring is possible but unlikely.
chromosomes) and symmetrical (reciprocal translocations)
exchange-type aberrations, insertions, inversions and chro-
mosomal breaks (reviewed in reference [C9]). The asymmet- B. Conclusions
rical exchange-type aberrations generally lead to prolifera-
tive cell death in subsequent mitoses and decline over time. 104. It remains difficult to establish a clear description
Symmetrical translocations, on the other hand, are generally of the relevance of clastogenic factors to overall cellular
stable over time and can persist, although they also appear to responses to ionizing radiation, particularly at low doses.
decline, albeit at a much slower rate than asymmetrical aber- In part, this is due to the paucity of data on the nature of the
rations [S20]. Since clastogenic factors from some irradiated factors and on their mechanism of action. Furthermore, how
individuals can induce chromosome damage, a role for these such clastogenic factors might influence the doseresponse
factors in the well-described persistence of chromosomal curve at low doses is not possible to discern at this time.
VI. IMPACT OF NON-TARGETED AND DELAYED EFFECTS
OF RADIATION ON FUTURE GENERATIONS
105. It is important to consider whether non-targeted effects 109. There was also a significant dose-rate effect for this
of radiation influence our consideration of the consequences type of mutation. Shimada et al. [S43] determined the fre-
of irradiation of a parent on end points in offspring. The fol- quency of specific locus mutations at five pigmentation
lowing sections summarize the data from non-human and loci in medaka spermatogonial stem cells after gamma
human studies and consider them in the context of the Com- irradiation at 0.03cGy/min and 95cGy/min. At each total
mittees current position on heritable effects of irradiation. dose, the mutation frequency was significantly lower in the
Several diverse studies have provided a somewhat confusing 0.03cGy/min group than in the 95cGy/min group. The ratio
picture of the potential non-targeted or delayed effects of ion- of the induced mutation frequency at 0.03cGy/min to that at
izing radiation in humans, mice and other organisms. Many 95cGy/min was approximately 0.42 for doses of less than
of the studies present technical difficulties and ambigui- 1.9 cGy and approximately 0.33 for doses of 1.94.75 Gy
ties in interpretation, for example, with respect to uncertain [S43]. There was some specificity as to when such mutation
radiation doses in human studies, potential strain dependency events can be induced during spermatogenesis. When sperm
of responses in mouse studies, and poorly defined criteria and late spermatids were irradiated, the mutation frequency
used to define effects in some molecular studies. These com- within non-irradiated maternally derived alleles was approx-
plicating factors will be highlighted throughout this section. imately three times higher than in the control group. In the F2
generation, however, no increase in mutation frequency was
106. Many of the studies examine effects in the F1 off- observed. Similarly, there was no significant increase in the
spring of irradiated parents, while other studies consider F2 F1 mutation frequency when stem cell spermatogonia were
and later generations. It is only these studies of F2 and later irradiated. These data suggest that irradiation of sperm and
generations that can be unambiguously considered transgen- late spermatids can induce indirect mutations in F1 somatic
erational. This is because the F1 studies may be revealing cells, supporting the idea that genomic instability arises dur-
mutations that occur during parental germ cell development. ing F1 embryonic development. Moreover, such instability
Thus F1 studies address heritable effects, while F2 and later apparently arises most frequently when eggs are fertilized
generation studies address transgenerational effects. just after the sperm are irradiated [S42]. It should be noted
that dose-rate effects and germ-cell-stage specificities for
mutational response were previously demonstrated for spe-
A. Studies in non-mammalian species cific locus mutations in mice, and such findings have been
factored into past decisions of the Committee regarding the
107. The first demonstrated transmission of genomic insta- estimation of the risk of hereditary effects. Although interest-
bility to subsequent generations was in Drosophila treated ing, these new findings in fish provide no reason to modify
with ionizing radiation and mustard gas. However, the end those estimates.
point used was lethality, which revealed little about the
nature or the mechanisms of the processes involved [A12]. 110. Microsatellite mutations have also been studied in
plants grown in heavily contaminated areas near Chernobyl
108. Shima and colleagues have developed a specific [K15, K16]. Kovalchuk et al. [K15] investigated the muta-
locus test system using the Japanese medaka fish, Oryzias tion rates of 13 microsatellite loci in wheat plants grown
latipes [S40]. The genetic end points available are dominant in a contaminated (900 Ci/km2) versus a control (<1 Ci/
lethal mutations, total specific locus mutations and viable km2) area, and found a 3.6-fold increase in germinal muta-
specific locus mutations. The medaka has a transparent egg tion rate in the contaminated versus the control plot. Elle-
membrane and embryo body, and both visible mosaics and gren et al. [E17] reported an increased frequency of partial
whole-body mutations can be detected during development albinism, a morphological aberration associated with loss
at an early-expressed pigmentation locus [S40]. When wild- of fitness, among barn swallows, Hirundo rustica, breed-
type +/+ males were gamma-irradiated and then mated with ing close to Chernobyl. Heritability estimates indicate that
wl/wl females, the frequency of F1 embryos with both wild- mutations causing albinism were at least partly of germ line
type orange leucophores (wl/+) and mutant-type white leuco- origin. Furthermore, evidence for an increased germ line
phores (wl/wl*) (mosaic mutants) was ~5.7 103Gy1. The mutation rate was obtained from segregation analysis at
frequency of embryos with only white leucophores (whole- two hypervariable microsatellite loci, indicating that muta-
body mutants) was ~1.3 103Gy1. These results suggest that tion events in barn swallows from Chernobyl were two- to
delayed mutations arise frequently in medaka fish embryos tenfold higher than in birds from control areas in Ukraine
that have been fertilized with irradiated sperm [S41]. and Italy.
45
B. Mouse studies Figure XII. Pre-implantation embryo chimera assay.

F0 CD1 male mice were exposed to 1Gy of 137Cs gamma rays and
1. Irradiation of the mouse zygote mated to non-irradiated CD1 females six weeks after F0 paternal
irradiation. F1 animals with a radiation history were mated with non-
111. A long-held belief regarding radiation teratogenesis irradiated females to obtain F2 embryos with a paternal F0 radiation
was that developmental defects are only inducible when history. These four-cell embryos were paired with non-irradiated
the conceptus is irradiated during organogenesis. In contra- CD1 control four-cell embryos, and the resulting chimeras were
diction to this, Streffer et al. [M26, P1, P7] demonstrated cultured to the blastocyst stage and transferred to a foster mother.
that irradiation of a single cell, the zygote, can induce The pups resulting from the transfer were screened, and those with
developmental abnormalities, particularly gastroschisis, in and without a paternal F0 radiation history were identified and bred
the resulting animal. Indeed, when irradiated during early with normal females. Sex-matched pairs could then be evaluated
embryogenesis, induced teratogenesis is suppressed in a for competitive cell proliferation disadvantage, protein kinase C,
TP53-dependent manner, where apoptotic cell death plays a MAP kinase and GST activities, as well as p21waf1 and TP53 protein
critical role [K23, N23, N24]. levels.
1 Gy 137Cs gamma rays
112. Streffers studies used the Heiligenberger (now the
HLG/Zte) mouse, which has a spontaneous frequency of
gastroschisis of ~3%. One gray of X-rays to the zygote
increased this to ~11%, leading the investigators to con- F0
clude that ionizing radiation enhances latent damage already
present in this predisposed mouse strain [H27, S34]. Similar
findings have been made by other investigators [G4, G20,
J7] after exposure to chemical mutagens [G15]. Streffer and Type B
Spermatogonia
colleagues extended these studies to demonstrate congenital
malformations in the 19-day-old foetuses after paternal irra-
diation (2.8Gy of 137Cs gamma rays) [M64]. This increased
lethality occurred after exposure of all stages of spermato F1
genesis with the exception of early spermatogonia.
113. One possible interpretation of the gastroschisis results Radiation history

is that this mouse strain has a peculiarly high susceptibility
to this type of gross abnormality and that the radiation treat-
ments induced many dominant lethal mutations in germ cells
or in the pronucleus that greatly exacerbated this extreme
inherent susceptibility. While it is important to be aware that
such situations exist, there does not seem to be any practical
way to apply data on a strain of mice with a strong predis-
position to a serious anomaly to the estimation of hereditary
risk in human populations.
114. The effect of in utero exposure to ionizing radiation F2

during the early phases of pregnancy has previously been
reviewed [J7, P1, S34]. The risk of congenital malforma-
tions, the role of genomic instability after irradiation during
the pre-implantation phase [S63], genetic susceptibility [J6]
and health consequences [H17] have been reviewed in detail
and will not be further considered here.
F3
Litter mates
2. Pre-implantation embryo chimera assay
ANALYSIS
115. Wiley et al. have used a pre-implantation embryo chi-
mera assay to demonstrate adverse effects in embryos after
acute whole-body paternal irradiation (figure XII). They display the phenotype, indicating that the type B spermato-
measured the competitive cell proliferation disadvantage of gonia were the most sensitive [W10]. Recently, Baulch et al.
an embryo with a radiation history after challenge by direct [B4, B5] have evaluated F3 mouse offspring from F0 paternal
cell-to-cell contact with a normal embryo in an aggrega- mice exposed to 1Gy of 137Cs gamma rays for gene products
tion chimera [O1, O2, W10]. The F1 embryos conceived that can modulate cell proliferation rate, including recep-
67weeks after paternal F0 irradiation were most likely to tor tyrosine kinase, protein kinase C and MAP kinases, and
protein levels of nuclear TP53 and p21waf1. All three-protein Intrachromosomal homologous recombination between the
kinase activities were altered, and nuclear levels of TP53 70kb repeats that delete one copy of a duplicated 70kb DNA
and p21waf1 protein were higher in F3 offspring with a pater- fragment at the pun locus restores the p gene and produces
nal F0 radiation history than in non-irradiated litter-mates. black pigment in the hair and retinal epithelium in wild-type
While there is clear evidence of effects, it is unclear how this mice. On the C57BL/6Jpun/pun inbred background, 510% of
rather novel and artificial phenotype can be related to clini- the mice spontaneously display fur spots and from four to six
cally important hereditary effects, and thus no attempt will eye-spots per unpigmented retinal pigment epithelium.
be made to apply these results to hereditary risk estimation
in humans. 119. The pun fur spot assay was used to demonstrate that
exposure of the parental germ line to ionizing radiation
results in induction of delayed DNA deletions in mouse off-
3. Mouse mutation assays spring [C16, S17]. Male pun assay/pun assay mice were irra-
diated with 1 Gy of X-rays and mated 28 days later with
116. To investigate whether preconception paternal irra- non-irradiated pun assay/pun assay females. The offspring
diation can lead to the heritable transmission of genomic showed a higher frequency of large fur spots. Since deletions
instability in mice, Luke et al. [L25] measured mutation fre- occurring early in embryogenesis should yield larger spots
quency in a transgenic mouse model tagged with a lambda than events occurring later, the large spots indicated deletion
shuttle vector. This assay system allowed mutations in the events occurring early in embryo development and many
lacI gene from the shuttle vector to be analysed in vitro after cell divisions after irradiation [C16]. Shiraishi et al. [S17]
the animal had been irradiated in vivo. The results indicated irradiated male mice with 6 Gy and observed an increase
that, as parental dose increased, there was a trend towards in pun assay reversions resulting in eye-spots, in the irradi-
higher mutation frequency in vectors recovered from DNA ated paternal pun assay allele as well as in the non-irradiated
from the bone marrow of F1 progeny. These data demonstrate maternal pun assay allele, indicating untargeted recombina-
heritable transmission of factors leading to genomic instabil- tion in the offspring. The number of spots per retinal epithe-
ity in F1 progeny following paternal pre-conception irradia- lium increased twofold when the male was irradiated at the
tion, although the results with a lambda shuttle vector would spermatozoa stage [S17], but pun assay instability was not
be complicated to apply in quantitative risk estimation for observed when radiation was delivered either to spermato-
humans because they do not involve mammalian genes. gonial stem cells or to late spermatids. It is noteworthy that
radiation-induced instability of the pun assay allele has been
117. An increase in micronucleus frequency in bone observed in F1 mice but not in the F2 generation (reported in
marrow erythrocytes from the F1 progeny of male BALB/c reference [N22]).
mice exposed to chronic low-dose gamma irradiation was
observed by Fomenko et al. [F11]. Mice were irradiated 120. Estimates by the Committee of hereditary risk for
with 10, 25 or 50cGy at dose rates of 1, 5 and 15cGy/day, exposures of males have been based on damage to sperma-
and were mated with non-irradiated females on day 15 after togonial stem cells because they are the only germ cells in
irradiation. The obtained offspring had an elevated micro- males that can accumulate appreciable doses under low-
nucleus frequency in bone marrow erythrocytes at the age dose-rate exposure conditions. The finding that there is no
of two months. This suggests the transmission of genomic induced pun instability in spermatogonial stem cells suggests
instability from damaged germ line cells of irradiated male that there is no need to revise current risk estimates upward.
parents to somatic cells of the progeny. It is unclear, how-
ever, if the effects on micronuclei represent chromosome
damage of consequence to clinical diseases beyond those 4. Alterations in tandem repeat DNA sequences
already covered by the Committees current methods to
estimate hereditary risk. 121. Alterations in tandem repeat DNA sequences, such
as minisatellite DNA and expanded simple tandem repeats
118. The pun mouse background allows visual detection of (ESTRs), in the genome have been used as markers of
~70kb DNA deletions in the pink-eyed unstable (pun) locus in genetic change. Such loci have high spontaneous rates of
developing mouse embryos. These are scored as black spots mutation, which facilitates the measurement of induced
on the light gray fur or black cells on the transparent retinal mutation in relatively small numbers of samples. Alterations
epithelium of the offspring [R2]. In the fur spot assay, 10-day- (mutations) are manifested as gains or losses in repeat units
old pups are observed for black spots on the light gray fur, and are detected either by pedigree screening or by amplifi-
and the number of animals with fur spots is counted. In the cations [N22, Y4]. Mutations in both minisatellite sequences
eye-spot assay, mice are sacrificed at ~20days, the eyes are and ESTRs appear to arise via indirect mechanisms rather
removed and the number of black cells in whole mounts of than by direct damage to the repeat locus itself [Y4]. The
the unpigmented retinal pigment epithelium are determined significance of these DNA sequence changes is unknown. If
[R2]. The C57BL/6Jpun/pun mouse strain contains a 70 kb they are genetically neutral they will not affect risk; never-
tandem duplication of the pink-eyed dilution (p) gene [B29], theless, the fact that they happen indicates that exposure to
the pun mutation. The pun mutation is autosomal recessive ionizing radiation can lead to genomic destabilization that
and results in a dilute, light grey coat colour and pink eyes. may occur by a non-targeted mechanism.
122. Minisatellites are tandem repeat loci, typically long arrays, up to 16kb in length, of short (<10bp) repeat
0.530 kb long, with repeat units in the range 6100 base units. Unstable ESTRs appear to be comprised almost exclu-
pairs. Thousands of minisatellites exist in the genome and sively of homogeneous arrays, with longer arrays exhibit-
frequently they show variability in repeat copy number and ing the highest rates of mutation [B30]. This is in contrast
therefore allele length [J1]. Some minisatellites are highly to the complex variant repeat distribution that makes up
unstable and undergo a frequent length change mutation common minisatellite alleles. ESTRs exhibit high levels of
spontaneously in germ cells, sometimes as high as 10-1 per somatic instability and also show different mechanisms of
gamete [J2]. ESTRs were formerly classified as minisatel- mutation from that observed in the highly mutable GC-rich
lites but are now recognized as a fundamentally different minisatellites [Y4]. Examples of alterations (mutations) in
entity. In contrast to minisatellites, ESTRs are composed of an ESTR in mice are presented in figureXIII.
Figure XIII. Mutation analysis at two mouse ESTR loci.

A: Ms6-hm loci. Lanes: 1: father; 2: normal offspring; 3: offspring with a maternal mutation (open arrow); 4 and 5: offspring with two different
paternal mutations (dark arrows); 6: mother.
B: Hm-2 loci. Lanes: 1: father; 2, 4, 6 and 7: normal offspring; 3 and 5: offspring with different paternal mutations (dark arrows); 8: mother.
[Figure kindly provided by Y. Dubrova, University of Leicester, United Kingdom.]
123. By analysing DNA fingerprints of the offspring of 60Co reported for stem cells, spermatids and spermatozoa, respec-
gamma-irradiated mice, Dubrova et al. [D10] have shown that tively [F2, N14]. Inherent imprecision in the methodology
tandem repeat loci mutations appear to be induced in sperma- used is likely to be the cause of these discrepancies [N22].
togonia by low doses of ionizing radiation, with an estimated
doubling dose of 0.5Gy. This estimated doubling dose was 125. To date, most laboratory studies demonstrating her-
subsequently revised downwards to 0.33Gy [D14], which is itable effects of radiation exposure have involved pater-
similar to that reported earlier in the specific locus test in nal irradiation [B4, B5, D14, D15, N14, S1, W10], and an
mice [R4]. This is an assay that has been relied upon by the approximately linear dose-response curve for paternal muta-
Committee to a large extent in estimating hereditary risk. tion induced at pre-meiotic stages was found [D14]. Germ
line mutation in mouse tandem repeat loci appears to be a
124. Dubrova [D21] has since compared the spectra and sensitive indicator of irradiation of pre-meiotic stage germ
dose response for mutations at ESTR loci in the germ line of cells [D10, F2, S1], and an elevated paternal mutation rate
male mice acutely exposed to low-LET X- or gamma rays at was found after irradiation of mouse pre-meiotic sperma-
pre-meiotic stages of spermatogenesis in five strains of labo- togonia. In contrast, post-meiotic irradiation of spermatids
ratory mice. He found that most mutation events involved the gave a result similar to that in control litters [D14]. How-
gain or loss of a relatively small number of repeat units, and ever, both pre- and post-meiotic exposures were reported to
the distributions of the observed length changes were indistin- increase mutation yield, suggesting that strains of mice may
guishable between the exposed and the control males. Overall differ in stage susceptibility [F2, N14, S1].
a significant bias toward gains of DNA repeats was detected,
with approximately 60% of mutants showing gains. The val- 126. Dubrova et al. [D14] also analysed the maternal muta-
ues for ESTR mutation induction produced doubling doses of tion rate in mice after paternal irradiation at different stages
0.440.98Gy. Doubling dose estimations were also made by of spermatogenesis, and found no difference in the frequency
Niwa and his group, and values of 3.4, 0.893 and 4.0Gy were of maternal mutation. In contrast, Niwa et al. have described
a small but statistically significant increase in the maternally been confirmed in some studies [H10, L20, L21, V3] but not
derived Ms6hm allele, in addition to the paternally derived all. For example, Cattanach et al. [C4], using the optimal
allele, when only male parents were irradiated at the sper- experimental conditions defined by Nomura [N17], found
matozoa stage [F2, N14, S1]. Niwa and Kominami [N14] that tumour incidence was no higher in the offspring of irra-
demonstrated a statistically significant increase in mater- diated BALB/cJ mice than in the non-irradiated controls.
nal allelic mutation rate in F1 mice born to irradiated male They did find that the proportion of fertile females and mean
parents. The authors concluded that, as a consequence of litter size were affected by the radiation, showing a dose-
male (sperm) irradiation, genomic instability is triggered in dependent, dominant lethal response. In attempting to rec-
the zygote, which then mutates the paternally derived allele oncile these differences, Cattanach et al. [C4] proposed that
in cis and the maternally derived allele in trans. inconsistencies in the animal experiments may in part be due
to lack of an appropriate concurrent control, whose periodic
127. Mutation rates at two ESTR loci have been studied or cyclic variation in tumour incidence may have been out
in the germ line of first- and second-generation offspring of of phase with that in the treated animals. Alternatively, the
inbred male CBA/H, C57BL/6 and BALB/c mice exposed to reported differences could reflect strain differences in the
either neutrons or X-rays. Paternal CBA/H exposure resulted mice used.
in increased mutation rates in the germ line of two subse-
quent generations. Comparable transgenerational effects were 130. Selby and Priest [S52] reported no induced leukae-
observed also in neutron-irradiated C57BL/6 and X-irradiated mias when male CBA/Ca mice were injected with 239Pu
BALB/c mice. The spontaneous mutation rates and radiation- citrate solutions at nominal activities of 6 and 60 Bq/g, to
induced transgenerational instability varied between strains give absorbed doses of approximately 0.3 and 4.0cGy, and
(BALB/c>CBA/H>C57BL/6). Pre- and post-meiotic paternal were mated to females of the same strain 5468days later.
exposure resulted in similar increases in mutation rate in the Nomura [N16] found no increase in leukaemia in the off-
germ line of both generations of CBA/H mice, which suggests spring of ICR mice derived from spermatogonia after acute
that radiation-induced expanded simple tandem repeat insta- irradiation. In contrast, when spermatogonia from the N5
bility is manifested in diploid cells after fertilization [B2]. mouse strain were irradiated, Nomura found a 10-fold-
Although there are some difficulties in interpreting these data greater incidence of acute lymphocytic leukaemia in the off-
[B41], they do suggest that excess transgenerational muta- spring than in the non-irradiated controls. Once again, this
tion at the unstable loci may be detected after irradiation of may be explained by differences in genetic predisposition to
developing male germ cells. leukaemia induction by radiation in these mouse strains.
128. Analysis of ESTR mutation induction in the mouse 131. Extending his original findings, Nomura hypothe
germ line suggests that mutations are likely to be due to sized that, if radiation-induced mutations in the germ line
pausing of the replication fork and subsequent polymerase led to heritable lung tumours in offspring, then all the cells in
slippage events [B31, D21]. The frequency of induced muta- the lung should be at increased tumorigenic risk. Following a
tion appears to be significantly greater than the predicted fre- subsequent challenge with the carcinogen urethane, Nomura
quency of radiation-induced DNA damage at a given tandem described significantly increased clusters of tumour nodules
repeat locus. This has led many investigators to conclude that in the lung [N17, N18]. Vorobtsova and Kitaev [V3] reported
the increased mutation rates observed at these repeats are similar findings, but Cattanach et al. [C21] were unable to
not necessarily the result of directly induced DNA damage replicate these results in C3H/HeH mice. Selby et al. [S53]
at the specific locus, but result from radiation-induced suggested that the explanation for the surprisingly high rates
damage elsewhere in the genome or cell [D13, D14, D15, of induction of dominant mutations that cause tumours sug-
F2]. While alterations in tandem repeat DNA sequences may gested by the experiments of Nomura and others might result
provide useful biomarkers of induced germ line effects, the from the confounding effect of the radiation-induced domi-
biological significance of such mutations remains unknown. nant lethality that often occurs in such experiments. Other
The similarity of the calculated doubling doses to those pub- possible non-mutational explanations for the high mutation
lished for specific-locus mutations in mice supports the rates reported for dominant tumour mutations by Nomura
validity of the tandem repeat DNA sequence data, although have been suggested by Selby [S51] and Cattanach et al.
the uncertainty in doubling doses in specific-locus experi- [C4, C21].
ments needs to be borne in mind [U1]. The comparative data
between germ cell stages for mutations that affect tandem 132. Lord et al. have also investigated the heritable effects
repeat DNA sequences remain of interest and potential of pre-conception paternal irradiation from injected pluto-
importance. nium (239Pu alpha particle irradiation), 137Cs gamma rays or
the Auger-electron-emitting radionuclide 55Fe. They demon
strated perturbed haemopoiesis in offspring, as well as
5. Tumour induction in the offspring of irradiated parents enhanced sensitivity to methylnitrosourea (MNU, 50mg/kg)
as a secondary carcinogenic insult [H10, L20, L21]. A major
129. Nomura first reported a significant increase in lung difference from the tumour experiments discussed above
tumours, mostly benign adenomas, in the F1 offspring of was that Lord et al. used much lower doses of radiation. As
X-irradiated ICR parental mice [N17, N18, N28]. This has a result, there would have been little or no induced dominant
lethality, and the possibility that this was a confounding individuals treated with chemotherapy and/or radiotherapy
effect is therefore removed. The mutation rates calculated for cancer [B18] nor the offspring of women treated with
from these results suggest that Nomuras results actually radiation during infancy for haemangiomas [K6] demon-
underestimated the extent of this phenomenon. Since these strated any significant effects attributable to parental expo-
studies rely on a secondary treatment with a carcinogen, sure to chemicals or radiation [U1]. Furthermore, a number
there seems to be no way to apply their results to revise the of studies involving the children of survivors of the Hiro-
Committees estimates of hereditary risk, which are made shima and Nagasaki atomic bombings have failed to detect
for radiation alone. any transmitted genetic effects of radiation exposure [K14,
N12, N13, S4, S5]. A cohort of 31,150 children born to par-
ents who were within 2kilometres of the hypocentre at the
C. Malformation induction in the offspring time of the bombing was compared with a control cohort of
of irradiated parents 41,066 children. During the childrens early years, congeni-
tal defects, sexual development, physical development and
133. There are several studies addressing the question of survival were all investigated. Later, cytogenetic studies and
malformation induction after irradiation of either female the electrophoretic properties of a series of serum proteins or
[K13, L50, M65, N17, N31, N32, N34, W22, W23] or male erythrocytic enzymes were analysed, in addition to a com-
[K12, K36, M64, N17, N31, N32, N34, R15] mice and plete medical evaluation. None of these indicators was sig-
looking for malformations in the next or subsequent [L50, nificantly modified by parental radiation exposure (reviewed
L51, N33, P7] generations. In all of these studies, condi- in reference [N10]).
tions were found that resulted in transmission of radiation-
induced germ cell effects in the form of malformations to 136. In addition, in a study that examined 50 families
the F1 or subsequent generations. The mechanism for the exposed after the Hiroshima and Nagasaki atomic bombings
development of these malformations is apparently differ- with 64 children, and 50 control families with 60 children
ent under these conditions from that which is responsible [K14], minisatellite analyses revealed no genetic effects at
for the development of malformations induced by radiation six human tandem repeat. This study was later expanded to
exposures during major organogenesis [S34]. The following include analysis of mutations at eight hypervariable mini-
conclusions can be drawn from the experiments: compara- satellite loci in the offspring (61 from exposed families,
tively high doses (>1Gy) are required for transgenerational in 60 of which only one parent was exposed, and 58 from
malformation effects to be detected. The effects seen after unexposed parents) of atomic bombing survivors with mean
female exposure are not due to indirect effects because of doses of >1Sv. They found 44 mutations in paternal alleles
radiation sickness of the mother, but must have, at least and 8 mutations in maternal alleles, with no indication
partly, a genetic background [L50, W22, W23]. This genetic that the high doses of acutely applied radiation had caused
background is quite obvious after radiation exposure of male significant genetic effects [K28].
mice. These transgenerational effects are not restricted to
low-LET radiation [K36]. It seems unlikely that there is a 137. In contrast to these observations, Dubrova et al. [D11]
direct relationship between chromosomal translocations and described elevated mutation rates in DNA tandem repeat
congenital anomalies [L50, N34], although some suspicion sequences in humans living in rural areas of the Mogilev
in that direction has been expressed [R15]. The basis of the district of Belarus, which was heavily contaminated with
malformations observed seems to be heterogeneous: some radionuclides from the Chernobyl reactor accident. The fre-
are due to genetic changes of high penetrance that are rap- quency of mutation was assayed both by DNA fingerprint-
idly eliminated; some are due to modification of genes of ing using one multilocus probe and by single-locus analysis
low penetrance; and some are probably of non-genetic origin using four probes, and this revealed mutation rates approxi-
[L50]. There are strain-specific differences as to the extent of mately twofold higher in the offspring of exposed parents
the transgenerational effect [R15]. There are indications that when compared with an unexposed population from the
a major proportion of mutations are eliminated in the first United Kingdom. These initial observations were expanded
generation and that only a minor proportion are transmitted to include analysis of families from rural areas in the Kiev
to later generations [L50]. and Zhytomir regions of Ukraine, which were heavily con-
taminated by radionuclides after the Chernobyl accident.
134. At present there are too many uncertainties about those A statistically significant 1.6-fold increase in mutation rate
data suggesting that dominant mutations and/or genomic was found in the germ line of exposed fathers, whereas the
instability cause tumours in progeny of irradiated mice to be maternal germ line mutation rate in the exposed families
able to apply such data in hereditary risk estimation. was not elevated [D9].
138. The initial report by Dubrova et al. [D11] generated

D. Human studies commentary centred largely on the selection of a non-exposed
population from the United Kingdom for comparison with
135. To date, no radiation-induced genetic, i.e. heredi- exposed parents from Belarus [S4], the failure to exclude
tary, diseases have been demonstrated in human popula- other contaminants such as pollutants and viral infections
tions exposed to ionizing radiation. Neither the offspring of [N11], and questions regarding the biological significance of
increased mutations in hypervariable tandem repeat alleles rate is not caused by DNA damage directly, it might well result
[N10]. These criticisms initially appeared to detract from the from non-targeted events associated with radiation-induced
significance of the findings of Dubrova et al. However, in a genomic instability [D13, D16, F2, N14, S1].
subsequent report, Dubrova et al. [D12] recruited more fami-
lies from the affected region and used five additional mini 142. The reasons for the discrepancy between the data
satellite probes, and once again their data indicated a twofold collected from the children of survivors of the Hiroshima
higher mutation rate in exposed families than in non-irradiated and Nagasaki bombings and the induction of human germ
families from the United Kingdom. They also used individual line mutation in the majority of studies involving the off-
radiation doses for external and internal chronic exposure to spring of parents living in radiation-contaminated environ-
137
Cs as an indicator of long-term population exposure and ments are not easily reconciled. The types of radiation to
found a significant positive correlation between radiation dose which individuals were exposed differed between the two
and mutation rate over multiple loci with the exposed families. populations, and there are uncertainties associated with the
Significantly, there were no obvious differences in the muta- doses. The bombings resulted in a single acute exposure
tion spectrum observed between the exposed and the con- to predominantly gamma radiation and a small amount of
trol families. In subsequent studies, children born to parents neutron radiation, whereas contamination from Chernobyl
who participated in recovery operations after the Chernobyl resulted in chronic exposures to internalized 131I. However,
accident also showed an elevated mutation rate at some loci this is unlikely to be the only reason for the discrepancy,
[L18, W5], as did children born to parents living around the because there are also negative results for the children of
Semipalatinsk nuclear test site in Kazakhstan [D8]. recovery operations workers exposed to low-dose-rate
external/internal exposures [F15, S55].
139. It should be stressed that the analysis of tandem
repeat loci mutation rate demands sophisticated molecular 143. The controversy surrounding the induction of muta-
biology, and it is important that observed mutants be vali- tions in tandem repeat sequences is far from resolved. May
dated. Jeffreys and Dubrova [J3] suggested that technical etal. [M5] examined the mutation frequency at hypervariable
artefacts might explain the sevenfold increase in mutation tandem repeats in sperm from three seminoma patients
rate in children of Chernobyl recovery operations work- following hemipelvic radiotherapy. Scattered radiation
ers described by Weinberg et al. [W5]. Questions of valid doses to the testicles were monitored, and the mutation rates
paternity, sample mix-up, variation between DNA samples in pre-treatment sperm DNA were compared with sperm
and the demands of the required technology are all potential derived from irradiated meiotic and post-meiotic cells. No
sources of variability and could explain differences in results evidence for radiation-induced germ line mutation at these
between different investigators. hypervariable loci was observed even though the patients
were monitored for a period of 1 to 11months.
140. Nevertheless, other studies have failed to reproduce
these positive findings [F15, L17, S55]. A way of reconcil- 144. Of all the reported studies, it is only those of the popu-
ing these apparently contradictory results was offered by lations living in the Semipalatinsk region of Kazakhstan that
Livshits et al. [L17]. They measured the frequency of inher- permit comment on the potential transgenerational effects
ited mutant alleles at seven hypermutable minisatellite loci (i.e. F2+ generations). In one such study, the F2 offspring of
in 183 children born to Chernobyl recovery operations work- those parents that received the highest external and internal
ers and in 163 children born to control families living in non- doses did not show any elevation of minisatellite mutation
irradiated areas of Ukraine. No significant difference in the frequency [D8].
frequency of inherited mutant alleles was found between the
exposed and the control groups. The exposed group was then 145. These and related studies have been summarized
divided into two subgroups according to the time at which in table2 and have recently been subject to critical review
the children were conceived in relation to the fathers work [B41]. To summarize the conclusions of Bouffler and the
at the power plant. Eighty-eight children were conceived expert review panel [B41]: only limited data are available
either while their fathers were employed at the facility or up indicating that germ line mutation of minisatellites can be
to 2months later (subgroup 1). The other 95children were detected in irradiated human populations. The data are incon-
conceived at least 4months after their fathers had stopped sistent and show only limited evidence of dose dependence,
working at the Chernobyl site (subgroup 2). The frequencies and the panel found that additional work would be necessary
of mutant alleles were higher for the majority of loci in sub- to establish the radiation responsiveness of these loci. Fur-
group 1 than in subgroup 2, suggesting that the timing of irra- thermore, the data on mutation of human tandemly repeated
diation during spermatogenesis had affected its mutagenic DNA loci do not warrant a dramatic revision of germ line or
potential. cancer risk estimates for radiation at present [B41].
141. Given the frequency of mutations in these hypervariable

alleles and the lack of evidence for significant differences in E. Cancer incidence in the offspring of irradiated humans
the mutation spectrum between control and exposed families
[D12], it is unlikely that the minisatellite loci themselves are 146. The risk of cancer in the offspring of humans irra-
the direct targets of the radiation. If the increased mutation diated prior to conception is also controversial. No excess
cancer incidence has been reported in children born to par- lack statistical power; this is probably due to the low doses
ents exposed to ionizing radiation by the atomic bombings in to which the populations were exposed and to the small
Japan [Y1, Y2] or in the offspring of cancer patients treated population sample size.
with radiotherapy [H4].
150. The Scientific Committee takes note of these conclu-
147. A major event early in this controversy was the con- sions by COMARE, which support its own view that the types
clusion by Gardner et al. [G2] from a case-control study that of genetic data discussed in this annex imply no modification
the increased incidence of leukaemia and non-Hodgkins of its own estimates of hereditary risk. It has been the Scien-
lymphoma among children living near the nuclear reprocess- tific Committees position that the mutation rates in experi-
ing plant in Sellafield in the United Kingdom was associated mental organisms upon which it has based its estimates of
with paternal employment and the recorded external dose of hereditary risk are sufficiently low as to make it unlikely that
whole-body radiation during work at the plant before con- analyses of the radiation-exposed human populations avail-
ception. This conclusion was controversial [D6] and was not able for study would show statistically significant increases
supported by the excess of childhood leukaemia observed at in hereditary diseases.
nearby Seascale [P4], or by an extensive study of radiation
workers and childhood cancers [D7]. Nevertheless, Dickin-
son and Parker [D4] published results of a cohort study that G. Genetic damage and malformation induction
supports the initial association with paternal radiation dose, in the offspring of irradiated parents
which suggests that it still remains a possible explanation
[B15], although population mixing [G17] is regarded as a 151. The densely populated costal regions of Kerala state
potentially important factor in this particular cluster. in southwest India have deposits of radioactive monazite-
bearing sand and provide a unique opportunity to investigate
148. The United Kingdom Committee on Medical the effects of high levels of natural radiation on human popu-
Aspects of Radiation in the Environment (COMARE), in lations [N35]. The background radiation levels range from
their seventh report, reviewed the evidence concerning 1.0mGy to >35.0mGy per year owing to naturally occur-
the incidence of childhood leukaemia and other cancers in ring thorium and its decay products. There is a comprehen-
the offspring of parents occupationally exposed to radia- sive programme to assess the biological and health effects
tion prior to conception [C17]. The COMARE agreed that, of this radiation exposure in humans, focusing mainly on
while a link between parental exposure and such effects constitutional chromosome abnormalities and the incidence
in the offspring was possible in principle, the epidemio- of congenital malformations in newborns. To date, the data
logical evidence from the offspring of radiation workers in do not reveal any effect on cytogenetic aberrations in lym-
the United Kingdom, the United States and Germany failed phocytes [C24] or the incidence of congenital malformations
to support an increased rate of solid tumours in children. in newborns [J11] that can be associated with exposure to
Furthermore, COMARE concluded that the balance of evi- ionizing radiation.
dence indicated that the likelihood of developing childhood
leukaemia or non-Hodgkins lymphoma was not related to
radiation dose. H. Impact of non-targeted and delayed effects
of radiation on future generations
F. Pregnancy outcomes in the offspring 152. Heritable effects are observed in first-generation off-
of irradiated humans spring and/or in later generations after one or both parents
have been irradiated prior to conception. Since it was estab-
149. In their eighth report, COMARE reviewed pregnancy lished, the Committee has made estimates of the genetic
outcomes following pre-conception exposure to ionizing effects of radiation in humans in offspring of irradiated
radiation in humans [C18]. They found that the available parents based upon clear demonstrations that mutations can
epidemiological data were inadequate to allow definitive be induced in experimental organisms, including experimen-
statements about the effect of pre-conception radiation expo- tal mammals. The UNSCEAR 2001 Report on the hereditary
sure on pregnancy outcomes. This was due to difficulties in effects of radiation emphasized that no radiation-induced
obtaining reliable figures for the end points of concern and genetic (i.e. hereditary) diseases have so far been demon-
to the possibility that the radiation exposures in most studies strated in human populations exposed to ionizing radia-
may have been too low to produce a detectable effect. The tion [U1]. No demonstrable adverse reproductive outcomes
conclusion reached by COMARE was that, from all the epi- were described for the survivors of the atomic bombings in
demiological data examined, there was little evidence that Japan, or for women irradiated during infancy for skin hae-
adverse reproductive outcomes in general are related to mangiomas. No demonstrable hereditary effects of radiation
parental radiation exposure. Similarly, the limited data avail- exposure resulting from the Chernobyl accident have been
able did not link miscarriage or neonatal death with parental described [U2]. Likewise, no increase in cytogenetic abnor-
irradiation. COMARE did point out, however, that almost malities [W19] or genetic effects [B39] has been reported in
all of the published studies on pregnancy outcome follow- survivors of childhood cancer exposed to ionizing radiation
ing parental exposure to radiation in human populations before reproduction.
153. Ionizing radiation is considered a universal mutagen. the types of mutation considered below might (1) be used to
Experimental studies in plants and animals have demon improve the Committees estimates of hereditary risk, and
strated that radiation can induce hereditary effects, and (2) indicate some type of genetic instability that could lead
humans are unlikely to be an exception in this regard. It was to modification of risk through subsequent generations.
for this reason that the Committee estimated hereditary risk
in humans in the absence of direct evidence in humans. This 154. Overall it is clear that irradiation of the parent can lead
annex presents a re-evaluation of some of the controversial to some changes in the offspring, but it is likely that most of
data, in view of newer findings, and also a review of some these are due to the manifestation of direct damage caused by
types of damage not considered in earlier UNSCEAR reports. radiation in the original germ cell. The high incidence of off-
Two assumptions are commonly made in the estimation of spring with mutations in ESTRs and the detection of muta-
genetic risk: (1) that the seven specific loci in the mouse tions in maternal alleles after paternal irradiation suggest that
constitute a suitable basis for extrapolation to genetic dis- non-targeted instability may be induced in specific circum-
ease in humans; and (2) that heritable mutations are induced stances. There is only very limited evidence that instability
by radiation damage (energy-loss events leading to double- is transmitted across into the F2 generation, and human data
strand damage) occurring within the genome and are induced are negative. Therefore the Committee considers that these
linearly with dose, at least at low doses. The issues of main data are insufficient to justify modification of current risk
importance in this section are whether the information on estimates for hereditary effects or cancer in humans.
VII. IMPLICATIONS OF NON-TARGETED AND DELAYED EFFECTS
155. A wealth of information has been reviewed that deals effects are essentially encompassed in current radiation risk
with possible radiation-induced non-targeted and delayed estimates for carcinogenesis.
genetic effects, as well as genetic end points that can occur
spontaneously. Most of the estimates of hereditary risk made 157. Radiation-induced instability and the existence of
by the Committee in the past have been based on classical bystander effects are well established and incontrovertible. A
mutation experiments. Such studies often require exceedingly common observation of these responses is that they dominate
large samples of offspring. For the reasons described above, at low doses and saturate with increasing dose (reviewed in
it does not appear that the new findings necessitate changes in references [P13, S18]). In addition to damage directly induced
the Committees estimates of hereditary risk. It is possible that by the deposition of energy in the nucleus of the irradiated
certain types of genetic damage detected by some of the assays cell, consideration must now be given to these indirect effects
have no relationship to clinically important phenotypes. It is of radiation. An irradiated cell can send out a signal and induce
also possible that the methods of hereditary risk estimation a response in a cell whose nucleus was not hit by radiation.
used by the Committee in the past adequately incorporate any This might result in genetic damage, genomic instability or
genetic risks of clinical relevance that might be associated lethality in non-irradiated cells. These non-targeted effects in
with the damage detected by the various assays considered. essence amplify the biological effectiveness of a given radi-
While it is clear that some of the assays permit demonstration ation dose by increasing the number of cells that experience
of effects of radiation using much smaller sample sizes than effects over those directly exposed to the radiation.
more classical methods, uncertainty remains as to whether
these effects correlate with the rare types of mutation that 158. Understanding of these non-targeted effects is still in its
cause clinically serious conditions. There is no convincing infancy, and much of the data to date have been obtained from
evidence of transgenerational instability in humans caused in vitro studies. While the significance of these indirect effects
by radiation that would lead to the propagation of clinically for human health remains to be elucidated, it would seem
important effects over succeeding generations. Because the prudent to consider the implications of non-targeted delayed
Committees current risk estimates already assume transmis- effects of radiation exposure when considering models of
sion of many of the effects found in the first generation to radiation carcinogenesis, particularly at low doses.
later generations, rare instances of such propagation would
have little impact on total risk estimates. 159. In vivo non-targeted effects are not new and have pre-
viously been implicated in radiation-induced carcinogenesis
156. The relevance of non-targeted and delayed effects [S22]. The recent revival of interest in these non-targeted
to the development of cancer and hereditary effects is not effects and the subsequent influx of new data suggest that it is
yet clear. Carcinogenesis involves a progression of genetic time to re-examine the concepts of radiation dose and target
events that are associated with specific stages of the malig- size. Many of the indirect effects described indicate that the
nant process. It is tempting to speculate that induced tissue volume in which detrimental effects of radiation may
genomic instability can drive the progression of genetic be observed is larger than the precise volume irradiated. This
changes and thus provide the impetus for acquiring those issue may have important implications for human health. Life
genomic alterations associated with carcinogenesis. Yet exists in a radiation environment, the use of radiation has
this must be tempered by the high frequency with which become an integral part of modern life, and the applications of
instability is observed both in vitro and in vivo, and the radiation in medicine and industry bring tremendous benefits
observation that instability generally tends to saturate at to society. Over time, biological systems have demonstrated a
low doses of radiation. Nevertheless, if radiation exposure remarkable ability to adapt to environments to which they are
induces a transgenerational instability that could be passed gradually exposed, and low doses of radiation are no excep-
through the germ line and increase a childs susceptibility tion. Higher doses of radiation can cause neoplasia. This pre-
to cancer or genetic effects, this would have health rami- sumably occurs through a combination of direct damage and
fications. Bystander effects could also have significant non-targeted effects, and models of radiation-induced car-
implications for human exposures, particularly to very cinogenesis should incorporate both direct and indirect effects
low fluences of high-LET radiation, e.g. to radon, where when evaluating radiation risks. Ultimately, understanding
only a small fraction of the cell population would be hit, the multitude of multicellular responses to radiation may pro-
i.e. subject to energy deposition events. However, bystander vide a framework for evaluating health risks associated with
effects appear to be limited to the irradiated organ, and radiation exposure and a logical means of intervening in the
since risk estimates are to an organ and not a cell, bystander development of suspected radiation-induced cancers.
55
CONCLUDING REMARKS
160. This annex has reviewed a multitude of studies on non- determined directly. Such effects can provide mechanistic
targeted and delayed effects of exposure to ionizing radia- information at doses of below ~200mGy that could be per-
tion. In addition to damage directly induced by the deposition tinent to evaluating health effects at these low doses. How-
of energy in the nucleus of an irradiated cell, consideration ever, in ascribing a mechanism to a particular biological
should now be given to these indirect effects of radiation. An effect, the data in question should be independently repli-
irradiated cell can send out signals and induce a response in a cated and show a strong coherence with the particular end
cell whose nucleus was not subject to energy deposition events point considered. The UNSCEAR 2000 Report considered
following irradiation. These non-targeted effects in essence the conventional view that the deposition of energy in the
amplify the biological effectiveness of a given radiation nucleus and the subsequent cellular processing of induced
dose by increasing the number of cells that experience effects DNA damage were consistent with the observed cancer/
over those directly exposed to the radiation. heritable effects induced by ionizing radiation.
161. In spite of the large body of new information avail- 164. In light of these considerations, the overall view of
able, considerable disagreement remains concerning any the Committee is that the data currently available do not
definitive relationship between these non-targeted effects require changes in radiation risk coefficients for cancer
and the observed health effects attributable to radiation. and hereditary effects of radiation in humans. The Com-
mittee will maintain surveillance of developments in the
162. The Committee stresses that direct epidemiologi- area of non-targeted and delayed effects, and recommends
cal observations and associated quantification of the health that future research pay particular attention to study design
effects of radiation incorporate all mechanistic elements, emphasizing replication, low-dose responses and associa-
including the targeted (direct) effects of irradiation as well as tions with health effects particularly in the human popula-
the non-targeted and delayed effects described in this report. tion. Ultimately, understanding the range and multitude of
multicellular responses to radiation will provide mechanis-
163. A specific role for non-targeted effects in the observed tic insights into how radiation induces its observed health
health effects associated with radiation exposure cannot be effects.
57
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ANNEX D
Effects of ionizing radiation on the immune system
Contents
Page
INTRODUCTION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
I. GENERAL FEATURES OF THE IMMUNE SYSTEM. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87

A. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
B. Organs and tissues of the immune system. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
1. Central lymphoid organs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
2. Peripheral lymphoid tissues. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
3. Remarks concerning organs and tissues of the immune system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
C. Cells and molecules of the immune system. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
1. Innate immunity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
2. Acquired immunity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
3. Human major histocompatibility complex. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
4. Antigen-presenting cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
5. Self tolerance and self-HLA-associated recognition. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
6. Cytokines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
7. Remarks concerning cells and molecules of the immune system. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
D. Physiological immunosenescence. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
1. Concept of immunosenescence. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
2. Main features of immunosenescence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
3. Remarks concerning immunosenescence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
E. Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
II. RADIATION-INDUCED ALTERATIONS OF THE IMMUNE SYSTEM. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109

A. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
B. Data concerning low-dose irradiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
1. Animal data. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
2. Human data. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
3. Remarks concerning low-dose/low-dose-rate irradiation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
C. Data concerning high-dose irradiation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
1. High-dose-induced immunosuppression. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
2. Immune reconstitution. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
3. Remarks concerning high-dose irradiation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
D. Influence of dose rate and radiation quality on immune response. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
1. Low-LET exposures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
2. High-LET exposures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
3. Remarks concerning the influence of dose rate and radiation quality. . . . . . . . . . . . . . . . . . . . . . . . . . . 121
E. Radiosensitivity of lymphocyte subsets. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
1. General considerations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
2. Review of published data. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
81
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3. Remarks concerning the radiosensitivity of lymphocyte subsets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
F. Alterations of the immune response after prenatal irradiation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
1. Animal data. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
2. Human data. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
3. Remarks concerning the effects of prenatal irradiation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
G. Immune dysfunction and hypersensitivity to ionizing radiation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
1. Human genetic disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
2. Autoimmune diseases and radiation response. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
3. Ionizing radiation and acquired immune deficiency syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
4. Remarks concerning human pathologies with immune dysfunction and hypersensitivity
to ionizing radiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
H. Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
III. possible MECHANISMS INVOLVED AND IMPLICATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133

A. Lymphocyte apoptosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
2. Remarks concerning lymphocyte apoptosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
B. TCR mutations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
2. Remarks concerning TCR mutations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
C. Modification of Th1/Th2 balance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
2. Remarks concerning modification of Th1/Th2 balance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
D. Bystander effects and genomic instability. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
2. Remarks concerning bystander effects and genomic instability. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
E. Shift towards an inflammatory profile. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
2. Remarks concerning the shift towards an inflammatory profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
F. Acceleration of immunological ageing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
2. Remarks concerning the acceleration of immunological ageing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
G. Modification of antigen presentation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
2. Remarks concerning modification of antigen presentation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
H. Autoimmune reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
2. Remarks concerning autoimmune reactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
I. Perturbation of immunological homeostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
2. Remarks concerning perturbation of immunological homeostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
J. Other possible mechanisms involved. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
2. Remarks concerning other possible mechanisms involved. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
K. Immune mechanisms and cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
2. Immune surveillance theory. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
3. Immune response against tumours . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
4. Immunologic promotion of tumours. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
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5. Remarks concerning immune mechanisms and cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
L. Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
IV. EPIDEMIOLOGICAL STUDIES. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151

A. Atomic bombing survivors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
2. Short-term effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
3. Long-term effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
4. Remarks concerning data on survivors of the atomic bombings. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
B. Chernobyl workers and residents. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
2. Emergency and clean-up workers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
3. Residents of contaminated areas. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
4. Radioiodine contamination, immune status and thyroid diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
5. Remarks concerning data on Chernobyl workers and residents. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
C. Techa River study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
2. Epidemiological data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
3. Remarks on the Techa River study. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
D. Hanford nuclear site . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
2. Hanford Thyroid Disease Study. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
3. Remarks concerning the Hanford nuclear site . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
E. Patients undergoing radiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
3. Remarks concerning data on patients undergoing radiotherapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
F. Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
V. Final summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
VI. CONCLUding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
Abbreviations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
83
INTRODUCTION
1. DNA lesions and defective DNA repair are usually U7, U8, U9]. A large number of new papers and technological
considered to be the key mechanisms that explain the bio- developments since then have fostered progress in under-
logical effects of ionizing radiation. Recently, radiation- standing the basic concepts concerning mechanisms under-
induced non-targeted effects, e.g. genomic instability or the lying the effects of ionizing radiation on the immune system.
bystander effect, have been described; they may represent In addition, there exists today a considerable amount of new
other critical mechanisms in the initiation and development data related to impaired immunological functions and the
of late radiation-induced effects at the cellular or tissue level. risk of diseases or mortality from causes other than cancer.
Acute effects of whole-body irradiation may manifest as
multiple organ failures (involving essentially the haemato 3. The scope of this annex includes reviews of:
poietic, digestive and central nervous systems as well as the
R adiation-induced alterations of the immune
skin). In this context, alterations of the immune system by
response, including immunosuppression (depres-
ionizing radiation represent a field that has not recently been
sion) or immunostimulation (activation);
thoroughly assessed.
Possible mechanisms by which the immune system
2. The effects of ionizing radiation upon immune system is altered following exposure to ionizing radiation;
function were first reviewed in detail by the Committee in Epidemiological assessments of immune system
1972 [U10]. Aspects of the subject were discussed in further alterations in various diseases, with emphasis on the
UNSCEAR reports, as summarized in table1 [U2, U4, U6, effects of ionizing radiation.
Table 1 Aspects covered by UNSCEAR documents concerning the effects of ionizing radiation upon immune system function
Content Reference
Volume II, annex F (Effects of radiation on the immune system): the general components of the immune response, effects of radiation on [U10]
susceptibility to infection, effects of radiation on antibody formation, effects of radiation on cellular immune reactions, radiation and immunological
tolerance, immunological aspects of radiation-induced carcinogenesis, effects of variation of condition of irradiation on immunological responses
Radiocarcinogenesis and the immune system. Effects of prenatal irradiation on the haematopoietic and immune systems [U9]
Effects of ionizing radiation on the haematopoietic and immune systems [U8]
Radiation-induced cancer: impairment of immunological surveillance [U7]
Haematological and immunological effects of ionizing radiation [U6]
Annex B, part III: Effects of ionizing radiation on the immune system in the context of adaptive response [U4]
Radiosensitivity and defective recombination in the immune system; immunological effects of exposure to radiation from the Chernobyl accident [U2]
85
I. GENERAL FEATURES OF THE IMMUNE SYSTEM
A. Introduction located in areas that come into close contact with foreign
substances. In these locations, they are perfectly positioned
4. The immune system consists of cells and tissues spread to recognize those substances as non-self or foreign. Upon
widely throughout the body that protect against infections such recognition, immune cells are activated and function to
and cancer. Following the recognition of foreign or novel neutralize or destroy the invading foreign substance.
antigens, which are present in an immense variety of organ-
isms or neoplastic cells, this system executes a complex 6. Immunophenotyping with combinations of antibodies
response in order to give protection. Organs or tissues trans- to various cell surface and cytoplasmic proteins allows the
planted from other individuals are also recognized by the identification of specific cell types, determination of the
immune system as foreign agents. Immune recognition of degree of cell differentiation and recognition of abnormal
these antigens generally leads to their elimination through cells. Most of these antibodies are against surface glyco
the destruction and removal of the foreign cells. proteins, which are often not only associated with particular
cell lineages but also vary in expression with maturation, and
5. The immune response is mediated by a number of dif- are thus referred to as differentiation antigens. These anti-
ferent cells and molecules. The majority of these cells are gens have been grouped together in clusters of differentiation
white blood cells (leucocytes) produced in the bone mar- (CD), numbered in the order in which they were identified.
row as precursors. Some develop into mature cells within Therefore, by incubating cell suspensions with monoclonal
the bone marrow, and others are transported by the blood to antibodies that bind selectively to these cell membrane com-
other tissues where they develop and mature further. Many ponents, it is possible to identify the phenotype of differ-
molecules of the immune system are soluble or cell sur- ent subsets of immune cells and determine their relative and
face proteins. The immunocompetent cells are strategically absolute abundance (see table2).
Table 2 List of CD antigens cited in the text

Adapted from reference [J1]
CD Cell populationa Functionb Molecular family
CD1 Dendritic cells, Langerhans cells, B-cells, thymocytes Antigen presentation (glycoplipids) Immunoglobulin
a, b, c, d, e
CD2 Thymocytes, NK cells, T-cells Adhesion molecules; binding to CD58 and Lck activating Immunoglobulin
T-cells
CD3 T-cells, thymocytes TCR-associated Immunoglobulin
CD4 Subpopulation of thymocytes, Th1 cells, Th2 cells, Co-receptor of TCR for class II MHC; Immunoglobulin
monocytes, macrophages receptor of HIV-1/2 gp120; fixation of Lck (src-family tyro-
sine kinase) to the inner surface of the cell membrane
CD5 Thymocytes, mature T-cells and B-cells Positive or negative modulation of TCR signalling Receptor
CD8 Subpopulation of thymocytes, cytotoxic cells Co-receptor of TCR for class I MHC; Immunoglobulin
binding to Lck on the inner surface of the cell membrane
CD11b NK cells and myeloid cells Binding with CD54, iC3b components and M subunit of -integrins
integrins
CD14 Monocytes, macrophages, weakly expressed in Receptor for the complex of LPS and LPB Receptor
neutrophils and myeloid dendritic cells
CD16 Neutrophils, NK cells, macrophages Low-affinity FcR component (FcRIII); mediator of phago -integrins
cytosis and cytotoxicity
CD19 B-cells Formation of complexes with CD21 and CD81; B-cell -integrins
co-receptor
87
CD Cell populationa Functionb Molecular family
CD20 B-cells Ca2+ channel formation; possible role in B-cell activation Possesses four transmem-
brane segments
CD23 Mature B-cells, activated macrophages, eosinophils, Receptor with low affinity for IgE Lectin-C-like
megakaryocytes, dendritic cells
CD25 Activated T-cells, B-cells, monocytes Subunit of the human interleukin-2 receptor -chain type I glycoprotein
containing two complement
control protein domains
CD27 Medullar thymocytes, T-cells, NK cells and certain Co-stimulator of T- and B-cells TNF receptor
B-cells
CD28 T-cell subpopulations, activated B-cells Naive T-cell activation; co-stimulatory pathway involving Immunoglobulin and CD86
CD80 and CD86
CD38 Activated T- and B-cells Multifunctional enzyme (NAD glycohydrolase, ADP-ribosyl Type II glycoprotein
cyclase, cyclic ADP ribose hydrolase); regulation of T- and
B-cell activation; also functions in cell adhesion, signal
transduction and calcium signalling
CD40 B-cells, macrophages, dendritic cells, basal cells, Co-stimulator of B-cells; cytokine production by macro- TNF receptor
epithelial cells phages and dendritic cells
CD43 Leucocytes (except resting B-cells) Anti-adhesive Mucine
CD44 Leucocytes, erythrocytes Link with hyaluronic acid; adhesion receptor Adhesion molecule
CD45 All haematopoietic cells Tyrosine phosphatase Fibronectin type III
CD45RO T- and B-cell subpopulations, monocytes, Isoforms of CD45 without A, B and C exons Fibronectin type II
macrophages
CD45RA Naive T-cells, monocytes Isoforms of CD45 with the A exon Fibronectin type II
CD48 All leucocytes except neutrophils Involved in lymphocyte activation through the interaction Adhesion molecule
with its receptor (CD2)
CD56 NK cells Isoform of NCAM molecules Immunoglobulin
CD69 Activated B- and T-cells, activated macrophages and Antigen of early activation Lectin C
NK cells
CD80 (B7.1) B-cell subpopulation Co-stimulator; ligand for CD28 and CTLA-4 Immunoglobulin
CD86 (B7.2) Monocytes, activated B-cells, dendritic cells Ligand for CD28 and CTLA-4 Immunoglobulin
CD95 Broadly expressed in different cell lines Binding with FasL (TNF-like), TNF receptor
apoptosis induction
CD117 (cKit) Haematopoietic progenitor cells Stem cell factor receptor Immunoglobulin, tyrosine
kinase
CD119 B-cells, monocytes, macrophages, endothelium Interferon- receptor Fibronectin type III
CD120 Broadly expressed TNF receptor TNF receptor
CD121 T-cells, thymocytes, B-cells, macrophages, monocytes IL-1 and IL-1 receptor Immunoglobulin
CD124 T-cells, B-cells, haematopoietic precursors IL-4 receptor Cytokine receptor,

fibronectin type III
CD125 Activated B-cells, eosinophils, basophils IL-5 receptor Cytokine receptor,

fibronectin type III
CD127 Monocytes, pro-B-cells, IL-7 receptor Fibronectin type III

T-cells, lymphoid precursors
CD130 Broadly expressed Common subunit shared with IL-6, IL-11 and leukaemia Immunoglobulin, cytokine
inhibitor factor receptor, fibronectin type III
CD132 B-cells, T-cells, NK cells, mastocytes, neutrophils -chain of the IL-2 receptor; common subunit shared with Cytokine receptor
IL-4, IL-7, IL-9 and IL-15
a NK = natural killer.
b TCR = T-cell receptor; MHC = major histocompatibility complex; HIV = human
immunodeficiency virus; LPS = lipopolysaccharide; LPB = LPS-binding protein;
TNF = tumour necrosis factor.
ANNEX D: EFFECTS OF IONIZING RADIATION ON THE IMMUNE SYSTEM 89
B. Organs and tissues of the immune system cells induce additional haematopoietic activity, resulting
in the rapid expansion of the white blood cells that par-
7. Like red blood cells (erythrocytes) and platelets (throm- ticipate in fighting infection. After a period of maturation
bocytes), the cells of the immune system arise in the bone and expansion within the bone marrow, more differentiated
marrow from pluripotent stem cells by a process called cells enter the bloodstream and are distributed throughout
haematopoiesis. Myeloid precursors develop into a group of the body in different tissues. B-lymphocytes develop and
white blood cells known as phagocytes. Phagocytes include mature in the bone marrow before entering the bloodstream,
monocytes, macrophages and neutrophils. Other myeloid in contrast to T-lymphocytes, which leave the bone marrow
descendants become granule-containing inflammatory as T-cell precursors and complete further m aturation in the
cells such as eosinophils, basophils and mast cells. Lym- thymus [A25].
phoid precursors develop into the small white blood cells
called lymphocytes. The two major classes of lymphocytes 10. The thymus is an organ located anterior in the upper
are B-cells and T-cells. Cells and molecules of the immune mediastinum. Immature T-lymphocytes migrate from the
system are discussed in detail in sectionI.C. bone marrow into the thymus, where they become mature
immunocompetent T-cells. A minority of lymphocytes
8. The bone marrow and thymus are termed the primary become mature T-lymphocytes by extrathymic maturation
(or central) lymphoid tissues, because mature lymphocytes processes. After thymic involution (see below), this path-
are produced within these organs. Mature lymphocytes way of extrathymic lymphocyte maturation becomes more
then enter the blood and travel to the secondary (or periph- relevant [B32]. Thymus cells are called thymocytes and are
eral) lymphoid tissues such as lymph nodes, spleen and predominantly immature T-cells at various stages of develop-
mucosa-associated lymphoid tissue. A notable feature of ment. There are also scattered epithelial cells, macrophages
lymphocytes is that they can cross from the blood into and dendritic cells [A25]. The thymus is very large in the
the lymphatic circulation and then return, a phenom- first years of life, reaches maximum size at puberty and then
enon referred to as lymphocyte traffic or recirculation. becomes smaller in a process called involution. During this
The direct migration of lymphocytes to specific tissues is degenerative process, connective tissue, fibres and fat cells
called homing. replace the previously functional tissue. Although only a few
pieces of functional tissue remain, they suffice to continue to
supply the organism with enough mature lymphocytes. Cer-
1. Central lymphoid organs vical lymphoid organs with thymic structure and function
have recently been found in BALB/c and C57BL/6 mouse
9. All cells of the immune system originate from just one strains. Although cervical thymus tissue has been observed
cell type, called a haematopoietic stem cell, in the bone in other species, the presence of cervical thymus tissue in
marrow of adults (for prenatal life, see section II.F below). humans is considered rare after birth [T18].
Pluripotent stem cells multiply to produce more pluri
potent stem cells (self-renewal), thus ensuring the steady 11. The main functions of the thymus include:
and lasting supply of stem cells. Homeostatic regulation
Production of immunocompetent T-lymphocytes;
stabilizes the number of pluripotent stem cells. Some of the
pluripotent stem cells differentiate to become committed to P
roduction of mature T-cells for peripheral tissues
one of two blood cell lineages: lymphoid or myeloid. Then and circulation;
lymphoid and myeloid stem cells become progenitor cells
R
egulation of T-cell maturation, proliferation and
for each type of mature blood cell. These cells have lost
function;
the capacity for self-renewal and are committed to a given
cell lineage: T- and B-cell progenitors, and progenitor cells I mmunological self tolerance via positive and
for granulocytes, monocytes, eosinophils, basophils, mast negative selection.
cells, platelets and erythrocytes. Dendritic cells belong to
the myeloid cell lineage, and it is likely that monocytes
and dendritic cells arose from a common myeloid precur- 2. Peripheral lymphoid tissues
sor. Progenitor commitment depends upon the acquisi-
tion of responsiveness to different growth factors such as 12. After maturing in the thymus, T-cells move through
colony-stimulating factors (CSFs), erythropoietin (EPO) the circulation to other organs. Lymph nodes are small,
and interleukins (ILs). The particular microenvironment bean-shaped structures that are spread throughout the body
within which the progenitor cell resides controls differ- along the lymphatic routes. They contain specialized com-
entiation. The haematopoietic cells grow and mature on a partments where immune cells congregate and where they
meshwork of stromal cells, which are non-haematopoietic can encounter antigens. Lymph nodes constitute groups in
cells that support the growth and differentiation of the areas where lymphatic vessels come together to form larger
haematopoietic cells (figure I). In the absence of infec- vessels, such as in the groin, neck and axilla. All lymphatic
tion, bone marrow stromal cells are the major source of vessels draining back to the venous circulation from the
haematopoietic cytokines. In the presence of infection, tissues pass through lymph nodes, which filter and purify the
cytokines produced by certain activated immunocompetent drain fluid of the lymphatic vessels (lymph) before it flows
Figure I. Regulation of haematopoiesis in the bone marrow by cytokines that stimulate the proliferation and/or differentiation
of various haematopoietic cells (adapted from reference [G14]).
GM-CSF: Granulocytemacrophage colony-stimulating factor.
Thymocyte
IL-7 IL-7
IL-2, IL-4
TH
T-progenitor
IL-7 IL-4, IL-2

IL-3 IL-5, IL-6
Lymphoid
stem cell B-progenitor TC
IL-3 B-cell
IL-3-like
Dendritic cell
Bone marrow
Self renewal stromal cell
GM-CSF,
CSF
GM-
F
M-CS Monocyte Macrophage
IL-3
GM-
CSF
G-CS IL-8
F
Granulocyte-monocyte
SF
progenitor
-C
GM
6
Neutrophil
3,
IL-
IL-
GM-CSF
IL-3 IL-5
SF
Myeloid GM-C
Eosinophil
stem cell IL- progenitor Eosinophil
GM 3
-CS
F IL-9
IL-
GM
GM
3, I EPO
-CS
-CS
F
L-1
IL-4
F,
Basophil
progenitor
GM-C
Basophil
IL-3
SF, EP
GM-CSF
O
EPO, IL-6
Platelets
Megakaryocyte
EPO
Erythrocyte
Erythroid progenitor
into the venous system [J1]. Several immune functions take residents, others can be recruited or are recirculating cells.
place in the lymph nodes: This concept of the SIS also includes human skin humoral
constituents such as immunoglobulins, cytokines, chemo
P
hagocytosis of microorganisms by fixed
kines, complement, cathelicidins, defensins, dermcidins,
macrophages;
prostaglandins and free radicals [B28, R13].
T-lymphocyte activation;
B
-lymphocyte activation and proliferation (plasma
3. Remarks concerning organs and tissues
cell formation and antibody production);
of the immune system
I nteraction between antigen-presenting cells and
circulating lymphocytes. 17. On the basis of the preceding discussion, some concepts
may be highlighted. The bone marrow and the thymus are
13. The spleen is a soft organ located in the left hypochon- the central lymphoid tissues. All cells of the immune sys-
drium that removes abnormal blood cells through phago- tem originate in the bone marrow from haematopoietic stem
cytosis, collects and disposes of senescent red blood cells, cells. After maturation and expansion, more differentiated
provides storage of iron from recycled red blood cells and immune cells enter the bloodstream to be distributed in the
plays a role in foetal and sometimes adult haematopoiesis. different tissues. Some immature lymphocytes move from
Spleen cells are called splenocytes. It is in the spleen that the the bone marrow to the thymus, where they become immuno
initiation of immune responses by B-cells and T-cells takes competent T-cells. Spread throughout the body, lymph nodes
place in response to antigens circulating in the blood. The are peripheral lymphoid tissues where immune cells congre-
spleen has a red pulp (its colour due to the presence of gate and where these cells can encounter antigens. It is in the
large numbers of erythrocytes in the blood vessels) that is spleen, another peripheral lymphoid organ, that the initiation
characterized by a parenchyma that consists of macrophages of the B- and T-cell immune responses to circulating antigens
and blood cells surrounded by numerous venous sinuses. takes place. MALT consists of connective tissue containing
The white pulp of the spleen is characterized by the lack of lymphocytes. The skin and mucous membranes are the first
these sinuses and consequently the presence of fewer eryth- line of defence against pathogens. Classically they have been
rocytes, and consists of B- and T-lymphocytes located in two described as anatomic barriers of the innate immune system
different areas of the spleen. B-cells are located in the lym- alone; however, around half of human skin cells are involved
phoid follicles scattered throughout the organ. T-cells are in both innate and acquired immunity.
located around the central arteries and form a kind of sheath
(periarteriolar lymphoid sheath) [G27].
C. Cells and molecules of the immune system
14. Mucosa-associated lymphoid tissue (MALT) consists
of connective tissue containing lymphocytes and is located 18. The cells and molecules of the immune system exe-
beneath mucous membranes of the respiratory, gastrointes- cute two different but related forms of immunity: innate and
tinal, urinary and reproductive tracts. MALT has no distinct acquired. While innate immunity is fully functional before
capsule like that of the lymph nodes but does often have a any foreign agent enters the body, acquired immunity is
germinal centre containing actively dividing lymphocytes. activated only after a pathogen has entered the organism.
Waldeyers throat ring (comprising the adenoids and the Acquired immunity mediated by B- and T-lymphocytes
palatine, lingual and pharyngeal tonsils), Peyers patches recognizes pathogens by rearranged high-affinity recep-
of the small intestine, and the appendix are all examples of tors. However, as acquired immunity involves activation and
mucosa-associated lymphoid tissue [J1]. gene expression as well as cell proliferation, it is often not
rapid enough to eradicate microorganisms. Innate immunity
15. The skin is the largest organ in the human body. It pro- provides more rapid defence mechanisms.
tects against injury, infection, heat and cold, and it stores
water, fat and vitamins [C30]. Although classically described
as an anatomic barrier of the innate immune system (see 1. Innate immunity
section I.C.1 below), the skin may also be considered as an
organ of the immune system. The ability of the cutaneous 19. The innate immune system comprises several defen-
barrier to help defend the body against pathogens depends sive barriers:
on both acquired and innate immune responses [B17, B27]. Anatomic barrier: skin and mucous membranes;
P
hysiological barrier: temperature, pH, lysozymes
16. The skin immune system (SIS) has been proposed and circulating factors such as interferon and
as the term for the complex of immune-response-associated complement;
cells present in normal human skin. Approximately half of
human skin cells are directly or indirectly involved in the I nflammatory barrier: cellular and chemical media-
immune response (e.g. keratinocytes, endothelial cells, tors of the inflammatory response (histamine, acute
dendritic cells, T-lymphocytes, monocytes/macrophages, phase proteins, fibrin, kinin);
granulocytes and mast cells). Some of these cells are skin Phagocytic barrier (see below).
20. Phagocytes include granulocytes, peripheral mono- role in the immune response. Among other functions, they
cytes, tissue macrophages and dendritic cells. Phagocytes seek out, ingest and destroy bacteria, viruses, tumour cells
are cells capable of surrounding, engulfing and digesting and other foreign material. They present foreign material to
complete microorganisms by phagocytosis. Some of them the cells of the immune system and in this way regulate the
play an important role in producing molecules involved immune response. The understanding of the role of macro
in the inflammatory response associated with infections. phages has changed since the identification of a particular
They migrate towards the site of infection by margination, family of receptors called pattern recognition receptors
diapedesis and chemotaxis. (PRRs). These PRRs recognize highly conserved antigenic
structures, termed pathogen-associated molecular patterns
21. Granulocytes include three types of cell: neutrophils, (PAMPs), shared by large groups of pathogens. PRRs are
eosinophils and basophils. Neutrophils play an essential secreted (complement, lectins) or expressed at the surface of
role in the bodys innate immune defence and are one of the cells (Toll-like receptors (TLRs)) [B23].
primary mediators of the inflammatory response. They are
highly specialized for their primary function, which is the 23. The TLR family constitutes an important component
phagocytosis and destruction of microorganisms. To defend of the innate immune system. Although most commonly
the host, neutrophils employ a wide range of microbicidal considered to be expressed on immune cells, e.g. phago-
products, such as oxidants, microbicidal peptides and lytic cytes and T-regulatory cells, TLRs are also known to be
enzymes. The generation of microbicidal oxidants by neu- functionally expressed on a variety of other cell types, such
trophils results in a respiratory burst with generation of as airway and gut epithelial cells [A3, A16, C3, G31, J2,
highly reactive oxygen and nitrogen species (ROS/RNS) K40]. Ten members of the TLR family have been identi-
[G13, Q1]. Eosinophils attack parasites and phagocytose fied in humans; each recognizes a small range of conserved
antigenantibody complexes. Basophils secrete anticoagu- pathogen molecules (table 3). The binding of PAMPs to
lant and vasodilatory substances, such as histamines and TLRs induces the production of pro-inflammatory cytokines
serotonin. Even though they possess phagocytic capabil- and the up-regulation of surface co-stimulatory molecules.
ity, their main function is the secretion of substances that Recent studies have identified intracellular signalling path-
mediate hypersensitivity reactions. ways specific for individual TLRs that lead to the release of
cytokine profiles specific for particular PAMPs. The ability
22. Monocytes in peripheral blood are young cells that of individual TLRs to discriminate among different PAMPs
already possess phagocytic capabilities. After migration is an important determinant of the unique gene expression
into tissues, monocytes undergo further differentiation to profiles activated in the host by different invading pathogens
become multifunctional tissue macrophages. Macrophages or environmental danger signals [V6]. Thus TLRs confer a
and dendritic cells present antigens to be recognized by certain degree of specificity to the innate immune response.
lymphocytes, and are thus called antigen-presenting cells Moreover, TRL-mediated recognition represents a cross-
(APCs). (Although less efficient, B-lymphocytes are also talk between the innate and the acquired immune system
APCs, as will be discussed later.) Macrophages play a central [A2, N8, R4].
Table 3 Ligands recognized by Toll-like receptors

TLR PAMP Ligand
TLR2 Gram (+) bacteria Peptidoglycan (PGN)

Gram (+) bacteria Lipoteichoic acid (LTA)
Bacteria Lipoproteins
Spirochaetes Glycolipids
Leptospiras and porphyromonas Lipopolysaccharide (LPS)
Mycobacteria Lipoarabinomannan
Yeast Zymosan
Trypanosoma Glycosylphosphatidylinositol (GPI)
Schistosoma Phosphatidylserine (PS)
Neisseria Porin
Klebsiella Membrane protein A
Host Heat shock proteins (HSPs)
TLR2/TLR1 Chemicals JBT-3002

Bacteria Lipoproteins
Neisseria meningitides Soluble factor
TLR2/TLR6 Staphylococcus Modulin

Streptococcus (Group B) Soluble factor
Mycoplasma Lipoprotein
TLR3 Chemicals Poly (I:C)

Virus Double-stranded RNA
TLR PAMP Ligand
TLR4 Gram () bacteria LPS, LTA

Chlamydia HSP60
Murine retroviruses Envelope proteins
RS virus F protein
Plant Taxol
Host HSPs
TLR5 Bacterial flagellum Flagellin
TLR7 Chemicals Imidazoquinolines
TLR9 Bacteria, virus, insects Unmethylated DNA rich in CpG

Host Chromatin-IgG complexes
TLR10 Unknown Specific ligands and functions are currently unknown
24. Natural killer (NK) cells are large granular lym- their function, NK cell receptors can be divided into acti-
phocytes able to kill a number of different target cells and vation and inhibition receptors; NK cells are regulated
that, in contrast to T- or B-lymphocytes, do not express clon- by the integration of these opposing signals [L3, M10].
ally distributed receptors for antigens [M10]. They belong Normally NK cells are prevented from lysing self cells
to the innate arm of the immune response because their by the interactions of inhibitory receptors on the NK
cytotoxic activity is spontaneous, although activation may cell surface with the major histocompatibility complex
be mediated by cytokines. NK cells do not show secondary (MHC). The MHC in humans is called the human leu-
or memory responses. NK cells may recognize, bind and cocyte antigen (HLA), which will be discussed in more
kill virus-infected host cells and tumour cells [H18, T12]. detail in section I.C.3 below. Upon self class I HLA bind-
ing, inhibitor NK receptors trigger a signalling pathway
25. The heterogeneity of NK cells presents a major prob- resulting in inhibition of cytotoxicity, thus providing pro-
lem in their identification. They do not express CD3, but tection for normal cells. Cells that have lost class I HLA
exhibit subsets expressing CD16 and CD56. Most human molecules, or express insufficient amounts of them, are
NK cells are mainly involved in cytotoxicity, have low- frequently found in viral infections or tumour transfor-
density expression of CD56 and have high levels of CD16 mation, are not able to trigger these inhibitory signals
(CD3 CD56low CD16high), but around 10% of NK cells and thus are lysed by NK cells. Although a combination
play a role in cytokine-mediated immunoregulation and of several activating receptors may also boost lysis by
are CD3 CD56high CD16/low [C14, S19]. It was recently NK cells, the higher affinity of the inhibitory receptors
reported that peripheral CD56high NK cells are terminally by self class I HLA prevents autoimmunity [B7, C5, L2,
differentiated cells indistinguishable from mature CD56low M11]. NK receptors may be classed within several fami-
NK cells activated by IL-12, and do not constitute a func- lies: killer cell immunoglobulin-like receptors (KIRs),
tionally distinct NK cell subset [L23]. lectin-like receptors (NKG2 and CD95), leucocyte Ig-
like transcripts (ILTs), natural cytotoxicity receptors
26. The different NK cell subsets have receptors on (NCRs) and Fc receptor III (CD16). These are described
their surface that are not antigen specific. Depending on in table4.
Table 4 Natural killer cell receptors
Familya Receptor Functionb Ligand Comments
KIR KIR2DL () HLA-C 2D: two extracellular Ig-like domains;

(KIR2DL4) (HLA-G) L: long cytoplasmic tail
KIR3DL () HLA-B 3D: three extracellular Ig-like domains;

HLA-A L: long cytoplasmic tail
KIR2DS (+) HLA-C 2D: two extracellular Ig-like domains;

S: short cytoplasmic tail
KIR3DS (+) HLA-B 3D: three extracellular Ig-like domains;

S: short cytoplasmic tail
Familya Receptor Functionb Ligand Comments
Lectin C CD94/NKG2A () HLA-E

(heterodimer) (indirect recognition of HLA-G as peptide
presented by HLA-E)
CD94/NKG2C (+) HLA-E

CD94 functions as a chaperone (transports NKG2 to cell
surface)
presented by HLA-E)
CD94/NKG2E (+) HLA-E

presented by HLA-E)
NKG2D/NKG2D (+) MICA MICA/MICB: up-regulated on stressed cells and overex-

(homodimer) MICB pressed in many tumours;
ULBP ULBP: UL16-binding proteins from human cytomegalovirus
ILT ILT2 () HLA-A Also termed leucocyte Ig-like receptors or CD85j

HLA-B
HLA-F
HLA-G
NCR NKp46 (+) Viral and tumour proteins Expressed in resting and activated NK cells
NKp30 (+) Viral and tumour proteins
NKp44 (+) Viral and tumour proteins Expressed only in activated NK cells
Fc CD16 (+) Low-affinity receptor for IgG Facilitates antibody-dependent cellular cytotoxicity
receptor
III
a KIR = killer cell Ig-like receptor (Ig superfamily); ILT = Ig-like transcript; b Functions: () = inhibitory; (+) = activating.
NCR = natural cytotoxicity receptor.
27. A particular type of lymphocyte called an NKT cell only maturing once in a tissue site. They are present in most
exhibits certain characteristics of both T-cells and NK cells. tissues in the vicinity of blood vessels, and are especially
NKT cells, by definition, are T-lymphocytes, as they express prominent near the boundaries between the outside world
a T-cell receptor (TCR) on the surface of their membranes. and the internal milieu (skin and mucosa). When activated,
This distinguishes them from NK cells, although NKT cells a mast cell rapidly releases its characteristic granules and
do share some markers characteristic of NK cells. In contrast various molecules into the intercellular environment: hista-
to conventional T-lymphocytes, the NKT cell TCR does not mine, heparin, serine proteases, prostaglandin, leukotriene
interact with peptide antigen presented by classical class I and cytokines.
or II HLA molecules but instead recognizes glycolipids pre-
sented by CD1d, a non-classical antigen-presenting mole 29. The complement system refers to a series of serum
cule. NKT cells also express a far more limited range of proteins produced by different tissues and cells, including
TCR variable (V) region genes. Unlike NK cells, NKT cells hepatocytes, macrophages and gut epithelial cells. These
develop in the thymus and are either CD4+ or CD4. When proteins circulate in an inactive form, but in response to the
activated, NKT cells secrete large amounts of cytokines, recognition of molecular components of a microorganism,
such as interferon- (IFN-) and interleukin-4 (IL-4). The they become sequentially activated in a cascade where the
activation of NKT cells can lead, paradoxically, either to binding of one protein promotes the binding of the next one.
suppression or to stimulation of immune responses, depend- Three pathways may activate the complement system: the
ing on the type of signal received. The cells play a critical classical complement pathway, the lectin pathway and the
and probably unique role in the immune system by linking alternative complement pathway. These pathways differ in
innate and acquired immunity. NKT cells have been impli- the manner in which they are activated. Antibodyantigen
cated in the regulation of immune responses associated with complexes activate the classical pathway. The lectin path-
a broad range of diseases, including autoimmunity, infection way is mediated by the mannan-binding protein (MBP),
and cancer [S9]. a protein that binds to the mannose groups found in many
microbial carbohydrates but not usually found in human
28. Mast cells (or mastocytes) are considered part of the carbohydrates. The alternative pathway provides a means
immune system, where they play a role in innate immunity. of non-specific resistance against infection without the par-
Although best known for their role in allergy and anaphylaxis, ticipation of antibodies and hence provides a first line of
mast cells are also involved in wound healing and in defence defence against a number of infectious agents. Activation of
against pathogens. Mast cells circulate in an immature form, the complement system results in the production of several
biologically active molecules (e.g. kinins, chemotactic fac- antigen, B-lymphocytes become mature antibody-secreting
tors and opsonins), which may lead to lysis, opsonization, cells called plasma cells. Plasma cells are rarely found in the
inflammation or clearance of immune complexes. circulation but reside mostly in connective tissue, beneath
epithelia, in the medullary cords of lymph nodes and in the
white pulp of the spleen. Most plasma cells in the spleen and
2. Acquired immunity lymph nodes migrate into bone marrow.
30. The main features of acquired immunity are the 34. B-cell receptors (BCRs) are able to recognize free
following: soluble antigens in unmodified form, referred to as native
antigens. B-cells can secrete antibodies in a soluble form
M
emory: recovery from one infection frequently
when they are activated and develop into plasma cells.
protects against subsequent infection by the same
The BCRs found on mature B-cells consist of a mem-
organism (the individual is said to have become
brane immunoglobulin (Ig) acting as an antigen-binding
immune);
subunit, associated with a signalling subunit, which is a
S
pecificity: recovery from infection by one patho disulphide-linked Ig-/Ig- heterodimer [M31]. Immuno
gen does not usually give protection against globulins are usually Y-shaped and consist of two light
another; chains ( or ) and two heavy chains (, , , or ). The
type of heavy chain determines the immunoglobulin iso-
D
iversity: the immune system can respond to an
type (IgA, IgD, IgG, IgE and IgM, respectively). Each light
immense variety of foreign antigens;
chain has a molecular weight of ~25 000 daltons and is
S
elf and non-self discrimination: an individual does composed of two domains, one variable domain (VL) and
not normally make an immune response against the one constant domain (CL). The heavy chain has a molecu-
antigens usually present in the body and distin- lar weight of ~50 000 daltons and contains one variable
guishes such antigens from those that do not belong domain (VH) and either three or four constant domains
to that individual (immune tolerance). (CH1, CH2, CH3 and CH4), depending on the antibody
class or isotype. Variable regions are contained within the
31. Lymphocytes are the predominant cells involved amino (NH2) terminal end of the polypeptide chain and
in acquired immunity, which includes humoral and cell- serve as the antigen-binding sites. Constant regions are, in
mediated responses. Soluble antibodies present in the serum comparison, rather uniform from one antibody to another
mediate humoral responses, while cell-mediated responses within the same isotype. The four polypeptide chains
result from the interaction between different types of cell. are held together by covalent disulphide (-S-S-) bonds
This distinction correlates, respectively, with the existence (figureII). While IgG is the predominant serum form, IgA
of two types of lymphocyte: B-cells and T-cells. is the main class of immunoglobulin found in secretions
such as saliva, breast milk and tears, and in the digestive
32. Cells involved in immune recognition have surface tract [G27].
molecules called receptors that allow them to interact with
other cell-attached or soluble molecules in their environ- 35. Although in certain conditions B-cells may be sus-
ment. Each receptor has a conformation complementary ceptible to T-cell-independent activation [F15], the major-
to the specific molecule (ligand) to be recognized. The ity of B-cells require interaction with helper CD4+ T-cells
ligand becomes bound to the receptor when recognition to become activated and proliferate. The B-cell first
occurs. The term antigen includes any molecule that expresses Ig on the cell surface as the B-cell receptor. If
can be recognized by an antibody or by a lymphocyte the B-cell receptor binds specific antigen, then the cell
receptor. However, lymphocyte receptors recognize only internalizes the antigen and presents it to T-cells, where it
a small part of a whole molecule or ligand. The different is recognized by the T-cell receptor (TCR). T-cell interac-
parts of an antigen that can be recognized by lymphocyte tion with the B-cell involves additional regulatory signals
receptors are called antigenic determinants or epitopes. involving stimulation, e.g. interactions CD40/CD40L and
The diversity and specificity of immune response imply CD28/CD80. Fas ligand binding to Fas between B- and
that an enormous number of different specific receptors T-cells may negatively modulate B-cell activation, induc-
should exist. The diversity of the receptor repertoire is ing apoptosis that limits B-cell proliferation and activa-
acquired during the maturation process of lymphocytes, tion. Cytokines such as IL-2, IL-4 and IL-10 also play an
which involves a large number of gene rearrangements important role in B-cell activation. B-cells express class II
and results, among the clones existing in the final mature HLA molecules. They can find T-cells in secondary lym-
population, in more than 108 types of receptor for differ- phoid organs shortly after antigen entrance, BCR-mediated
ent specific epitopes [J1]. endocytosis allows them to concentrate small amounts of
specific antigen, and BCR signalling and class II HLA
33. B-lymphocytes are the effector cells of the humoral expression direct their antigen-processing machinery to
response. They originate and mature in the bone marrow, favour presentation of antigens internalized through the
then they move through the circulation to various sites BCR. These characteristics allow B-cells to be considered
throughout the body. Upon interaction with a foreign as antigen-presenting cells (APCs).
Figure II. Molecular structure of immunoglobulins (adapted from reference [J1]).
2 NH
Antigen NH 2 Antigen
binding binding
2 NH
NH VH
VH 2
VL VL
1 CH
CH 1
-S-S- -S-
S-
Fab fragment
CL CL
-S-S-
CH2 -S-S- CH2
H CO
O OH
CO carbohydrate
Fc fragment
Isotype CH3 CH3

determinants
COOH COOH
36. T-lymphocytes move from the bone marrow into the functions in the immune system. Cytotoxic T-lymphocytes
thymus as immature cells, take up residence and become are effector cells that, once activated, can remove foreign
thymus-dependent or mature T-lymphocytes. Prothymo- organisms. Helper T-lymphocytes induce other immune cells
cytes in the superficial cortex of the thymus (CD2+) give to become better effectors. There are at least two subsets of
rise to cortical thymocytes (CD1a+, CD2+, CD3+) and helper T-cells (Th1 and Th2); they secrete very different
mature T-cells (CD4+ or CD8+). Medullary thymocytes cytokines upon activation [S36]. While the Th1 subset pro-
are fewer and larger, and express CD4 or CD8 [A25]. duces large amounts of cytokines that promote cell-mediated
Mature T-cells pass through the circulation to find homes immune response, the Th2 subset produces an environment
in lymph nodes, mucosa-associated lymphoid tissue or the favouring humoral immunity by providing B-cell help for
spleen. Most of the T-cells belong to one of two subpopula- antibody production. The Th1 response (now sometimes
tions, distinguished by the presence on their surface of one called type 1 immunity) is characterized by production of
of two glycoproteins, designated CD8 and CD4. The type IFN-, IL-2, TNF- and TNF-. Characteristics of the Th2
of these glycoproteins present determines the cell type to response (type 2 immunity) include production of IL-4,
which T-lymphocytes can bind (see section I.C.3 below). IL-10, IL-13 and IL-5, and stimulation of the production of
The majority of CD8+ T-lymphocytes are cytotoxic T-cells, IgE and IgG1 antibodies [K11]. Immune regulation involves
and the majority of CD4+ T-lymphocytes are helper T-cells. homeostasis between Th1 and Th2 activity directing differ-
Cytotoxic and helper T-lymphocytes perform very different ent immune response pathways (table5).
Table 5 Characteristic molecules produced by CD8+ and CD4+ T-cells

T-cell type Molecule Action
CD8+ Perforins Pore-forming proteins

Production of molecules with Granzymes Proapoptotic intracellular proteases
cytotoxic activity Fas ligand Transmembrane death activator
IFN- Inhibition of viral replication
TNF- Cell death
TNF- Cell death
T-cell type Molecule Action
CD4+/Th1 IFN- Control of viral replication, Th2 inhibition

Production of molecules capable TNF- Cell death
of activating macrophages Fas ligand Transmembrane death activator
GM-CSF Granulocytemacrophage colony stimulation
CD-40-L Activation of target cells (via CD40 receptor)
IL-3 Growth and differentiation of target cells
TNF- Cell death
IL-2 Lymphocyte activation and proliferation
CD4+/Th2 IL-4 B-cell activation

Production of molecules capable IL-5 Eosinophil growth and differentiation
of activating B-cells IL-6 Plasma cell and stem cell differentiation, antibody secretion, acute phase response
CD-40-L Activation of target cells (via CD40 receptor)
IL-3 Growth and differentiation of target cells
GM-CSF Granulocytemacrophage colony stimulation
IL-10 Macrophage inhibition
TGF- Chemotaxis and IL-1 synthesis
Eotaxin Attracting eosinophils
37. Although most CD4+ T-cells belong to either the Th1 naive. They become activated to carry out their specific
or Th2 subsets, 510% of CD4+ T-cells do not belong to functions when an immune response is triggered. Activated
these two subsets; these cells express CD25, the receptor for lymphocytes begin to proliferate in a process termed clonal
IL-2, and the TCR. Their repertoire of antigen specifici- expansion, giving rise to a clone of descendant cells. This
ties is as broad as that of naive T-cells. These T-regulatory activation also induces the cells to differentiate into pri-
(Treg) cells are activated by binding to the class II HLA mary effector T-cells, which can secrete cytokines and kill
molecule, and they also receive co-stimulatory signals that infected cells, and leads to rapid clearance of the pathogen.
serve to initiate, maintain and regulate the activation cascade. Once the response has ceased, lymphocytes revert to their
Most CD25+ CD4+ Treg cells are produced by the normal previous inactive state, the primary effector cell popula-
thymus as a functionally distinct and mature subpopulation tion begins to contract and the majority of the cells die by
of T-cells [S5]. The major function of Treg cells is to inhibit apoptosis over the following weeks. A minority of cells,
other T-cells from mounting an immune response against however, escape this period of cell death; the cells that sur-
self components, thus protecting against autoimmunity. vive constitute an expanded population of memory cells
Upon TCR stimulation, Treg cells secrete large amounts of able to trigger a vigorous and effective secondary response
powerful immunosuppressor cytokines, which inhibit both should the same antigen be encountered in the future. The
Th1 help for cell-mediated immunity and Th2 help for anti- maturation status of CD4+ and CD8+ lymphocytes (naive/
body production. memory) can be determined on the basis of expression of
CD45RA molecules. The phenotypes are CD45RA+ for
38. Treg cells also express several members of the TLR naive T-cells and CD45RA for memory T-cells. Although
family. Stimulation of Treg cells through TLRs can expand T-cells express CD45RO, the expression of CD45RO by
their numbers and strengthen their suppressive activity T-cells is not a marker per se for memory cells, because
[S4]. This effect is apparently in opposition to the TLR- other types of immune cell also express it. Phenotypically
dependent stimulation of APCs, which enhances production naive T-cells also express high levels of CD27 and CD28
of pro-inflammatory cytokines, thereby augmenting T-cell- molecules (CD45RA+ CD27+ CD28+). T-cells belonging to
mediated acquired immunity. However, the PAMP concen- the memory pool have lost CD45RA expression (CD45RA
trations required for stimulation of Treg cells through TLRs CD27+ CD28+). After repeated stimulation by antigen,
are several orders of magnitude higher than those required memory T-cells down-regulate CD28 and subsequently
for activation of APCs. If a large amount of PAMP, e.g. CD27, and give rise to memory/effector cells (CD45RA
bacterial lipopolysaccharide (LPS), is produced, Treg cell CD27 CD28) and terminally differentiated effector T-cells
activation may prevent severe systemic reactions, such as (CD45RA+ CD27 CD28) [V2]. The number of memory
septic shock due to the production of large amounts of pro- cells remains remarkably constant over time; this is due to
inflammatory cytokines [S4]. Therefore CD4+ CD25+ Treg their ability for self-renewal by undergoing slow, periodic
cells are an evolutionarily unique T-cell subpopulation bear- turnover, referred to as homeostatic turnover, and these
ing two kinds of receptor: TCRs and TLRs. This dual signal- cells can protect against secondary infections [A10, C1, J3].
ling source, together with other signals, may enable CD4+
CD25+ Treg cells to finely tune their activity to modulate 40. T-cells can be divided into two subsets on the basis of the
acquired response against self and non-self antigens. structure of their TCRs. Most T-cells express a TCR hetero
dimer consisting of - and -chains ( T-cells), whereas a
39. Normally lymphocytes are in a resting state, and minor subpopulation expresses an alternative TCR isoform
before any contact with an antigen they are referred to as made of - and -chains ( T-cells). Each chain consists
of a variable domain, a constant domain, a transmembrane Figure III. Structure of the TCR/CD3 complex (adapted
domain and a cytoplasmic domain. The TCR is encoded by from reference [J1]).
multiple constant (C), joining (J), diversity (D) and variable
T-cell
(V) gene segments that are selectively recombined to gener-
ate TCR diversity. This diversity is necessary for the recog-
nition of the many antigenic peptides possible. First, V(D)J
recombination assembles unique BCR and TCR genes from
three separate gene segmentsthe V, D and J genesduring
lymphocyte differentiation. In addition to this recombination,
which occurs in the central lymphoid tissues, somatic hyper- CD3 CD3
mutation may take place during a late phase of the immune
response in peripheral lymphoid tissues [G37]. As imma-
ture T-cells undergo maturation in the thymus, the TCR and
other molecules are responsible for the selective processes TCR
involved in creating immunocompetent T-cells [J1]. While Peptide fragment
T-cells only recognize ligands presented within class I or presented
class II MHC (see section I.C.3), most T-cells recognize
intact proteins, as well as a variety of other types of organic
molecule that are fundamentally different from the short pep-
tides seen by T-cells in the context of MHC. Most of these MHC
T-cells have neither CD8 nor CD4 on their surface (they do
not recognize class I and class II HLA) [H28].
41. The multichain TCR/CD3 complex is one of the most

elaborate cell surface signalling receptors and plays a key
role in antigen recognition, T-cell activation and triggering
antigen-specific immune response. This process is induced
by direct interaction of the TCR with an antigen presented
by the MHC on APCs. Upon the structural and functional Antigen-presenting cell
cooperation of the TCR with the CD3 complex, the activat-
ing signal is transmitted through the cell membrane to the
nucleus [F10, S2]. The structure of the TCR/CD3 complex HLA-DR. Only a low percentage of circulating lymphocytes
is represented schematically in figureIII. are in an activated state in healthy individuals; these activated
lymphocytes can be rapidly mobilized against aggressors and
42. Engagement of the TCR by the antigen leads to a series they help in the further recruitment of defending cells [J1].
of intracellular biochemical events culminating in the transcrip-
tion of new genes and T-cell activation. One or more tyrosine 43. The stages of T-cell development within the thymus are
kinases phosphorylate first the CD3 chains themselves and identified by the expression of specific cell surface markers,
subsequently other substrates. Subsequent to tyrosine kinase such as TCR, CD3 (which serves as the signal transduction
activation, a series of secondary events follow TCR engage- component of TCR) and CD4/CD8. Direct cell-to-cell interac-
ment, including activation of serine/threonine kinases, acti- tion between these cells and thymic cells induces their prolif-
vation of the guanosine triphosphate (GTP)-binding protein eration and also differentiation. Pre-T-cells do not express any
p21ras and activation of transcription factors for receptors and of the above-mentioned T-cell markers; at this stage they are
growth factors such as the major T-cell growth factor IL-2. The referred to as double-negative cells (CD4 CD8). At this
CD4 and CD8 co-receptors bind a tyrosine kinase (p56Lck) by point the -chain of TCRs undergoes rearrangement. The suc-
their intracytoplasmic tail, which plays a critical role in T-cell cessful rearrangement of this chain serves as a signal for these
signalling. However, TCR binding is not sufficient to acti- cells to undergo further proliferation. During this time, both
vate T-cells, and a second (co-stimulatory) signal is required. CD4 and CD8 start to be expressed; thus these cells are referred
Indeed, as originally envisaged in the two-signal hypothesis, to as double-positive cells (CD4+ CD8+). It is only at this
T-cell activation required stimulation both by the TCR (sig- point that the -chain of the TCR undergoes rearrangement. At
nal 1) and through additional co-stimulatory molecules (sig- the double-positive stage, a second molecular sensor assembles
nal 2). The principal co-stimulatory molecules expressed on and controls the transition to the single-positive CD4+ CD8 or
APCs belong to the B7 family: B7-1 (CD80) and B7-2 (CD86). CD4 CD8+ stage on the basis of the specificity of the TCR
T-cells display receptors for these B7 moleculesCD28 and heterodimers (table6). Likewise, thymocytes committed to
cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)with the lineage also find a checkpoint at the penultimate double-
similar structures but opposite functions. While CD28 helps to negative stage (CD44 CD25+), which counterbalances the
initiate T-cell activation, CTLA-4 down-regulates the response stochastic nature of the concurrent TCR and rearrangements
[I14, L30]. Activated T-lymphocytes may be identified by the and allows only cells expressing a TCR to mature rapidly
expression of certain surface markers, e.g. CD25, CD38 and into CD25+ CD4 CD8 cells and leave the thymus [N15].
Table 6 T-cell + development and its correlation with CD expression on the cell surface
Double-negative Double-positive
(CD4- and CD8-negative) (CD4- and CD8-positive)
Surface CD44+ CD44+ Pre-TCR Proliferation CD4/CD8 TCR Single-positivea

molecule CD25 CD25+
CD2
C-Kit
CD44
CD25
CD3
CD4 a
CD8 a
CD24
a Single-positive: CD4+ or CD8+.
44. The expression of CD4, CD8, CD3 and TCR chains protein through DNA modification within immunoglobu-
changes during the different stages of thymocyte develop- lin genes. Beside these three DNA-altering mechanisms,
ment, and this is shown in figure IV. First, immature thymo- B- and T-lymphocytes are also exposed to general DNA
cytes do not express the above-mentioned markers. These injuries known to occur, for example, during DNA repli-
double-negative CD4 CD8 cells are precursors of two cation, as several waves of intense cellular proliferation
populations of cells: a minor proportion are CD3+ + thy- accompany not only their maturation but also their expan-
mocytes and a larger proportion are CD3+ + thymocytes. sion during immune responses. Lastly, one important aspect
CD3+ + thymocytes express neither CD4 nor CD8, even of an immune response relies on the inflammatory reaction,
when they reach maturation and are exported to the periph- during which several soluble factors and/or natural reactive
ery. In contrast, CD3+ + thymocytes go through further metabolites are produced that can be considered as possible
stages of development, including changes in CD4 and CD8 causes of DNA damage. Altogether this demonstrates that
expression. Large double-positive thymocytes (CD3+ + the lymphoid tissue is at particular risk for mutagenic events
CD4+ CD8+) differentiate into small double-positive cells, inflicted through defective DNA repair machineries [R20].
and the majority (97%) die by apoptosis within the thymus.
The remaining cells (3%) lose the expression of either CD4
or CD8 and become single-positive thymocytes (CD3+ 3. Human major histocompatibility complex
CD4+ CD8 or CD3+ CD4 CD8+), which are exported to
the periphery after maturation. 46. TCRs recognize specific epitopes on the surface of
APCs, once these are degraded into small peptides, a form
45. The immune system is a site of intense DNA modi- referred to as processed antigen. The major histocom-
fications, which result from programmed and specific patibility complex (MHC), which in humans is called the
mechanisms during its maturation, or as a consequence of human leucocyte antigen (HLA), plays a fundamental role in
non-specific injuries inflicted during cellular proliferation enabling T-cells to recognize antigens by forming complexes
and/or cellular activation. The V(D)J recombination is initi- with the peptides. Antigen processing and presentation are
ated by lymphoid-specific proteins through the introduction intracellular processes that result in fragmentation (prote-
of a DNA double-strand break. The terminal maturation of olysis) of proteins, association of the fragments with MHC
B-lymphocytes, which occurs during an immune response molecules and expression of the peptideMHC complexes at
in the germinal centre of secondary lymphoid organs such the cell surface, where they can be recognized by the TCR on
as the spleen, is characterized by two important modifica- a T-cell (figure V). The peptide-binding cleft of MHC mole
tions of the rearranged immunoglobulin genes. The isotype cules is the location where an antigen is attached for display
class switch recombination and the generation of somatic to a T-cell. However, not the entire antigen is bound to the
hypermutations ensure the production of efficient antibod- cleft. Only a few anchoring residues of the antigen need
ies of various isotypes. These two B-cell-specific processes actually to attach to the MHC molecule for the antigen to
are triggered by the activation-induced cytidine deaminase be displayed. This makes it possible for only a few common
residues on antigens to allow binding to one form of MHC. specificity. Furthermore, the size of the peptide-binding cleft
This is important because it allows many different antigens (larger in class II MHC) is proportional to the size of the
with only a few residues in common to be displayed by one peptide that it can accommodate (class II MHC molecules
form of an MHC molecule, giving these molecules broad bind larger residues).
Figure IV. Stages of thymocyte development. The expression of CD4, CD8, CD3 and TCR chains changes during the different
stages of thymocyte development (adapted from reference [J1]).
Double-negative
thymocytes CD3-4-8-
Large double-positive
thymocytes CD3+
preT: +4+8+
CD3+:+CD4-8-
Peripheral exportation
>95%
Small double-positive
thymocytes CD3+ : +4+8+
Apoptosis <5%
Small single-positive Small single-positive

thymocytes CD4+ 8- thymocytes CD4- 8+
Peripheral exportation Peripheral exportation
47. The MHC is a complex of closely linked genes that very small set of different HLA genes and expresses one
code for two families of glycoproteins (class I and class II (homozygous) or a maximum of two (heterozygous) alleles
MHC). While class I molecules are constitutively expressed for each locus.
by virtually all somatic nucleated cells, class II molecules
are expressed only by APCs. The class I MHC family in 48. HLA-G is a non-classical class I MHC molecule
humans is divided into classical and non-classical sub- involved in immunotolerance, with restricted tissue distribu-
families composed of HLA-A, -B and -C, and HLA-E, -F tion. It was first found in extravillous cytotrophoblast cells
and -G, respectively. The Class II MHC family in humans [C4] and was subsequently demonstrated in a variety of
includes HLA-DR, -DP and -DQ. Classic class I and class II normal tissues, including T-cells. The class I MHC chain-
HLA molecules are characterized by polymorphisms; within related molecule MICA belongs to a novel family of heat-
each class, and even at a single locus, an enormous number shock-induced proteins, by which the immune system can
of variants (alleles) are found among different individuals recognize and destroy stress-induced cells. This represents
in a population. A haplotype is a group of alleles that are an immune surveillance mechanism for the detection of dam-
inherited together on a single chromosome. Even though aged, infected or transformed cells [D4, S12]. MICA mole
the human population is outbred, because the HLA genes cules are recognized by TCR . It has been demonstrated
are tightly linked, they are frequently inherited together, that HLA-G mediates a dominant negative signal leading to
and patterns of inheritance have been identified among cer- tumour escape from immune surveillance by counteracting
tain groups of HLA antigens. Each individual has only a the MICA-activating signal [R9].
Figure V. Upper panel: origin of the peptides presented by MHC; lower panel: mechanism of antigen presentation to CD8+
and CD4+ T-cells by class I and class II MHC (adapted from reference [J1]).
ORIGIN OF THE PEPTIDES PRESENTED BY CLASS I AND II MHC

CYTOSOLIC PATHOGENS INTRAVESICULAR PATHOGENS EXTRACELLULAR PATHOGENS
Endoplasmic
AND TOXINS
Endogenous antigens Extracellular pathogens
Endoplasmic Exogenous antigens reticulum
and toxins Endoplasmic
reticulum reticulum
Golgi Golgi Golgi

apparatus apparatus apparatus
Nucleus Nucleus Nucleus

All the cells Macrophage B-cells
MECHANISM OF ANTIGEN PRESENTATION TO CD8+ AND CD4+ T-CELLS BY CLASS I
AND II MHC
CD 8+ T-CELL CD 4+ T-CELL CD 4+ T-CELL
T-cell receptor T-cell receptor T-cell receptor
CYTOSOL Degradation by Degradation by

proteases proteases
GOLGI
APPARATUS
Fusion Fusion
CYTOSOL CYTOSOL
GOLGI GOLGI
APPARATUS APPARATUS
Endoplasmic
reticulum
MHC-I TAP transporter
Peptide Endoplasmic Endoplasmic

fragments MHC-II reticulum MHC-II reticulum
Immunoproteasome
CYTOSOL CYTOSOL CYTOSOL
Presentation by the Presentation by the Presentation by the

class I MHC molecule class II MHC molecule class II MHC molecule
49. The central MHC region or human class III encodes, for presentation by the class I HLA pathway. In mammals,
within a ~700 kb sequence located between the centromeric activation of the immune system leads to the release of
class II MHC and the telomeric class I MHC regions, a cytokines, causing the activation of immunoproteasomes
heterogeneous collection of more than 60 genes where a few and degradation of the antigenic protein into peptides about
families do emerge. These genes include those involved in 10amino acids in length. These peptides are then transported
the activation cascades of the complement system, steroid from the cytosol into the endoplasmic reticulum, where each
hormonal synthesis, inflammation and cell stress (tumour enters the groove at the surface of a class I HLA molecule.
necrosis factor, lymphotoxins, heat shock proteins) and This peptideHLA complex then moves through the Golgi
extracellular matrix organization (tenascin), as well as apparatus and is inserted into the plasma membrane, where
immunoglobulin superfamily (Ig-SF) members. The remain- it can be recognized by CD8+ T-cells to induce cell death
der (the majority) of the loci are involved mainly in more (cytotoxicity) [R6, T3] (figureV). Exogenous antigens are
core biological functions with no immediate implication degraded by APCs by endocytosis. The pH of the endosomes
for the immune system [H21]. containing the engulfed pathogens progressively decreases,
activating proteases that reside within these acidified endo-
50. T-cells are grouped functionally according to the class cytic vesicles to degrade the engulfed material. The resulting
of HLA molecules that associate with the peptides they peptides are located within class II HLA molecules, which
recognize. CD8+ cytotoxic and CD4+ helper T-cells tend are then exported towards the cell surface. Toxins are extra-
to recognize peptides bound to class I and class II HLA cellular pathogens, for example the majority of bacteria,
molecules, respectively. Endogenous antigens may be viral which mainly reside and replicate extracellularly. They are
proteins synthesized within the infected cell or the specific degraded inside intracellular acidified vesicles and associate
proteins synthesized by tumour cells. These cytosolic patho with class II HLA molecules to be presented to CD4+ T-cells
gens are degraded into peptide fragments that form com- that can help B-cells to secrete Ig against these bacteria.
plexes with class I HLA and are then transported through the Other exogenous antigens, for example some bacteria and
endoplasmic reticulum towards the cell surface. Proteasomes parasites, grow intracellularly (intravesicular pathogens).
are the major non-lysosomal protein degradation machin- Once degraded in acidified vesicles, their peptides are also
ery in eukaryotic cells. They deal primarily with endog- bound to class II HLA and presented to CD4+ T-cells. Upon
enous proteins. Specialized proteasomes called immuno recognition of these peptides by the TCR, the presenting cell
proteasomes are responsible for the processing of antigens is activated to kill the pathogens (table7).
Table 7 Origin of the peptides presented by class I and II HLA
Property Cytosolic pathogen Intravesicular pathogen Extracellular pathogen or toxin
Degraded in Cytoplasm Acidified vesicles Acidified vesicles
Peptides bind to Class I HLA Class II HLA Class II HLA
Presented to CD8+ T-cells CD4+ T-cells CD4+ T-cells
Effect on presenting cell Cell death Activation to kill intravesicular bacteria Activation of B-cells to secrete Ig to
and parasites eliminate extracellular bacteria or toxin
4. Antigen-presenting cells co-stimulatory molecules (namely B7 molecules), and only

then activate T-cells, by interacting with B7 receptors.
51. The immune system contains three types of antigen-
presenting cell (APC): macrophages, dendritic cells and 52. Macrophages are part of the innate response. Unlike
B-lymphocytes. These three types of APC present different T- and B-cells, they do not contain specific receptors but
sets of antigens and may also serve to activate helper T-cells do express TLRs that allow them to recognize differen-
at different points during the immune response. As previ- tial PAMPs on foreign cells. Stimulated macrophages up-
ously discussed, T-cell activation requires stimulation both regulate class II HLA and express co-stimulatory molecules
by the TCR and through additional co-stimulatory mole- (B7 molecules). It is at this point that antigen presentation by
cules. The most relevant property of APCs is that, in addition class II HLA will activate CD4+ helper T-lymphocytes.
to antigen presentation, they provide co-stimulatory signals.
APCs (except dendritic cells) do not constitutively express 53. Dendritic cells are mostly found in the skin and
these co-stimulatory molecules. Since these cells potentially mucosa epithelium (Langerhans cells). Dendritic cells also
phagocytose both self and infectious materials, there has possess TLRs that can recognize PAMPs, and they continu-
to be some mechanism for the recognition of self and non- ously express high levels of co-stimulatory molecules (B7
self. Upon this recognition, the APCs will up-regulate their molecules). Upon recognition of infectious particles, these
cells migrate through the lymphatic system to the near- receptor-mediated endocytosis. Thus B-cells can present
est lymph node, where they come into close contact with specific antigens to activated T-cells. However, resting
naive T-cells. Unlike macrophages, however, dendritic cells B-cells do not express co-stimulatory molecules; in order to
can also recognize viral particles as non-self. In addition, do so, most of the B-cells need to be activated by helper
they can present antigen via both class I and class II HLA. T-lymphocytes. The role of B-cells as APCs in vivo is not
Thus they can directly activate both CD8 and CD4 T-cells. very well understood [R21].
Once the T-cells are activated, they leave the lymph nodes
and travel to the sites of inflammation. Since dendritic cells
present viral particles, these should also activate CD8 cells, 5. Self tolerance and self-HLA-associated recognition
the main effector cells for fighting viral infections. Dendritic
cells are also very numerous in the thymus, where they act 58. As seen, a diverse and polymorphic T-cell repertoire
in T-cell selection during development. While a role of den- is generated in the thymus by random recombination of dis-
dritic cells in the negative selection in the thymus has been crete TCR gene segments. This repertoire is then shaped by
well established [W13], their role in the positive selection is intrathymic selection events to generate a peripheral T-cell
still questionable [W11]. pool of self-HLA-restricted, non-autoaggressive T-cells.
To ensure that self tolerance is achieved, self antigens are
54. The skin is equipped with specialized cells called presented to the matured T-cells by APCs in the thymus.
Langerhans cells (LCs) which play a central role in the At this stage, these cells undergo the processes of positive
skins immune system as an integral part of the bodys total and negative selection. During positive selection, double-
defence system. LCs are epidermal antigen-presenting den- positive T-cells that can recognize self HLAs are selected
dritic cells originating in the bone marrow. They migrate to for proliferation, and those T-cells that do not recognize
the epidermis, where they form a regularly ordered network self HLAs die by apoptosis. Positive selection has been
representing 1.86% of all epidermal cells. A constant numer- associated mainly with cortical thymic epithelial cells and
ical ratio (1:53) exists between LCs and the other epidermal their associated HLA molecules, both of which are neces-
cells. The surprisingly constant relationship of LCs to other sary and sufficient for positive selection of double-positive
epidermal cells supports the hypothesis of an epidermal LC thymocytes and the development of single-positive cells
unit where one LC seems to be responsible for the immune [G15]. By negative selection, those T-cells that are strongly
surveillance of 53 epidermal cells [B21]. activated by self HLA and self peptides are eliminated in
the thymus. This process of clonal deletion prevents lym-
55. After contact with the corresponding antigens (viruses, phocytes from subsequently reacting against self antigens
contact allergens, skin transplants), LCs migrate from the and causing autoimmune diseases. Mature T-cells leave
epidermis to the regional lymph nodes for presentation of the thymus, go into the circulation and eventually find
antigenic peptides to T-cells. On their journey, LCs undergo their way to lymph nodes, mucosa-associated lymphoid
a maturation process leading to the presentation of the anti- tissue or the spleen [J1] Although the majority of self-
gen on the cell surface. The migrating LCs are replaced by a reactive T-cells are clonally deleted in the thymus, some
corresponding number of new LCs from the bone marrow. In mature lymphocytes may remain capable of responding to
the lymph nodes the mature LCs activate the helper T-cells self antigens. Intrinsic biochemical and gene expression
that have the matching antigen-specific receptors on their changes, as well as a lack of co-stimulation, can reduce
surfaces. In this way they direct the reaction of the immune this ability by triggering a process generally termed clonal
system [K42]. anergy. Finally, even if the lymphocytes have evaded these
controls, mechanisms of extrinsic control, such as active
56. Epidermal LCs have a spectrum of different functions suppression by Treg cells, can prevent the danger of self-
with implications that extend far beyond the skin. They have reactive receptors [G37].
the potential to internalize particulate agents and macro
molecules, and display migratory properties that endow 59. The achievement of immunological self tolerance
them with the unique capacity to journey between the skin raises the question of how T-lymphocytes that are reac-
and draining lymph nodes where they encounter antigen- tive to proteins expressed only by non-thymic tissues can
specific T-lymphocytes. In addition, LCs are considered be identified and addressed. The clinical relevance of this
to play a pivotal role in infectious disease, allergy, chronic question is related to the fact that many of these tissue-
inflammatory reactions, tumour rejection or transplantation restricted proteins (e.g. insulin, thyroglobulin, myelin, reti-
[V10]. Factors influencing the activity of the LCs in the epi- nal S-antigen) are associated with organ-specific autoim-
dermis include cytokines such as IL-10, immunosuppres- mune diseases (e.g. type 1 diabetes, thyroiditis, multiple
sive drugs such as corticoids, and ultraviolet and ionizing sclerosis, uveitis). A classical explanation for this phenom-
radiation [K39]. enon was that, while tolerance to ubiquitously expressed
or blood-borne antigens is centrally achieved in the
57. B-cells are the least efficient APCs. Unlike the other thymus, tolerance to tissue-restricted antigens is secured
two APCs, they possess specific antigen receptors (surface by peripheral extrathymic mechanisms. However, ectopic
immunoglobulins). B-cells effectively ingest soluble anti- synthesis of these peripheral tissue-restricted proteins has
gens that bind to cell surface immunoglobulin receptors by recently been demonstrated in thymic medullar epithelia
cells [A22]. A startling discovery for the understanding of 6. Cytokines

this ectopic synthesis is the autoimmune regulator AIRE
61. As described above, the immune system has many dif-
gene that enables a battery of tissue-restricted antigens to
ferent types of cell acting together to deal with unwanted
be expressed in thymic medullar epithelia cells, thus play-
infections and altered cells. Cytokines are small proteins
ing an important role in controlling tolerance induction. In
produced by the immune cells for signalling and for orches-
the absence of AIRE, autoimmunity, and ultimately overt
trating the attack. They generally act over short distances
autoimmune disease, develop [A23, M16]. Although AIRE
and short time spans and at very low concentrations by bind-
transcripts are by far most abundant in the thymus, they
ing to specific membrane receptors, which then signal via
were also detected in peripheral lymphoid organs at signifi-
second messengers, often tyrosine kinases. Responses to
cantly lower levels [A22].
cytokines may include increased or decreased expression
of membrane proteins, secretion of effector molecules and
60. Although 124% of T-cells are alloreactive, i.e. they cell proliferation. By these actions cytokines mediate and
respond to MHC molecules encoded by a foreign haplo- regulate immunity, inflammation and haematopoiesis.
type, it is generally believed that T-cells cannot recognize
foreign peptides binding foreign HLA molecules [D21]. The 62. Many cell populations make cytokines, but the pre-
term MHC restriction refers to the phenomenon whereby dominant producers are CD4+ helper T-cells and monocytes/
T-cells from one individual recognizing an antigen fail to macrophages. Cytokines made by lymphocytes are called
recognize cells presenting the same antigen unless the pre- lymphokines, and cytokines made by monocytes are called
senting cells express one or more HLA alleles identical to monokines. Other groups of cytokines include interferons
those on this individuals cortical thymic epithelial cells, (IFNs) and chemokines. While IFN- and IFN- inhibit
in which those T-cells matured. This phenomenon derives virus replication in infected cells, IFN- has the additional
in part from the requirement to recognize self HLA (self- property of stimulating HLA expression. Chemokines are
HLA-associated recognition) and in part from the different cytokines with chemotactic properties that attract leucocytes
peptide-binding specificity of different HLA alleles. Through to infection sites. The general term interleukins (ILs) is used
positive and negative selection in the thymus, self peptides to define cytokines made by one leucocyte and acting on other
bound to autologous HLA molecules determine the reper- leucocytes. Interleukins have been numbered in the order in
toire of peripheral T-cells, which then respond to infection which they were identified. Thus the first IL identified was
by recognizing foreign peptides bound to those same HLA named IL-1; about 30 different ILs have been identified so
molecules [P13]. far (table8).
Table 8 Main cytokines and their functions

Cytokinea Main sourceb Target cells Function
IL-1 and APCs Th cells Co-stimulation
B-cells Maturation and proliferation
NK cells Activation
Various Haematopoiesis, inflammation, fever, acute phase response
IL-2 Th1 cells T-, B- and NK cells Activation, growth, proliferation
IL-3 Th1 cells, NK cells Stem cells Growth and differentiation
Mast cells Growth and histamine release
IL-4 Th2 cells, mast cells B-cells Proliferation, differentiation, IgG and IgE synthesis
T-cells Proliferation
Macrophages Expression of class II HLA
IL-5 Th2 cells Eosinophils Proliferation
B-cells Proliferation, differentiation, IgA synthesis
IL-6 APCs, Th2 cells, stromal cells B-cells Differentiation (into plasma cells)
Plasma cells Antibody secretion
Stem cells Differentiation
Various Acute phase response

Cytokinea Main sourceb Target cells Function
IL-7 Marrow stroma, thymus stroma Stem cells T- and B-lymphopoiesis
IL-8 Macrophages, endothelial cells Neutrophils Chemoattractant

T-cells
IL-9 T-cells Stem cells, thymus cells Haematopoiesis and thymopoiesis
IL-10 Th2 cells, macrophages, Macrophages, Inhibition of cytokine production

Tc cells, B-cells B-cells, Proliferation, differentiation, Ig synthesis
mast cells Inhibition of growth
Suppression of cell-mediated immunity
IL-11 Stromal cells Marrow cells Haematopoiesis and thrombopoiesis
IL-12 Macrophages, Tc cells Differentiation, promotion of cell-mediated immunity

B-cells NK cells Activation, proliferation, IFN- production
IFN- and - Macrophages, neutrophils, Various Inhibition of viral replication

fibroblasts Induction of class I HLA expression
IFN- Th1 cells, NK cells Various Inhibition of viral replication
Various Induction of HLA expression
B-cells Ig switch to IgG2a
Th2 cells Inhibition of proliferation
TGF- T-cells, monocytes Macrophages Chemotaxis and IL-1 synthesis
B-cells IgA synthesis
Various Inhibition of proliferation
TNF- Monocytes, NK cells, mast cells Macrophages Cytokine expression
Tumour cells Cell death
TNF- Th1 cells, Tc cells APCs Phagocytosis, NO production
Tumour cells Cell death
a IL = interleukin; IFN = interferon; TGF = transforming growth factor; b Th = CD4+ helper T-cells (Th1- or Th2-type); Tc = CD8+ cytotoxic T-cells.
TNF = tumour necrosis factor.
63. Cytokines have several important characteristics: A

utocrine functions: cytokines may act on the same
cells that secrete them;
T
he same cytokine may be made by a number of
different cells; E
ndocrine functions: some cytokines may act in
some instances on distant cells.
P
leiotropy: the same cytokine may have differ-
ent effects and/or may act on several different cell
types; 7. Remarks concerning cells and molecules
R
edundancy: similar functions can be induced by of the immune system
different cytokines;
64. The preceding paragraphs concerned cells and mole
S
ynergy: cytokines often act together and increase cules of the immune system. Anatomic, physiological,
one anothers effects; inflammatory and phagocytic barriers constitute the innate
A
ntagonism: some cytokines may cause opposing immune system. Phagocytes (granulocytes, monocytes/mac-
effects; rophages and dendritic cells) engulf and digest pathogens.
They express a special family of receptors (TLRs) capable
C
ascade effect: cytokines are often produced in a of recognizing PAMPs. NK cells also belong to the innate
cascade, as one cytokine stimulates its target cells arm of the immune response. NK cells can recognize, bind
to make additional cytokines; and kill virus-infected and tumour cells. Spontaneous NK
P
aracrine actions: cytokines act on cells near to cytotoxic activity is regulated through activating and inhib-
them or that they actually touch; iting membrane receptors. NKT cells are a particular type
of lymphocyte expressing some NK surface markers and in immune function have been well documented [H13, R7].
TCRs, and that bridge innate and acquired immunity. As part A reduction with age has been reported in the overall capac-
of the innate immunity, mast cells are involved in allergy, ity for renewal of haematopoietic stem cells, indicating that
anaphylaxis, wound healing and defence against pathogens. some of the deficits of immunosenescence may be initiated
The complement system circulates in an inactive form. In at the stem cell level [H1, L1].
response to the recognition of certain molecular patterns of
pathogens, complement activation results in the production
of biologically active molecules, which may lead to lysis, 2. Main features of immunosenescence
opsonization and inflammation.
69. The immune property most sensitive to ageing is the
65. Lymphocytes are the predominant cells involved in production and export of T-cells from the thymus, which
acquired immunity. B-lymphocytes and T-lymphocytes are is manifested by a decrease of naive cells with age [H16].
the effector cells of the humoral and the cellular response, Naive cells have the greatest diversity of TCR repertoire.
respectively. B-cells recognize native antigens through With ageing, the thymus involutes, the supply of naive
the immunoglobulins expressed on their surface as BCRs. T-cells falls and there is a gradual accumulation of mem-
T-cells recognize antigens previously processed into small ory T-cells. Thus in elderly persons the T-cell population
peptides through the TCR/CD3 complex expressed on shifts to a lower naive/memory T-cell ratio, and the TCR
their surface. B-cell/T-cell interactions involve additional repertoire available to respond to new antigens is reduced
co-stimulatory signalization. Most of T-cells belong to the [H1, V2, V4].
CD8+ or CD4+ subpopulations. CD8+ cytotoxic T-cells are
effectors that, once activated, can remove foreign organisms. 70. There is a progressive increase with age in the propor-
CD4+ helper T-cells induce other immune cells to become tion of CD8+ T-cells that lack expression of CD28, a criti-
better effectors. cal co-stimulatory molecule [E2, H16]. This results in lower
proliferative capacity, decreased IL-2 production, telomere
66. By secreting different cytokines, Th1 and Th2 CD4+ erosion and less response to TCR stimulation. Taking into
helper T-cells promote cellular or humoral immunity, account the fact that specific effector cells should be able to
respectively. A minority of CD4+ T-cells belong to neither proliferate sufficiently to fight an infection, the age-related
Th1 nor Th2 subsets and are called regulatory T-cells that limitation of cell division could have devastating conse-
express CD25, the receptor for IL-2. These CD4+ CD25+ quences for immune function [E1]. Immunosenescence also
Treg cells protect against autoimmunity and prevent severe involves hyporesponsiveness to mitogens, lowered lytic
systemic reactions such as septic shock. Naive (CD45RA+) capacity, decline in transmembrane signalling and higher
lymphocytes have never encountered an antigen. When an oxidative stress [B6, B15, V2].
immune response is triggered, they become activated and
proliferate (clonal expansion). Once the response ceases, 71. As a result of thymic involution, the kinetics of the
most of the activated lymphocytes die by apoptosis, but a transition from CD4 CD8 (double-negative) to CD4+
minority of them remain as memory (CD45RA) T-cells. CD8+ (double-positive) thymocytes is altered in old age. It
has been demonstrated that thymic levels of p56Lck, a fac-
67. TCRs recognize antigenic peptides bound to the MHC tor involved in the maturation of T-cells from CD4 CD8
(in humans called HLA) on the surface of APCs (dendritic double-negative into CD4+ CD8+ double-positive T-cells,
cells, macrophages and B-cells). While CD8+ T-cells recog are negatively correlated with age, which could lead to the
nize endogenous antigens bound to class I HLA, CD4+ accumulation of CD4 CD8 double-negative T-cells in the
T-cells recognize exogenous antigens bound to class II HLA. elderly [H15].
Through positive and negative selection in the thymus, self
antigens bound to autologous HLA molecules determine the 72. There exists a chronic inflammatory state in the
repertoire of T-cells to ensure immunological self tolerance. elderly due to an increased release of pro-inflammatory
Cytokines are proteins, mainly produced by CD4+ T-cells cytokines such as TNF- and IL-6 [B6, E1]. Dysregula-
and monocytes/macrophages, that bind to specific membrane tion of TNF- and IL-6 may be involved in age-related
receptors that act as second messengers. diseases such as osteoporosis, atherosclerosis, Alzheimers
disease, diabetes, cardiovascular disease and cancer [H16].
The balance between Type 1 and Type 2 cytokines, impor-
tant for the outcome of several infectious diseases, also
D. Physiological immunosenescence changes with age. Evidence suggests that, while a Th1-type
response predominates in adults, a Th2 response predomi-
1. Concept of immunosenescence nates in the elderly. This shift from a Th1 to a Th2 cytokine
profile is a possible mechanism for age-associated immune
68. Immunosenescence can be defined as the progressive dysfunction [R1, S7].
decline in immune function observed in the elderly; it results
in a higher susceptibility to infections and increased morbid- 73. As a result of ageing, the immune system may lose
ity and mortality [B6, G2, H16]. These age-related changes the ability to distinguish self versus non-self antigens.
Age-related changes in humoral immunity involve reduced Increase in the absolute number of NK cells, with a
vaccine responses and increased production of autoanti decrease in their cytotoxic capacity;
bodies. Although the ability of B-cells to generate antibody Gradual decline in melatonin synthesis.
responses declines with age, many of the humoral changes
observed in the elderly are related to declining T-cell func-
tion with dysregulation of T-cell/B-cell interactions [B15, E. Summary
F3, H1, L5]. The B-cell repertoire changes with age, and the
77. The general features of the immune system can be
altered spectrum of expressed immunoglobulins may affect
summarized as follows:
the quality of the antibody response in the elderly and be
highly relevant for health [V4]. The main function of the immune system is to
protect against infections and cancer;
74. The innate response is not free from the effects of The bone marrow and the thymus are the primary
ageing. The production of reactive oxygen and nitrogen lymphoid tissues where maturation of lymphocytes
species (ROS/RNS) by neutrophils and macrophages in takes place;
the elderly is significantly impaired, which diminishes
the capacity to destroy bacteria. In contrast to the case Mature lymphocytes travel by the bloodstream
with T- and B-cells, the absolute number of NK cells is towards the lymph nodes, spleen and mucosa-
increased in elderly persons, but their cytotoxic capacity associated lymphoid tissue, which are considered
on a per-cell basis is impaired [B15, H1]. NK cells from the secondary lymphoid tissues;
elderly people show a decreased proliferative response The ability of the cutaneous barrier to help defend
to IL-2 [H16]; NK cells are thus less able to destroy the body against pathogens relies on both acquired
virus-infected and tumour cells in the elderly [P8]. The and innate immune responses;
immune system in older people is also characterized by Monocytes, macrophages, polymorphonuclear leu-
an increased proportion and number of NKT cells in the cocytes, dendritic cells, natural killer cells and mast
peripheral blood [M9]. cells are the immune cells involved in the innate
immune response;
75. Several aspects of immune response exhibit diur-
nal and seasonal circadian rhythmicity related to the Lymphocytes are the predominant cells involved in
level of melatonin, which exerts immunoenhancing and the acquired immune response. While B-lymphocytes
antioxidant actions. Such rhythms play an important are the effector cells of the humoral response,
role in immune homeostasis [S22]. The gradual decline T-lymphocytes (with their two subsets CD4+ helper
of pineal melatonin synthesis and secretion over the T-cells and CD8+ cytotoxic T-cells) are responsible
lifespan could cause immunocompetence to deteriorate for cell-mediated responses;
in the elderly [K6]. The main features of the acquired immune response
are memory, specificity, diversity and self/non-self
discrimination;
3. Remarks concerning immunosenescence There is a crosstalk between the innate and the
acquired immune response;
76. The main features of immunosenescence are: Cells involved in immune recognition have surface
Thymic involution; receptors that bind to specific antigens;
Progressive decrease of the naive cell pool with age The lymphoid tissue is naturally prone to DNA
(shift to a lower naive/memory ratio); modifications that occur during the maturation of B-
and T-lymphocytes and during immune responses;
Reduced TCR repertoire;
The MHC complex (HLA in humans) plays a
Increase in the proportion of CD8+ CD28 T-cells; fundamental role in enabling T-cells to recognize
Accumulation of CD4 CD8 T-cells; antigens;
Chronic inflammatory status; APCs present antigens and activate helper T-cells
by co-stimulatory signals;
Progressive loss of the ability to distinguish self
versus non-self antigens; Cytokines are small proteins that mediate and regu-
late immunity, inflammation and haematopoiesis;
Dysregulation of T-cell/B-cell interaction, resulting
Immunosenescence is a complex process involving
in humoral changes;
dysregulation, rather than a simple unidirectional
Impaired phagocytic activity; decline of the whole immune system function.
II. RADIATION-INDUCED ALTERATIONS OF THE IMMUNE SYSTEM
A. Introduction Radiological Protection [I2] deems that the dose and dose-
rate effectiveness factor (DDREF) should be applied.
78. Radiation-induced effects on the immune system have
attracted interest from the research community for several
decades, and lymphocyte radiosensitivity was one of the ear- B. Data concerning low-dose irradiation
liest subjects of experimental radiobiology [A13, A27, A28,
A29, D11, D29, H24, K54, M30, P12, P15, T19]. Immuno 80. The effects of low doses of ionizing radiation on the
suppression is a consequence of whole-body irradiation immune system were reviewed by the Committee in 1994,
(WBI) at medium to high doses. Localized radiotherapy can in the context of adaptive response [U4]. At that time, some
also result in immunosuppression. In contrast, it has been evidence in animals seemed to indicate that low doses of
reported that very low doses of ionizing radiation may give ionizing radiation may enhance immune response, but the
rise to immunostimulatory effects, particularly at short times evidence for a similar effect on the human immune system
after irradiation. Because of these divergent effects, ioniz- was sparse. It was concluded that further investigations were
ing radiation is probably better considered as an immuno needed on these effects and their clinical significance.
modulatory rather than as an immunosuppressive agent [M2,
U4]. This section summarizes the main alterations induced
by ionizing radiation in the immune system and considers 1. Animal data
the influence of dose, dose rate and radiation quality. Data
concerning the radiosensitivity of the different lymphocyte 81. The effects of external low-dose irradiation upon the
subpopulations are analysed. Particular attention is given to blood and the immune system of experimental animals have
alterations of the developing immune system following pre- been studied at several centres. The doseresponse relation-
natal irradiation. Several human immune pathologies asso- ship of immunological parameters following exposure to
ciated with hypersensitivity to ionizing radiation are also ionizing radiation is affected by a number of factors, the
reviewed. most important of which are the target cells under obser-
vation, dose range, dose rate and dose spacing, as well as
79. For the purposes of this annex, low doses are defined the temporal relationship of the changes and the strain of
as <0.2Gy to the whole body. Low-dose-rate exposures are animal used [L20]. Table 9 summarizes the most commonly
considered to be those delivered at <0.1 Gy/h. These are observed alterations of immunological parameters in low-
the levels below which the International Commission on dose/low-dose-rate (LD/LDR) irradiated animals.
Table 9 Effects of ionizing radiation on the immune system of animals irradiated at low doses and low dose rates
Parameter Animal species Dose rate Time of detection of effect, Trend of change Reference
(mGy/d) or total dose
Leucocyte score Dogs 3128 0200d Decrease [S40, N23]

(blood)
2001700d Accommodative phase
Lymphocytes (spleen, CBA mice 1060 30d Decrease [Y1]

thymus)
C57BL mice 50 100200800mGy No change [J6]
C57BL mice 100 2a No change [C16]
Haematopoietic
progenitors
CFU-GM Dogs 75 0200d Decrease [S39]
200800d Recovery phase
CFU-GM Dogs 18.8 150d Decrease [N23]
7001200d Partial recovery
109
Parameter Animal species Dose rate Time of detection of effect, Trend of change Reference
(mGy/d) or total dose
Lymphocyte mitogenic Dogs >20 >300d Increase (T-cells) [Y1]

response
C57BL mice 50 100200800mGy Increase (T-cells) [J6]
C57BL mice 40 20d Increase (T-cells) [N20]

No change (B-cells)
C57BL mice 40 200mGy Increase (T-cells) [P11, S16, S17]
BALB/c mice 75mGy Increase (T-cells) [L18]
Cytokines Mice 75mGy IL-10 decrease [L19]
IL-12 increase
Mice 75mGy IL-1, IL-2 increase [J8]
C57BL mice 40mGy IL-1, IFN- increase [I6]
Rats 200mGy IFN-, TNF- increase [H20]
TGF- decrease
C57BL mice 40 200mGy IFN- decrease [P11]
Macrophage CBA mice 0.02 + 180d Decrease [G18]

phagocytosis and nuclides
NK activity
BALB/c mice 100200mGy; 48h Increase [C21]
BALB/c mice 200mGy; 2472h Increase [C21, N24]
C57BL mice 40 200mGy Increase [P11]
82. Yagunov et al. [Y1] reviewed extensively the haema phase and a later recovery phase preceding the changes
topoietic and immune system effects of LD/LDR irradia in blood leucocyte concentration [N23, S39]. Results also
tion in animal studies. These long-term effects of LD/ showed that 75mGy/d represented a threshold below which
LDR irradiation seem largely dependent on the capacity the haematopoietic system retained either partial or full tri-
of radiosensitive tissues to repair DNA damage induced lineal cell-producing capacity (erythropoiesis, myelopoiesis
by a given daily dose. Post-irradiation changes in the and megakaryopoiesis) for periods of exposure longer than
peripheral blood counts of experimental animals returned one year [S41]. One might interpret these observations as
to control levels within several months of the start of irra- evidence of an adaptive effect and acquisition of resistance
diation. The precise mechanisms by which these adaptive to radiation exposure. However, at long times after expo-
or accommodative processes occur are largely unknown, sure, animal populations experienced a high incidence of
although repair, cell cycle and cell selection are considered myeloid leukaemia and related myeloproliferative disorders
to play a role [S40]. The effect of low-daily-dose gamma [S49]. These animal data also indicated that a high degree of
irradiation (3128mGy/d) on the blood-forming system of individual variability existed.
canines was studied by Seed et al. [S40]. Low but signifi-
cant suppression of blood leucocytes, including granulo- 84. Post-irradiation recovery of marrow precursors and
cytes, monocytes and lymphocytes, occurred at 3mGy/d. mature cells was incomplete, as evidenced by a deficient
As the dose rate increased from 3 mGy/d to 128 mGy/d, response to challenge stimuli (acute haemorrhage or gamma
the rate of suppression increased approximately eightfold. irradiation). Several factors may account for deficient
The time required to achieve accommodation decreased as haematological recovery after chronic irradiation [Y1]:
the daily dose rate increased. Within the time required to
Persisting post-irradiation deficiency of haema
reach a cumulative dose of 700mGy, none of the dose rates
topoietic stem cells observed after exposures of
affected blood cells sufficiently to compromise short-term
>10mGy/d for several months;
immune function.
Accelerated cell cycling of marrow precursors in
83. Clear associations were found between the tissue irradiated animals, leading to increased ratios of
responses and marrow progenitor responses of chroni- S-phase populations among stem cells (colony-
cally irradiated dogs. The granulocytemacrophage (GM)- forming units (CFUs)) and committed marrow
committed progenitor marrow numbers showed a suppressive precursors;
Shortened lifespan of immature erythroid and single LDR exposure (100 mGy, 10 mGy/min), Sharetskii
myeloid cells due to decreased cell viability in et al. [S18] observed increased thymus-dependent humoral
irradiated animals. immune response and polyclonal activation of B-cells. The
study of the dynamics of primary immune response showed
85. Internal irradiation of animals (using tritiated water that the period of radiation-induced elevation was followed
incorporation) caused much more severe and prolonged by a phase of profound reduction of antibody formation.
immune depression than did external irradiation at the same
total doses, thus indicating the higher relative biological 88. On the other hand, a large number of studies have
effectiveness (RBE) of incorporated radionuclides, even for described stimulative effects of low-dose irradiation, includ-
this low-LET (linear energy transfer) beta emitter [Y1]. ing stimulation of growth rate, enhancement of survival after
lethal high-dose irradiation, prolongation of lifespan, down-
86. The experimental findings of studies, mainly conducted regulation of tumour incidence and activation of immune
in rodents and canines, reviewed by Yagunov et al. [Y1] are function.
summarized as follows:
89. Regarding the activation of the immune function,
Haematopoietic stem cells and blood cell progeni-
LDR WBI of mice increased the proliferative response of
tors seem to be the main target of chronic LD/LDR
splenic and thymic lymphocytes to mitogens such as con-
irradiation;
canavalin A (Con A), phytohaemagglutinin (PHA) or anti-
Direct radiation damage to the blood/immune CD3, with an acute exposure of 20 or 75 mGy [I5, L16,
precursor pool results in a decrease of stem cell L18] or fractionated doses of 200800mGy, 40mGy/d [J6,
fraction; J7, N20, S16, S17]. James and Makinodan [J6] investigated
Radiation-induced depletion of the stem cell and the proliferative capacity of differentiated effector cells in
progenitor pools results in accelerated cycling of the spleen and its correlation with alterations in thymic
bone marrow precursors; precursors and peripheral T-cell subsets. In C57BL/6J
mice exposed to 40 mGy/d over 20 d, the increase in
Decreased viability of mature blood cells results
spleen cell proliferative response was associated with
from ineffective haematopoiesis, thus causing
an increase in the proportion of thymic progenitor cells
restriction of myeloid (and probably lymphoid) cell
(L3T4 Lyt2 equivalent to CD4 CD8) and an increase
reserves;
in the proportion of mature L3T4+ (CD4+) thymocytes. In
Disturbances of cellular and humoral immunity are the spleen, the L3T4+ and Lyt2+ (CD8+) cell proportion
likely to be caused by extreme radiosensitivity of was increased and the double-negative cell proportion was
lymphoid tissues and by a restricted progenitor cell decreased. Interestingly, caloric restriction independently
pool; altered functional activity and T-cell subpopulations in the
Post-irradiation recovery is characterized by gradual same direction as low dose rates. The changes observed are
reconstitution of peripheral blood and bone marrow consistent with an increase in proliferative capacity and
patterns. However, residual deficiency of haema could reflect adaptive mechanisms operating with LDR
topoietic and lymphopoietic precursors may be a irradiation and/or caloric restriction. Interpretation could
limiting factor in blood/immune system recovery; be complicated by the metabolic status of the irradiated
animals. Using the same irradiation protocol, comparable
An increased percentage of S-phase marrow cells
results were obtained by Nogami et al. [N20]. A finding
well after prolonged radiation treatment presents
of interest in this last study is the demonstration that LDR
a typical response of the haematopoietic system
exposure can significantly enhance the proliferative activ-
to LDR irradiation, since this is not observed after
ity of splenocytes in response to T-cell mitogens, but the
acute or subacute irradiation or following chronic
response to LPS, a B-cell mitogen, was not influenced by
exposure to certain heavy metal ions;
the LDR treatment. Recently, Pandey et al. demonstrated a
DNA misrepair following chronic irradiation may preferential activation of CD8+ T-cells as compared with
result in stable chromosome aberrations, increased CD4+ T-cells in mice following stimulation with Con A
incidence of micronuclei, and detectable point after fractionated 200mGy exposure [P11].
mutations in blood/immune populations.
90. Assays of mitogenic-induced proliferation were
87. Courtade et al. [C16] irradiated C57BL/6 female mice also performed using co-cultures of non-irradiated
at 100 mGy/a for two years. No changes were found in splenolymphocytes and peritoneal macrophages preirradi-
cellular immunity parameters regarding CD4+ and CD8+ ated with 20 and 40mGy. The response was increased to
cells in the thymus and the spleen. In this work, cell subsets 120% and 145% of the control, respectively, suggesting
were evaluated by flow cytometry before and after stimula- that the enhancement in Con-A-induced proliferation
tion with lectins. While the number of B-cells in the spleen resulting from LDR exposure was caused not by direct
also remained unchanged, a significant decrease in IgG1, activation of splenocytes but by activation of macrophages
IgG2a and IgG2b was observed, at 12, 24 and 18 months in the spleen, and that the lymphocytes were activated
post-irradiation, respectively. Using mice irradiated with a indirectly [I5]. LDR exposure acts on both the APCs and
the T-lymphocytes, facilitating the intercellular reactions cytokines exert a regulatory effect on lymphocytes, promot-
within the immunologic synapse formed between these two ing their activation. Hashimoto et al. [H20] showed increased
categories of immune cells [L20]. expression of the genes coding for TNF- and IFN- in
splenocytes of tumour-bearing rats given 200mGy of WBI,
91. Data also indicate that enhancement of immune while mRNA of transforming growth factor (TGF-) had
response parameters takes place at a certain very narrow decreased. These findings suggest immune activation, since
range of dose rate and dose. When WBI with an acute dose IFN- plays a key role in both innate and acquired immune
was changed from 20 to 200 mGy, the proliferation was defences and also has antitumour properties, while TGF- is
inhibited [I5]. Likewise, a change in the dose rate from 40 to an immunosuppressive cytokine that allows tumour escape
100mGy/d decreased the proliferative response to PHA or from immune destruction. All of these changes might con-
produced no effect [J7, N20]. tribute to a shift of the immune response in favour of Th1
differentiation.
92. The enhancement of T-cell-dependent immune response
as measured by plaque-forming cell counts after immun- 95. In contrast to these observations, Gridley et al. found
ization with sheep red blood cells (SRBCs) was reported to that LDR irradiation (50mGy at 0.030mGy/h) enhanced the
be stimulated by both single-dose WBI of mice (75 mGy, intracellular expression of IFN- in CD3+ CD4+ T-cells from
12.5mGy/min) [L15] and continuous 1.2mGy/h irradiation C57BL/6 mice. Surprisingly, it did not result in increased
for up to 140 days [I9, I13]. The in vivo T-cell response was levels of secreted IFN- after protracted irradiation alone or
also evaluated by delayed-type hypersensitivity (DTH) after when mice were exposed to a protracted low-dose followed
immunization with Myccobacterium vaccae or dinitrofluoro- by an acute high-dose irradiation [G11]. In the carefully con-
benzene (DNF). While DTH to M. vaccae and DNF was sup- ducted study of Pandey et al. on immunomodulation induced
pressed in C57BL/6 mice, DTH to M. vaccae was increased by LDR irradiation, the secretion of IFN- by C57BL/6 mouse
in BALB/c mice, and DTH to DNF was not significantly spleen cells stimulated by Con A was considerably reduced
changed [S17]. In the same study, the authors reported an in the group irradiated at 200mGy. This may appear contra-
inverted proliferative response to Con-A, with enhancement dictory to the enhanced cytotoxic T-cell response observed
in C57BL/6 mice and suppression in BALB/c mice. Thus in the same study, but IFN- may also have other important
the outcome may depend on the strain of animal, the type of regulatory roles in the immune system [P11].
antigen and the type of response [S17]. Ina and Sakai [I13]
examined the effects of continuous LDR irradiation of the 96. Evidence for the suppressive effect of LDR irradiation
whole body of several wild-type mouse strains and observed on tumour growth, metastases and carcinogenesis has been
a significant activation of the immune system both before and presented. Ishii and colleagues reported a decreased incidence
after the immunization with antigens. The different strains of spontaneous thymic lymphoma in AKR mice as a result
displayed different levels of response but with the same ten- of chronic fractionated low-dose whole-body X-irradiation
dency: significant increases of CD4+ T-cells, CD8 molecule [I1]. In another well-recognized model of thymic lymphoma
expression and CD40+ B-cells, and significant enhancement induced in C57BL mice by fractionated WBI (four acute
in SRBC-antibody-producing cells by immunization. The doses of 1.8Gy, one per week), preirradiation with 75mGy
age at exposure may also determine the intensity of immuno given before each 1.8 Gy dose decreased the frequency of
enhancement, since the presence of a non-involuted thymus tumours from 90% to 63%. This level was further lowered to
contributes to this response [P11]. 43% by continuous WBI at 1.2mGy/h for 450 days starting
35days before the first 1.8Gy dose. Interestingly, continu-
93. Furthermore, the efficiency of the immune response ous irradiation to a total dose of 7.2Gy over 258 days yielded
was measured by the NK activity of splenocytes [C21, N24], no thymic lymphoma. In parallel, CD4+ T-cells, CD40+
functional response of macrophages and cytokine secretion B-cells and plaque-forming-cell counts in the spleen were
[G11, H20, L18, L19, P11, S33]. Enhanced cytotoxic activity significantly increased by continuous 1.2mGy/h irradiation
of NK cells was found between 24 and 72h post-irradiation alone, indicating the involvement of immune activation in
in whole-body-irradiated BALB/c mice with single doses of tumour suppression by LDR irradiation [I9]. However, other
100 and 200mGy [C21, N24]. LDR irradiation also enhanced modifying factors, such as DNA repair and elimination of
the phagocytic activity of macrophages from C57BL/6 mice injured cells by apoptosis, are involved in the mechanisms
exposed to a total dose of 200mGy (40mGy/d) [P11]. for suppression of tumours. In addition, the complex nature
of murine thymic lymphoma, with involvement of cell kill-
94. Regarding the modulation of cytokine expression by ing in the aetiology of the tumour, makes the interpretation
LDR irradiation, increased secretion of interleukins that acti- of the data difficult [C34].
vate T- and NK cells, such as IL-2 by mouse splenocytes,
and IL-1 and IL-12 by APCs, has been described, as well 97. Significant suppression of the development of pul-
as down-regulation of IL-10 synthesis in splenocytes fol- monary tumour nodules was reported by Ju et al. [J8] and
lowing WBI with 75mGy [J8, L14, L18, L19]. There have Cai [C33], who irradiated mice with single doses of Xrays
been observations of the increased secretion of TNF- and ranging from 50 to 150mGy, 24h before injection of B16
IL-1 by macrophages in response to WBI of mice with both melanoma or Lewis lung cancer cells. These results were cor-
low and high doses [I6, S33]. These two pro-inflammatory roborated later by Cheda et al. [C21], who injected syngeneic
low-immunogenic sarcoma cells into BALB/c mice 2h after Their results indicated that the percentage of thymocyte
WBI with 100 or 200 mGy. This resulted in significantly apoptotic bodies decreased, the arrest of G1 and G2/M
reduced pulmonary tumour colonies. The authors associated phases diminished and the frequency of cells in S-phase
the effect with stimulation of NK-cell-mediated cytotoxicity increased. However, when the priming dose was 200mGy,
detected in splenocyte suspensions obtained from irradiated the adaptive response was no longer induced. Furthermore, a
mice but not from sham exposed mice. dose-dependent increase in thymocyte apoptosis was found
with doses of 250 mGy or higher [M27]. The question of
98. A report of the French Academy of Sciences exten- threshold dose for the immune-enhancing effects is critical.
sively reviewed published data concerning the doseeffect It depends on the end point tested, but the dependence on
relationship and carcinogenic risk of low doses of ionizing other factors such as animal species and the radiation dose
radiation [F11]. A database of cancer induction by LDR rate is still an open question [S34].
irradiation obtained from 472 different animal experiments
was analysed [D30]. The meta-analysis showed that the 102. Selective changes in the expression of proteins are
spontaneous cancer rate fell significantly after LDR irradia- reported to accompany LDR exposure [S17]. Increased lev-
tion in only 40% of those experiments that could potentially els of stress proteins were observed in mitogen-stimulated
have revealed the effect. It was suggested that, together with splenocytes of mice exposed to LDR radiation. The bio-
other mechanisms, the finding could partly be explained by logical relevance of this was supported by the demonstration
the stimulation of immunological mechanisms. However, that splenocytes that failed to elevate their constitutive levels
the author states that the statistical strength of the overall of heat shock proteins following LDR irradiation also were
observations has not yet been determined. Although many unable to increase their capacity to proliferate [N20]. Later,
observations show a reduction in the cancer rate and a longer Chen et al. isolated a 10 kD protein from thymocytes after
life in low-dose-irradiated animals, these studies should act LD WBI. This protein, named RIP10, potentiates spontan-
as a focus for further research in order to confirm or disprove eous thymocyte and mitogen-induced splenocyte prolifera-
the generality of the effects. tion, and modulates apoptosis [C23]. In addition, changes in
cell cycle and apoptosis-related intracellular and extracellu-
99. The adaptive response to radiation is a biological lar proteins accompanying increased response to Con A in
defence mechanism in which low-dose ionizing radiation (a mouse lymphocytes following WBI were reported [S16].
priming dose) elicits cellular resistance to the genotoxic
effects of subsequent irradiation (the challenge dose) 103. Although growing evidence suggests that low-dose
[S37]. The adaptive response to radiation in animal and WBI can be immunostimulatory, many of the questions
human populations, as well as its effects on the immune about immunoenhancement remain unanswered and require
system, have been extensively considered in the UNSCEAR further experimental studies. One important aspect is the
1994 Report, annex B [U4]. molecular basis of the stimulatory effect of LDR irradiation.
Experimental data have been accumulating in this field. It
100. The adaptive response has been observed after WBI. has been reported that the intracellular free Ca2+ concentra-
The experiments show that a priming exposure to chronic tion increases after LDR irradiation and that protein kinase
irradiation can induce radioresistance in mice. The manifest- C (PKC) also increases in response to different doses of radi-
ation of this resistance is reduced mortality (from the haema- ation, leading to the activation of early genes. Another signal
topoietic syndrome) of pre-exposed mice after a challenge pathway involved is the cyclic adenosine monophosphate/
acute irradiation [S43]. Yonezawa et al. have reported that cyclic guanosine monophosphate protein kinase A (cAMP/
pre-exposure of mice to 500mGy two weeks before a lethal cGMP-PKA) cascade: the cAMP/cGMP ratio falls after LDR
(78Gy) WBI induced marked radioresistance and survival irradiation, with PKA responding in the same pattern. A
of the mice [Y7, Y8]. Later, using the same priming dose third pathway is phospholipase 2-prostagalandin E2 (PLA2-
and a challenge dose of 5 Gy for haematopoietic studies, PGE2), which is also down-regulated. An adaptive response
they investigated whether preirradiation favours recov- mediated by a feedback signalling pathway involving p38
ery of pluripotent haematopoietic stem cells. They found mitogen-activated protein (p38 MAP) kinase, phospholipase
that radiation-induced resistance to lethality appeared to C (PLC) and PKC has been demonstrated [L20].
be closely related to the recovery of endogenous colony-
forming units of the spleen (CFU-S), with a maximum
response when the priming dose was given 14 days before 2. Human data
the challenge dose [Y5]. In addition, they demonstrated that
the adaptive response at a challenge dose of 5Gy seemed to 104. Although few data are available on the effects of
be induced through a reduction of p53-dependent apoptosis low-dose exposures on humans, some reports suggest that
in haematopoietic stem cells [H29]. chronic low-dose radiation exposure can lead to effects
on the human immune system. Chang et al. analysed the
101. Gong and co-workers [G28] studied thymocyte immune status in residents of buildings constructed using
apoptosis and cell cycle progression induced by WBI in 60
Co-contaminated steel rods [C7]. They evaluated CD3+,
Kumming mice, using priming doses of 25200mGy and CD4+, CD8+ and HLA-DR+ markers in lymphocyte sub-
challenge doses of 12Gy given 6h after the priming dose. sets in 196 exposed subjects with a mean cumulative excess
dose of 169mSv (range 81,662mSv) protracted over 213 Research Centre (Seibersdorf), exposed during the pre-
years. These results were compared with those obtained in ceding 3 months to very low doses of gamma radiation
55 close relatives considered to be the non-exposed refer- (from 0.2 to 4.9mSv). The percentages of CD2+, CD4+,
ence population. They analysis was restricted to individuals CD8+ and NK cells were investigated in peripheral blood
with no apparent history of medical conditions that could lymphocytes. Data were pooled in two groups of individual
compromise their immune profile. The mean percentages doses: <0.5mSv and >0.5mSv. Except for a slight increase
of CD4+ T-lymphocytes and HLA-DR+ lymphocytes and in the relative number of cells expressing CD2 (a marker
the CD4+/CD8+ ratio in the exposed individuals were sig- of T-cell activation), radiation-associated changes were not
nificantly lower than those in the reference population, while observed [T8].
total CD8+ cell counts in the exposed individuals were mod-
erately increased compared with the reference population. 108. Previously, the same group of authors had reported
In addition, changes in the percentages of CD4+ T-cells and that lymphocytes of radiation workers exposed to 0.14
HLA-DR+ activated T-cells were significantly associated 0.98 mGy/month exhibited an enhanced capacity to repair
with radiation dose, while CD4+/CD8+ ratios were only DNA damage inflicted by an in vitro challenge dose of ultra-
moderately associated with dose [C7]. Low CD4+/CD8+ violet (UV) radiation [T17]. More recently, Mohankumar et
ratios are observed in primary or secondary immune defi- al. have analysed the UV-induced DNA repair capacity of the
ciencies, and this ratio has been proposed as a method for lymphocytes of 16 healthy, non-smoking radiation workers of
estimation of the cellular immune status [H25]. The results the Indira Gandhi Centre for Atomic Research, Kalpakkam,
presented by Chang et al. suggest that protracted gamma India, who received whole-body gamma exposures ranging
radiation exposure in a residential environment may induce between 1 and 6.3mGy during a period of 3months prior
a dose-dependent decrease of cellular immunity. However, to the study [M25]. At very low gamma doses (11.9mGy),
these findings should be interpreted cautiously, taking into they found higher UV-induced unscheduled DNA synthesis
account the wide range of cumulative doses and their pro- (UDS) levels in samples receiving gamma irradiation in vitro
traction among the exposed subjects. A new analysis of these than in control samples, but there was no such increase in the
results separating subgroups of people with narrower dose radiation workers samples, owing mainly to the large stan-
ranges could allow higher-quality conclusions to be drawn. dard deviation values of the means. For doses of over 2mGy,
both in vitro and in vivo irradiated samples show higher
105. Immune status was evaluated by Godekmerdan et al. UDS levels. De novo synthesis of repair enzymes induced
in 50 radiology workers [G26]. A decrease of CD4+ helper by low-dose ionizing radiation exposure was suggested as an
T-cells with diminished levels of immunoglobulins (IgA, explanation for these results. Particularly in the dose range
IgG and IgM) and complement (C3 and C4) was found, 37mGy, the UV-induced DNA repair capacity of radiation
suggesting impairment of cellular and humoral immunity. workers lymphocytes was higher than that of cells exposed
The authors make reference to the fact that there was no in vitro. These authors tried to explain these findings as an
significant difference between subjects exposed for more adaptive response of lymphocytes to radiation, due to cell
than or less than 5 years. This study does not provide data renewal mechanisms, that led to a shift in the lymphocyte
concerning either cumulative doses or dose rates. There is population in favour of a cell type with greater DNA repair
no mention of the type of medical procedure performed capacity. They also postulated a possible involvement of
by the subjects involved in this study or the area of the the endocrinological system. However, the sample size was
radiology department in which they worked. Thus it is not too small to confirm the observations and to sustain these
possible to establish a relationship between these findings hypotheses.
and radiation dose.
109. Tuschl et al. [T9] investigated some immunological
106. Rees et al. did not find significant changes in the parameters in 10 nuclear power plant (NPP) workers exposed
immune profiles of 325 male workers occupationally during a 4-week period to external radiation (1.49.8mSv)
exposed to external low-LET radiation at the British Nuclear and tritium inhalation (committed effective doses of 1.2
Fuels facility at Sellafield, United Kingdom. The cumula- 2.8mSv). Blood samples were taken 25 days after the start
tive exposures were >200mSv in a period of from 19.1 to of this exposure period for quantification of lymphocyte sub-
45.7years in one group and <27.5mSv in a period of from sets and evaluation of their mitogenic response to PHA. Data
15.1 to 32.5 years in the other. No statistically significant dif- were compared with reference values obtained in healthy
ferences in circulating T- and B-cell total counts, CD4+ and donors. CD4+/CD8+ ratios were increased in NPP workers
CD8+ T-cell subsets, CD4+/CD8+ ratio or CD3+/HLA-DR+ owing mainly to an increase in absolute numbers of CD4+
were observed [R3]. This study took account of possible T-cells. The authors interpreted these findings as a potenti-
confounding factors such as age, sex and cigarette smoking, ation of the immune response by low radiation doses and
and the sample size was sufficient to substantiate the conclu- suggested selective cell renewal of CD4+ T-cells as a pos-
sion that occupational exposure to low doses does not affect sible underlying mechanism. Although the tritium burden in
the immune profile of workers. these workers was very small (0.476.3kBq/24h in urine),
they postulated that the RBE of beta particles from tritium
107. Similar findings were reported by Tuschl et al. in may account for this effect, which was not observed in other
employees working at the research reactor of the Austrian studies of occupationally exposed workers. Nevertheless, the
sample under investigation was too small, and further studies Ramsar residents [G20]. Concerning humoral immunity,
are needed to substantiate this hypothesis. IgG and IgA levels were not different, whereas a significant
increase in IgE levels was observed in Ramsar residents.
110. Beta particles from tritium are of greater biological The authors interpreted this finding as radiation-induced
effectiveness than gamma rays and Xrays. At low doses or immunostimulation due to a shift from a Th1 to a Th2
low dose rates, RBE values of 23 have been proposed for response. While no differences were found in the expression
the oxide form and even higher values when tritium is bound of CD69 (a marker of lymphocyte activation) in unstimu-
to organic molecules [S47]. However, depending on the end lated samples, the expression of CD69 was higher in PHA-
point and the irradiation conditions, RBE values for beta stimulated CD4+ helper T-cells of Ramsar residents, a finding
particles from tritium may greatly differ [M26, T10, T14]. that the authors considered as an indication of a higher risk of
The total number and percentage of leucocyte subpopula- proto-oncogene activation. However, taking into account the
tions were determined in 54 workers exposed to tritium in lack of consistency between these two papers [G1, G20], the
the workplace. Tritium contamination was well below the results are not conclusive, and these hypotheses appear rather
annual limit on intake for occupationally exposed subjects speculative. The frequency of chromosome aberrations was
(mean tritium activity in urine: 1.9kBq/litre). The functional also higher in residents from other HLNRAs in Brazil [B18]
status of leucocytes was evaluated by alkaline phosphatase and China [C22]. It has been reported that smoking plays a
(AP) and myeloperoxidase (MP) activity staining. While more significant role than natural radiation in the induction
total leucocyte counts did not differ from those of the con- rate of stable lymphocyte aberrations in those areas [Z2].
trol group, lymphocyte and eosinophil counts were higher However, this statement should be interpreted with caution
in radiation workers. AP and MP activities were lower in since a recent meta-analysis from retrospective biological
exposed workers [M23]. The author interpreted the increase dosimetry data from seven European laboratories indicated
in lymphocyte counts as a stimulation of the immune system that there was a strong variation of translocation yield with
by tritium and eosinophilia as a compensatory reaction of age, but no variation was detectable with sex or smoking
the bone marrow, where tritium had entered and disturbed habits [W17].
enzyme synthesis in leucocyte precursors. The author stated
that the workers had no clinical manifestations of immun-
ity disorders. The selected end points seem inappropriate for 3. Remarks concerning low-dose/low-dose-rate irradiation
evaluation of both innate and acquired immune response.
The biological significance of these data cannot be readily 113. On the basis of the previous paragraphs, the following
discerned, and these results are inconclusive. remarks may be made concerning LD irradiation data. It has
been reported in some animal studies that under protracted
111. Few data have been published concerning the impact gamma ray exposure at low dose rates, the normally highly
on the immune system of people living in high-level nat- radiosensitive haematopoietic system adapts and becomes
ural radiation areas (HLNRAs). Comparison of cord blood radioresistant. Depending on the dose and dose rate, induced
samples from newborns from the Kerala coast in India (aver- the pattern of changes in leucocyte populations can be
age dose rates of greater than 1.5mSv/a) with samples from described as an initial suppressive phase followed by a stable
newborns from areas with lower levels of natural radiation accommodative phase. This pattern of changes is preceded
(less than 1.5mSv/a) did not show any significant difference by similar changes in the haematopoietic progenitor cell
in the frequency of dicentrics, translocations, inversions or compartment. However, it was suggested that the recovery
other types of aberration known to be associated with radia- of marrow precursors might be incomplete.
tion exposure [C26]. Ghiassi-Nejad et al. reported in 2002
that no differences were found either in laboratory tests of 114. In animal experiments there is evidence demon-
the immune system or in haematological parameters among strating that LDR irradiation can produce activation of the
people living in Ramsar, an HLNRA in the Islamic Republic immune function. Enhancement of the proliferative response
of Iran, where the mean dose rate is 260mSv/a [G1]. Simi- of splenic and thymic lymphocytes to mitogens, enhance-
lar results had previously been reported for people living in ment of NK activity and increased secretion of cytokines
Yangjiang, an HLNRA (6.4 mSv/a) in China [Z1]. In this with regulatory effect on immune cells promoting their
preliminary study, Ghiassi-Nejad et al. did not observe sig- activation, inter alia, have been reported. Nevertheless, the
nificant differences in the basal frequency of chromosome data are not entirely consistent, and the observed effects are
aberrations in peripheral blood lymphocytes between people highly dependent on the range of dose and dose rate, and
living in Ramsar and people living in normal background upon the animal and strain of animal studied.
areas. Following a dose of 1.5Gy of gamma rays in vitro,
lymphocytes of Ramsar residents showed a significantly 115. Data demonstrating suppressive effects of LDR expo-
reduced frequency of chromosome aberrations. The authors sure on tumour growth, metastases and carcinogenesis have
interpreted their findings as an adaptive response induced by been reported. An association of these effects with enhanced
chronic radiation exposure. NK activity of splenocytes, higher antibody-dependent
cellular toxicity and increased levels of CD4+ cells, CD40+
112. Two years later the same group published new results B-cells and plaque-forming cells in the spleen has been
showing a higher frequency of chromosome aberrations in found.
116. An adaptive response to radiation is another pheno may be normal or minimally depressed below baseline levels
menon observed in many systems. Interestingly, radiation- 35 weeks after exposure [G23]. The haematopoietic syn-
induced resistance to lethality after WBI with a high drome may be seen following doses of >1Gy. Acute whole-
challenge dose in mice appeared to be closely related to body doses of below 2 Gy induce mild cytopenia without
the recovery of CFU-S after the priming dose. It was also significant bone marrow damage. Laboratory analysis in
related to the reduction of apoptosis in the haematopoietic cases with WBI of greater than 2 Gy can show an initial
stem cells, giving insight into the possible mechanisms by granulocytosis, with pancytopenia evident within the first
which these adaptive processes occur. month after exposure [G23]. Mitotically active haemato
poietic progenitors are unable to divide after a whole-body
117. Regarding human data, while some authors have dose of >23 Gy, resulting in haematological crisis in the
reported evidence for effects after chronic LDR irradiation, following weeks [G22]. During this symptom-free period of
others have not found such evidence. A dose-dependent ARS (latency phase), the blood-producing cells in the bone
decrease of cellular immunity, mainly evaluated by the marrow begin to diminish and are not replaced, leading to a
CD4+/CD8+ ratio and HLA-DR+ activated T-cells, was severe shortage of white blood cells, followed by a shortage
described for residents of buildings constructed with of platelets and then red blood cells. The shortage of white
Co-contaminated materials, although these findings should
60
blood cells can lead to severe immunodeficiency, increasing
be interpreted cautiously. In contrast, no significant changes the risk of infectious complications and impairing wound
were observed in the same parameters of workers occupa- healing [D1, G23].
tionally exposed to external low-LET radiation in nuclear
facilities. 123. The rate of decrease for different leucocytes in the
blood after WBI is dependent on their particular cell cycle
118. Concerning tritium incorporation, it would appear kinetics. Neutrophils have a relatively short lifespan, and
to have a higher RBE than external irradiation at the same thus they have a tendency to be depleted over a matter of days
doses. This has been observed in both experimental studies following acute WBI, owing to radiation-induced damage to
and human studies, but the results are inconclusive. their progenitor cells. They show an initial increase within
the first few days after doses of >2Gy; this increase is greater
119. In the same way, when the impact on the immune after higher doses. This first abortive rise may be due to
system of living in areas with high levels of natural radia- a cytokine-dependent transient mobilization from bone
tion was analysed, the results were controversial, and the marrow or extramedullar sites and to accelerated maturation
significance of these findings remains unclear. of granulocyte precursors. A progressive neutropenia then
occurs, the rate and extent of which are dose-dependent; this
may be followed by a second abortive rise following doses
C. Data concerning high-dose irradiation of <5Gy as a result of haematopoiesis recovering from pre-
cursor cells. This second abortive rise is not seen follow-
1. High-dose-induced immunosuppression ing doses of >5Gy, indicating the failure of haematopoiesis
to recover permanently after very high doses, a finding that
120. The effects of radiation on the immune system gen- may be clinically helpful as a prognostic indicator [G22].
erally intensify with the dose received. Massive cell death, The duration of neutropenia may be long, requiring pro-
inflammation and infection are the acute effects of high-dose longed administration of haematopoietic growth factors,
radiation exposure. Human data concerning the effects on the blood product support and antibiotics.
immune system of WBI have been widely studied in victims
of radiation accidents and in patients undergoing WBI as a 124. In non-uniform exposures, evaluation of cytopenia
conditioning regime for bone marrow transplantation. The may be somewhat misleading because the cumulative curve
effects of high doses of ionizing radiation upon immune sys- of the granulocytes averages the actual production by
tem function were reviewed by the Committee in 1988 [U6]. different portions of the bone marrow that have received dif-
ferent doses. Temporal parameters in such cases are more
121. Acute radiation syndrome (ARS) occurs after WBI relevant to the magnitude of the dose, and blood counts are
or substantial partial-body irradiation of greater than 1Gy, more correlated to the volume of damaged bone marrow.
delivered at a relatively high dose rate [G22]. With the Lymphopenia in non-uniform WBI is more prolonged than
exception of the haematopoietic syndrome, the other clinical in uniform WBI [G34]. When the ARS is associated with
components of ARS (gastrointestinal and cerebrovascular) cutaneous radiation syndrome, the lymphohaematopoietic
are not the subject of this annex, and they are reviewed else- suppression impairs wound healing and increases the risk of
where [K45, W9]. Since granulocytes and lymphocytes are wound bleeding and infection [B16].
an essential part of the immune system, profound abnormali-
ties of immune function are expected as a consequence of 125. A follow-up of neutrophil values for several days
high-dose WBI. post-irradiation was found to correlate well with dose. The
time to reach the critical level of 500 granulocytes/mL has
122. A patient who receives acute external WBI in the been proposed as a dosimetric bioindicator [B30]. However,
range 0.51Gy is generally asymptomatic, and blood counts in many cases of overexposure, an earlier approximation of
dose is required for efficient medical intervention. This can of dosimetry [G3]. This technique was further extended
be achieved by counting the decrease of lymphocytes, as to include analysis of various types of criticality accident.
their nadir is reached much earlier than for other cell types. Lymphocyte depletion in high-level mixed gammaneutron
The predictability of lymphocyte depletion following high accidents was found to be approximately equal, at a given
doses of ionizing radiation, which may be recognized within effective dose, to that for gamma ray accidents. This finding
hours of exposure, has allowed the development of biodosi- indicates that, in terms of lymphocyte depression, the RBE
metric models. This approach was originally developed to of neutrons could be close to unity [G24].
give a rough categorization of the magnitude of exposure
(figureVI).
2. Immune reconstitution
Figure VI. Classical Andrews lymphocyte depletion curves 128. Reconstitution of the immune system after radiation-
and clinical severity ranges. induced bone marrow aplasia has been widely studied in
Whole-body doses: curve (1), 3.1Gy; curve (2), 4.4Gy; curve (3), patients undergoing bone marrow grafting. Bone marrow
5.6Gy; curve (4), 7.1Gy [G3]. transplantation is characterized by a subsequent period of
immunodeficiency, the duration and severity of which vary
Patterns of early lymphocyte according to graft manipulation, choice of graft type (donor
response in relation to dose
and source), development of graft-versus-host disease and
level of residual thymic activity.
3000
129. During the first month, T-lymphocytes reconsti-

tute by peripheral expansion of the T-cells present in the
graft. Thereafter, starting from 100 days after transplanta-
Normal tion, the production of substantial numbers of new naive
LYMPHOCYTE COUNT (L-1)
range T-cells by the thymus can be detected [D9]. Rapid early

2000 expansion of transferred or residual mature T-lymphocytes
(1)
of extrathymic origin results in inversion of the CD4/CD8
ratio, which persists primarily as a result of delayed CD4+
T-cell recovery. Normalization of the CD8+ subset after
60days was reported, while persistent CD4+ reduction has
(2) Moderate been observed after 2 years, and normalization of the CD4+
subset was achieved only after 6 years in a long-term study
1000
[L4]. The different behaviour in this immune reconstitu-
Severe Injury tion may be explained by an extrathymic origin of CD8+
(3)
cells, while the CD4+ subset recovery, which is thymus-
500 dependent, is impaired in the adult population. In children,
Very who are characterized by having greater amounts of active
(4) severe thymic tissue and more effective thymopoiesis than adults,
100 there is a more rapid recovery of CD4+ T-cells, which
0 express a naive phenotype (CD45RA+). This finding may
0 1 2 have significant implications for attempts to generate pro-
TIME (DAYS) tective immunity against pathogens and clinically relevant
antitumour responses by vaccination strategies in the
post-transplantation period [P7].
126. A mathematical biodosimetric method for evaluating
uniform WBI by peripheral blood lymphocyte and neutrophil 130. Oligoclonal B-lymphocyte repopulation can be dem-
counts was widely used and validated following the Cherno- onstrated in the early post-transplantation period, achieving
byl accident [B31, U6]. The doses evaluated by peripheral normal values after 90120 days [L4]. Serum immunoglobu-
blood cell counts, chromosome aberrations and electron spin lin levels usually decrease post-transplantation, followed by
resonance of tooth enamel were highly correlated [B30]. a gradual increase and normalization in a sequential pattern
similar to that identified in neonates. Recovery initially
127. A mathematical model for lymphocyte depletion fol- occurs in IgM levels (26 months), followed by IgG levels
lowing gamma irradiation, intended only for providing a first (318 months) and finally IgA levels (636 months), the time
approximation of dose, was developed on the basis of acci- depending to some degree on conditioning and graft charac
dent cases with recorded haematological data and physically teristics [P7]. Cooperation between T-cells and B-cells is
reconstructed doses. During the first 8 hours after exposure, necessary for antibody production. Thus, although B-cells
the decrease in lymphocytes followed a single-term expo- transferred with the graft may confer temporary protection
nential curve, and the rate constant for this decrease corre- against pathogens, antigen-specific T-cells must be regener-
lated well with dose estimates obtained from other sources ated in order to ensure sustained B-cell competence [L4].
131. Reconstitution of innate immunity following trans- D. Influence of dose rate and radiation
plantation is characteristically more rapid than for acquired quality on immune response
immunity. Most studies have shown early normalization
or even rebound increases in NK cell numbers in the early 135. Several studies have examined the immunomodulat-
months [P7]. NK cells might provide an efficient defence ing effects of whole-body exposure to different qualities of
against pathogens and residual tumour cells, especially radiation. The driving forces for these investigations are the
immediately after transplantation, where the lack of coop- challenges created by exposures in the space flight environ-
eration between T-cells and B-cells results in an inability to ment (which are dominated by charged particles [S21, S28]),
produce antibodies. clinical use of proton radiation in the management of cancer
[L9, S23] and exposures due to radon and its progeny [N1].
132. The results presented all support the conclusion that
normalization of immunological function is achieved within
several years after transplantation. The functional capacity 1. Low-LET exposures
of the recipient thymus appears to be the dominant influence
on thymus-dependent reconstitution. Thymus-independent 136. The effects on the immune system of radiation, such
reconstitution, which accounts for the majority of the early as gamma rays or Xrays, have been extensively investi-
reconstitution, might be predicted to depend more heavily gated and reviewed [A13, S1, U8, U10]. Variability in the
on stem cell sources. biological response may reflect differences in the total dose,
dose rate, end points measured and time of evaluation post-
exposure. Analysis of the influence of each of these variables
is of importance not only in radiation therapy but also for
environmental or occupational radiation exposure [G8].
3. Remarks concerning high-dose irradiation
137. Pecaut et al. [P6] investigated early effects on mice of
133. As discussed in the preceding paragraphs, acute gamma ray doses of up to 3Gy at low and high dose rates.
WBI in the range 0.51 Gy is generally asymptomatic, They observed a significant dose-dependent loss of spleen
and leucocyte counts may be minimally depressed or even and thymus mass, which was somewhat independent of dose
normal. Acute radiation syndrome (ARS) occurs after rate. Decreasing lymphocyte and leucocyte numbers in the
acute whole-body or substantial partial-body exposure of blood and the spleen with increasing dose, as well as dose-
>1Gy. While mild cytopenia is observed within the range dependent decreases in lymphocyte subpopulations (CD4+
12Gy, initial granulocytosis (first abortive rise) followed helper T-cells, CD8+ cytotoxic T-cells and CD19 B-cells)
by pancytopenia within the first month result from whole- were observed at both dose rates. While the percentages of
body doses of greater than 2 Gy. A second granulocyte CD4+ increased with increasing dose (with some differences
abortive rise may be seen when the whole-body dose is between blood and spleen), the percentages of the CD8+
below 5 Gy. In non-uniform exposures, temporal blood population remained stable in both compartments, and
cell parameters are more relevant for dose estimation than CD19+ cells declined markedly with high or low dose rate.
the magnitude of cytopenia. Mathematical models have The number and proportion of NK cells remained stable.
been developed for correlating the dose with the kinet- Because of the differences in phenotypic radiosensitivities,
ics of lymphocyte depletion during the first hours after a decrease in lymphocyte counts sometimes results in a pro-
exposure. portional enrichment of specific cell types. Overall, these
data indicate that the changes observed were highly depend-
134. Acquired immune reconstitution after radiation- ent on dose but not on dose rate, and that cells in the spleen
induced bone marrow aplasia includes both thymus-dependent are affected more by dose rate than those in the blood.
and thymus-independent pathways. T-lymphocytes recon-
stitute during the first month by peripheral expansion, and, 138. Similar data have been reported for high-dose treat-
during the following months, new naive T-cells begin to ment under comparable experimental conditions [H11, W5].
appear from the thymus. However, an inversion of the CD4/ A more pronounced dose-rate effect was seen in spleen
CD8 ratio persists for several years. While CD8+ T-cells mass, probably owing to a change in homing receptors in cir-
normalize within two months, the recovery of CD4+ T-cells culating populations of splenic endothelial cells [P6]. It has
may be achieved within 6 years. Central T-cell recovery been demonstrated that ionizing radiation can up-regulate
in adults is delayed relative to that in children, probably the expression of ICAM-1 and E-selectin, both of which
owing to differences in thymic function. B-lymphocyte are important in leucocyte trafficking. CD44, a molecule
repopulation takes place during the first 4 months. Follow- involved in the migration and homing of immune cells, was
ing an initial decrease of immunoglobulin levels, recovery altered in irradiated lymphoid cells [H3, N1].
gradually occurs in IgM levels (26 months), IgG lev-
els (318 months) and Ig A levels (636 months). Innate 139. Using the same animal model, the functional charac-
immune reconstitution is more rapid than reconstitution of teristics of splenocytes and cytokine expression was evalu-
acquired immunity. NK cells normalize or even increase in ated after WBI at various total doses and at low and high
the early months. dose rates [G8]. An assay of spontaneous blastogenesis in
leucocytes is sometimes performed in order to determine end points, including chromosome aberration induction in
the proliferative capacity and activation of lymphocytes. human lymphocytes. Immediate early death of lymphocytes
Mitogen-induced cell proliferation is employed exten- and thymocytes after neutron irradiation seems to be com-
sively to assess the general responsiveness of lymphocytes parable to that for low-LET gamma rays and X-rays when
to stimulating agents. The data showed that at 4 days post- assayed by apoptosis, suggesting that the neutron RBE
irradiation, increasing doses resulted in a rise in spontaneous is close to unity for this end point. Moreover, the route to
blastogenesis in blood and spleen leucocytes. This finding cell death is independent of dose rate. These observations
was correlated with a reduction in white blood cells [P6], are in marked contrast to the much larger RBE values and
and suggested that cell regeneration was in progress. Spleno- dose-rate effects typically seen in many systems of clono-
cyte response to LPS (bacterial lipopolysaccharide), a potent genic survival, replicative death and chromosome aberration
non-specific stimulator of B-cells, was inversely related to formation.
radiation dose. This finding is consistent with the demon-
stration that B-cells are the most radiosensitive lymphocyte 143. Warenius and Down compared apoptosis in mouse
subpopulation [C6, P6, W14]. Lymphocyte responsiveness thymocytes following exposure to low doses of fast neutrons
to T-cell mitogens (PHA and Con A) was shown to depend (62.5 MeV) and photons (4 MeV). Both the time course
on experimental conditions. A decreased ability of spleno- and the radiation doseresponse curves were similar for
cyte mononuclear cells to respond to mitogens after WBI high- and low-LET radiation modalities [W16]. Vral etal.
(07Gy) was described by Harrington et al. [H5]. examined the effectiveness of fast neutrons compared with
60
Co gamma rays for inducing apoptosis in human lympho
140. Acute doses of some centigrays, as well as chronic cytes. Doses ranging from 0.05 to 5 Gy were applied at
WBI, can enhance mouse splenocyte response to these 0.2 Gy/min (fast neutrons) or 1.5 Gy/min (gamma rays).
mitogens [L15, N13]. Furthermore, WBI induced changes To investigate the role of DNA repair in apoptosis induc-
in expression of CD25 (IL-2 receptor) and CD71 (transfer- tion, they also performed irradiations at low dose rates
ring receptor) activation markers [M7]. IL-2 secretion by (0.006Gy/min). They found that apoptosis induction was
PHA-activated splenocytes was reduced in a dose-dependent independent of LET and dose rate (the calculated RBE for
manner. Plasma levels of transforming growth factor fast neutrons was close to unity), suggesting that the ini-
1 (TGF-1) and splenocyte secretion of tumour necrosis tial DNA damage, as opposed to DNA repair, dominates
factor (TNF-) were not affected by either the dose or the the induction of apoptosis in resting lymphocytes [V7].
dose rate of radiation [G8]. The data demonstrate that the Ryan et al. examined apoptosis in human lymphocytes fol-
responses of the blood and the spleen for the immune para lowing doses of between 0.25Gy and 5Gy of low-energy
meters studied were largely dependent upon the total dose of fast neutrons (280keV mean energy) and of 137Cs gamma
radiation and that dose rate was not a significant factor. radiation. They found that neutrons are equally as effective
as gamma radiation at inducing apoptosis in lymphocytes
141. Even though the quantity of energy deposited is [R23]. Goans et al. analysed lymphocyte depletion kinetics
minimal, a repetitive irradiation inflicts a series of small in various types of criticality accident (high-level mixed
insults on the tissue. Each delivered fraction contributes to gamma/neutron fields). The results were approximately
the development of inflammation. For a repetitive radiation equal, at a given effective dose, to those for gamma acci-
exposure with low to medium doses, the amount of the cumu- dents, suggesting that the RBE of neutrons could be close
lative dose is more important than the number of fractionated to unity for this end point, regardless of the structure of
doses. Gremy et al. [G32] showed a modulation of expression their energy spectra [G24].
of inflammation mediators during fractionated gamma radia-
tion restricted to a colorectal zone in the rat (5Gy 3 times a 144. Huiskamp et al. compared the effect of WBI with
week, maximum dose 45Gy). The IL-1 mRNA showed an fission neutrons (1MeV mean energy) and 300kVp X-rays
overexpression from a cumulative dose of 20Gy. The level on the supportive role in T-cell differentiation of the
of IL-10 mRNA was highly repressed at 45Gy. The mono- thymic stroma of neonatal CBA-H mice, after transplanta-
cyte chemoattractant protein 1 (MCP-1) chemokine expres- tion to athymic nude mice. Doses varied from 2.75Gy to
sion progressively increased with the cumulative dose, while 6.88 Gy (0.1 Gy/min) for neutrons and from 6 to 15 Gy
IL-8, less overexpressed, went to a maximum expression at (0.3Gymin) for X-rays. Although irradiation had no effect
20Gy. Some signalling pathways were altered, exacerbated on the stromal and T-cell composition of grafts, the graft
or suppressed, triggering a neutrophil recruitment to the size decreased in a dose-dependent manner with an RBE
inflammatory site at the end of the irradiation protocol. of 2.1 for fission neutrons [H32]. Holl et al. evaluated the
effect of WBI with 65 MeV neutrons or 15 MeV X-rays
on spleen cells of BALB/c mice following doses ranging
2. High-LET exposures from 0.2 to 3Gy. Their results indicated that the RBE of
neutrons differs depending on the end point selected, since
(a) Neutrons they found that the level of apoptosis was equal for high-
and low-LET radiation (RBE = 1), whereas spleen weight
142. Neutrons have been shown to have high values of and cellularity were reduced to a greater extent by fast
relative biological effectiveness (RBE) for some biological neutrons (RBE = 2) [H31].
(b) Protons of 10mGy/min or 800mGy/min). Treatment with protons

caused a significant dose-dependent increase in spontaneous
145. Since cells of the immune system are among the blastogenesis in the blood and the spleen, suggesting that
most radiosensitive in the body, an investigation of the acute cell death had stabilized by day 4 post-irradiation,
effect of proton radiation on these cells would support more and that DNA synthesis and regenerative mechanisms
realistic estimates of the risks associated with space flight. were increasingly stimulated by an increasing magnitude
Furthermore, a better understanding is needed of the bio- of cell depletion. The authors also observed a greater effect
logical interactions following exposure to protons, in view of irradiation by protons than by gamma rays at the same
of the increasing number of patients undergoing proton doses. A dose-dependent decrease in the response to T- and
radiotherapy. B-cell mitogens was observed, and the splenocyte response
to Con A was significantly lower than that of the gamma-
146. Both early and long-term effects on the immune sys- irradiated group. The underlying mechanism for this effect is
tem of mice undergoing whole-body proton irradiation have not known. The authors suggest that it may have been due to
been reported [G9, K2, P4]. Gridley et al. drew attention to greater impairment of DNA synthesis in the T-cells capable
lymphoid organs and specific leucocyte populations of mice of responding to Con A. Although the dose rates employed
receiving WBI with 0.53 Gy of 250 MeV protons at two represented a range within which dose-rate-dependent
dose rates: 1 cGy/min and 800 mGy/min [G9]. Four days changes in sublethal damage do occur, no dose-rate effects
post-irradiation, highly significant dose-dependent reduc- were observed.
tions were observed in the mass of the thymus and the spleen,
and in the numbers of leucocytes and CD3+ T-cells, CD4+ 149. Although a large number of studies have provided
helper T-cells, CD8+ cytotoxic T-cells and CD19+ B-cells experimental results of long-term effects of radiation on the
in both blood and spleen. A less pronounced dose effect immune response [C16, V1], there are few data on effects
was noted for NK cells in the spleen. Monocyte (but not following proton irradiation. Pecaut et al. [P4] studied the
granulocyte) counts in blood were highly dose-dependent; immune status of mice exposed to 3 or 4Gy of 250MeV
the numbers for each population tended to be lower with protons and sacrificed at day 122 post-irradiation. The main
high-dose-rate than with low-dose-rate irradiation. Increases points that emerged are the following:
in the percentage of CD3+, CD4+ and NK cells, and in the
There were no effects on thymus, spleen or liver
CD4+/CD8+ ratio, were noted with increasing doses. A sig-
mass;
nificant dose-rate effect was found in the percentages of T-
and B-cell monocytes and granulocytes, and in the CD4+/ There were significant dose-dependent decreases
CD8+ ratio. The majority of the dose-related decreases in in macrophage, CD3+ CD8+ cytotoxic T-cell, NK
the spleen were highly linear. Results from gamma- and cell, platelet and red blood cell populations;
proton-irradiated groups were similar, although proton
In contrast, dose-dependent increases were observed
irradiation gave consistently lower values in some measure-
in spontaneous, but not in mitogen-induced,
ments. Very rough calculations of RBE for protons ranged
blastogenesis;
from 0.82 (based on percentage of B-cells in the spleen) to
1.55 (based on percentage of NK cells in the spleen) [G9]. Effects of radiation were more evident in leucocytes
RBE values for CD4+ T-cells ranging from 0.9 to 1.4 and in the spleen than in the peripheral circulation.
for CD8+ T-cells from 0.7 to 0.9 were reported by Radojcic
and Crompton, who compared the induction of apoptosis in
human peripheral lymphocytes following irradiation with (c) Densely ionizing particles
300kVp Xrays or 138MeV protons [R18].
150. Laboratory studies with mice have provided evi-
147. In other studies [K2, K3] that also directly compared dence for acute and chronic effects of high-LET particles
the effects of these two forms of radiation at the same dose on the immune system. Utilizing carbon ions, Erofeeva et
(dose: 3 Gy; proton dose rate: 0.4 Gy/min and 1 Gy/min; al. [E4] and Grigorenko et al. [G12] reported changes in the
photon dose rate: 0.3Gy/min), CD19+ B-cells were the most cell architecture and distribution of lymphoid cells in both
radiosensitive, although recovery back to normal levels was the spleen and the thymus that persisted at 60 days post-
observed by day 15. T-cell (CD3+) and CD4+ helper T-cell irradiation. Gridley et al. [G10] evaluated the effects of 56Fe
recovery was evident by day 29, while CD8+ cytotoxic and 28Si irradiation on the lymphoid cells and organs of mice
T-cell counts remained significantly below normal. Plasma at days 4 and 113 after whole-body exposure. In the short
TGF-1 was elevated on day 7 in the 60Co-irradiated but not term, dose-dependent decreases were noted in spleen and
in the proton-irradiated mice. However, few differences in thymus masses, but there was a greater dependence on dose
assay results were seen between animals exposed to protons for thymus mass than for spleen mass. With low-LET radia-
versus photons. tion, in contrast, the spleen mass is more linearly dependent
on dose than is the thymus mass [G10]. This suggests that
148. Pecaut et al. [P5] assessed the functional character- the response of different lymphoid organs may be dependent
istics of mouse leucocytes following whole-body proton on radiation quality. Irradiation resulted in a marked reduc-
irradiation at doses of between 0.5 and 3 Gy (dose rates tion in the number of lymphocytes and granulocytes on day 4
post-irradiation. Interestingly, it was observed that high-LET total cellularity of most lymphoid organs (such as the thy-
radiation might shift the nadir of peripheral neutropenia to an mus, spleen, peripheral lymphoid nodes and lung-associated
earlier point. The radiosensitivities of lymphocyte subpopu- lymph nodes) was observed compared with controls. The
lations were consistent with those obtained using gamma percentage of T-cells increased while that of non-T-cells
rays or protons. There were no significant differences in the decreased in peripheral lymphoid organs at both doses. It
response to T- and B-cell mitogens or secretion of IL-2 and was interesting to note that in the thymus at 2,500 WLMs, a
TNF- by PHA-stimulated splenocytes. In contrast, proton dramatic decrease in the number of CD4+ CD8+ T-cells and
irradiation induced significant depression in the response an increase in CD4 CD8 T-cells were observed.
to all three mitogens [P5]. Overall, the radiation-induced
changes on day 4 were significantly more pronounced in the 155. The exact mechanism by which radon affects T-cell
blood than in the spleen. differentiation in the thymus is not clear. Radon exposure led
to differential expression of CD44 in lung-associated lymph
151. By day 113 post-irradiation, most of these radiation- nodes. CD44 is an adhesion/homing receptor involved in
induced changes were no longer evident. However, B-lympho lymphocyte and macrophage homing to lymphoid and other
cyte numbers and percentages in blood were significantly organs. These data suggest that lymphocytes and macro-
increased. The percentages of total T-cells and CD8+ T-cells phages may migrate in different patterns to other organs. In
were low in both blood and spleen. According to the authors the lung-associated lymph nodes, where one would predict
[G10], these findings suggest that 56Fe irradiation may have the largest number of damaged cells to be present, there was
compromised cell-mediated or acquired immune responses. a significant decrease in T-cell responsiveness to mitogens,
These long-term effects seen with 2Gy 56Fe irradiation were while the B-cell response was not affected. This may be due
not observed following exposure to 2Gy 28Si ions. Exposure to the fact that in lung-associated lymph nodes there may
to 28Si ions did, however, result in increased responsive- be a marked loss of macrophages, the accessory functions
ness to PHA and LPS, and in lower numbers and percent- of which are essential for T-cells to respond to mitogens.
ages of NK cells in both blood and spleen. Thus it appears Interestingly, radon exposure caused an increase in the T-
that exposure to 28Si ions, which have a depthdose profile and B-cell responsiveness to mitogens in the spleen and
considered to be optimal for maximizing high-LET particle peripheral lymph nodes.
effects, may result in chronic immune dysfunction.
152. The above observations differ somewhat from those 3. Remarks concerning the influence of
reported from examination of the long-term effects of expos- dose rate and radiation quality
ures to 250 MeV monoenergetic protons, where irradiated
animals had significantly increased basal DNA synthesis and 156. Overall, the data presented in the preceding para-
no differences in mitogen-induced blastogenesis. These data graphs show that both high and low dose rates of sublethal
suggest that different immunomodulatory consequences may gamma radiation induce significant depression in the major-
be induced by densely ionizing particles. ity of the parameters evaluated at early times after irradia-
tion. The changes observed were highly dependent on total
dose but not on dose rate.
(d) Radon
157. The RBE of neutrons differs depending on the end
153. Data concerning health effects of radon exposure are point considered. The level of lymphocyte apoptosis is
reviewed in annex E, Sources-to-effects assessment for almost equal for neutron and photon exposures, whereas
radon in homes and workplaces. Only some data concern- immune organ weight and cellularity are reduced to a greater
ing the effects of radon exposure on the immune system will extent by neutron irradiation.
be reviewed here. Since previous studies have demonstrated
that exposure to radon can trigger genotoxic damage in rat 158. The response of mononuclear cells following proton
macrophages and deep-lung fibroblasts [K10], it is possible irradiation is highly dependent on the total dose but not on
that lymphocytes migrating through the blood or the lym- dose rate, at least in the range of doses and dose rates ana-
phatic circulatory systems of the lung may be exposed to lysed. Some cell types exhibited differences in the response
alpha particles from radon progeny. to proton versus photon radiation, proton irradiation giving
consistently lower values. Significant depressions in some
154. The effect of radon on the immune response was lymphocyte subpopulations were observed after long-
studied by Nagarkatti et al. [N1]. Mice were exposed 18 h/d
for 10 (or 25) days to a concentration of radon and its prog- litre of air that results in the ultimate release of 1.3105MeV of potential
eny giving a total cumulative exposure of 1,000 (or 2,500) alpha energy. Exposure of a worker to this concentration for 170hours (a
working level months (WLMs)1. A marked decrease in the working month) results in an exposure of one working level month (WLM).
However, while the cumulative exposure expressed in working level months
provides an estimate of the exposure to radon and its decay products (pri-
1
A working level (WL) is a unit of concentration in air of the potential alpha marily of the bronchial epithelial tissues of the lung), it does not provide
energy released from the decay of radon and its daughter products. The a direct measure of the dose to lymphoid tissues. (See annex E for further
WL is defined as any combination of the short-lived radon daughters in one discussion of the dose due to radon and its decay products.)
term evaluation. Increased spontaneous blastogenesis is a Activation-induced cell death is a form of apoptosis in which
relatively persistent phenomenon throughout short-term to activation of T-cells occurs through proper engagement of
long-term evaluations. TCRs by specific antigen bound to an HLA molecule, and
influenced by antigen concentration and co-stimulatory sig-
159. Lymphoid cells and tissues are markedly affected nals. Activation-induced cell death plays an essential role in
by high-LET radiation at relatively low doses, and some both central and peripheral deletion (clonal deletion) events
rearrangements persist long after exposure. Depression in involved in self tolerance and homeostasis [Z4].
the percentage of cytotoxic T-cells, and enhancement in the
total number of lymphocytes and B-cells, were observed at
long times post-irradiation. Increased basal DNA synthesis 2. Review of published data
is a persistent phenomenon.
163. In 30 patients who were treated with 12 Gy
160. Radon exposure induces marked changes in thymus (fractionated) of WBI, it has been reported that T- and
subpopulations and alters the expression of CD44, a molecule B-lymphocytes showed a sharp radiation-induced decrease,
involved in the migration and homing of immune cells. A sig- with B-lymphocytes being the most sensitive population
nificant decrease has been observed in T-cell responsiveness [C11]. CD3+ CD4+ CD45RO+ (memory helper T-cells),
to mitogens in lung-associated lymph nodes. CD3+ CD4+ CD45RA+ (naive helper T-cells), CD4+
and CD8+ cells appeared equally sensitive. The CD34+
cell subset (progenitor/stem cells) remained basically
E. Radiosensitivity of lymphocyte subsets unchanged, and the CD3 CD56+ CD16+ (an NK cell
subset) was relatively radioresistant compared with the
1. General considerations other lymphocyte subsets. This study provides evidence
that T- and B-cell subsets seem to be highly radiosensi-
161. The dose required to induce a defined percentage tive in vivo, while progenitor/stem cells and NK cells seem
of cell death in a given cell population defines the level to be more radioresistant. Similar findings were reported
of radiosensitivity of that cell population [N19]. Although in eight patients undergoing external beam radiotherapy
the sensitivity of different lymphocyte subsets to ionizing to the pelvis [L21]. NK cells were the most radioresistant
radiation has been extensively studied, there are still con- and B-cells the most radiosensitive lymphocytes. No sig-
troversial results in the literature. The radiosensitivity of nificant differences between helper T-cells and suppressor/
lymphocytes is related to the population under study. For cytotoxic T-cells were observed.
B-lymphocytes it depends on their degree of differentia-
tion, and for each subset of T-lymphocytes it depends on 164. Data concerning the radiosensitivity of CD4+ helper
their state of activation. Activated lymphocytes have long inducer and CD8+ cytotoxic T-cells are controversial. Sev-
been known to be more resistant to ionizing radiation than eral factors (e.g. the radiation dose, the end point selected
their resting (non-activated) counterparts [A13]. The radio- and the time period over which this end point is evaluated)
sensitivity of lymphocyte subsets is higher when irradiation could modify the findings. The tendency to spontaneous
is performed on sorted purified lymphocyte subp opula- and radiation-induced apoptosis of lymphocyte subpopu-
tions rather than on unsorted peripheral blood lymphocytes lations differs among individuals. In addition, age and sex
irradiated as a whole [M29]. are factors that may influence the apoptotic response [S8].
Nakamura et al. did not find any difference in the radiosen-
162. Radiation-induced apoptosis in lymphocytes is trig- sitivity of CD4+ and CD8+ cells [N4]. By using an in vitro
gered by two pathways: the mitochondrial pathway (intrinsic lymphocyte colony assay, they demonstrated that D10 (the
pathway) and the death receptor pathway (extrinsic pathway). dose required to reduce the surviving fraction to 10%) was
Apoptosis via both pathways is mediated by the activation of similar for these two types of cell: 3.13 0.10 Gy (mean
a series of cysteine proteases, the caspases. Although both SD) for CD4+, 3.34 0.50Gy (mean SD) for CD8+ and
pathways of apoptosis involve activation of common effector 3.14 0.17Gy (mean SD) for unsorted cells.
or executioner caspases, they differ in the activation of api-
cal or initiator caspases. The first one, through Bax protein, 165. Several studies have considered B-cells to be more
induces cell death by acting on mitochondria and accounts radiosensitive than T-cells [P12, R5, S8, V1, W14]. However,
for the differential radiosensitivity among lymphocyte sub- taking into account the spontaneous apoptosis of each differ-
populations. The second one is mediated by plasma mem- ent lymphocyte subpopulation, Wilkins et al. [W4] arrived
brane signals via interaction of the tumour necrosis factor at a different conclusion. Using the modified neutral comet
receptor (TNFR) with its ligand (tumour-necrosis-factor- assay (MNCA) they demonstrated that, following 1 Gy of
related apoptosis-inducing ligandTRAIL) and does not low-LET radiation, CD8+ T-cells had the highest radiation-
seem to be related to intrinsic radiosensitivity of lymphocyte induced apoptotic fraction, followed by CD4+ T-cells.
subsets [M29]. Interactions between TRAIL and ceramide
signalling pathways in regulating apoptotic death have been 166. Crompton and Ozsahin [C17], using a method based
reported [L25]. Apoptosis of lymphocytes through the death on assessment of DNA internucleosomal degradation
receptor pathway also occurs in physiological conditions. through flow cytometry, demonstrated that CD8+ T-cells
were the most radiosensitive population, followed by account for differential lymphocyte radiosensitivity. Mori
CD19+ B-cells. For interpreting these results, it should be et al. [M29] investigated the profile of gene expression
taken into account that the frequency of radiation-induced in peripheral lymphocytes 8 hours after in vitro Xray
apoptosis was calculated by subtracting the fraction of apop- irradiation. Cell suspensions of magnetically purified
totic cells at 0Gy (spontaneous apoptosis) from the fraction lymphocyte subpopulations were irradiated with a dose
induced by the radiation treatment of samples. Although of 1Gy at a dose rate of 0.3Gy/min. A total of 18,433
the results were identical to those reported by Stewart et al. unique sequences were screened for their transcrip-
[S30], it is important to keep in mind that the latter studies tional response to ionizing radiation. The authors found
were performed using high-dose-rate irradiation. 102 genes whose expression was modulated by radia-
tion exposure: 75 were up-regulated and 27 were down-
167. Reports concerning the effects of ionizing radiation regulated. The most strongly activated genes belonged to
on NK cells have been contradictory. As NK cells exhibit apoptosis, cell cycle and DNA repair functional classes,
so large a degree of interindividual variability, it is dif- with a clear predominance of the p53 pathway. The auth-
ficult to reach firm conclusions concerning the effect of ors reported no difference in the basal level of expression
ionizing radiation on this lymphocyte subpopulation. Seki of the proapoptotic genes among lymphocyte subsets. In
et al. [S11] reported that NK cells were the most radio contrast, their levels of activation following exposure to
sensitive in vitro and that CD8 cells and B-cells showed X-rays differed among cell subtypes. For example, Bax
lower susceptibility to radiation, whereas CD4+ cells were expression levels increased in lymphocytes in the follow-
relatively radioresistant. On the other hand, Mori and ing order: NK cells < CD4+ T-cells < CD8+ T-cells <
Desaintes reported that, among peripheral blood lympho- CD19+ B-cells, reflecting their differential radiosensi
cyte subpopulations, NK cells are more highly resistant tivity [M29]. On the other hand, the expression level of
in vitro to ionizing radiation than are T- and B-lympho the TNFR gene in irradiated cells did not differ among
cytes [M28]. In exploring the potential radioprotective these lymphocyte subsets.
effect of different types of cytokine on radiation-induced
apoptosis, it was shown that IL-2 inhibited the apoptosis
of NK and that IL-2, IL-4 and IL-7 were able to rescue
3. Remarks concerning the radiosensitivity
both CD4+ and CD8+ T-cells from radiation-induced
of lymphocyte subsets
cell death [S11]. The viability of B-cells in culture was
maintained by the presence of IL-4 but not by other cyto-
171. The data presented in the preceding paragraphs indi-
kines. The authors speculated that the protective effect by
cate that the radiosensitivity of lymphocyte subsets, in terms
each cytokine might be attributed in part to an enhance-
of the radiation dose required to induce a defined percentage
ment of cellular induction of the expression of the bcl-2
of cell death, depends on several factors:
protein family. However, while overexpression of bcl-2
leads to the inhibition of cell death [V5], it is important to Lymphocyte subset under study;
remember that there exist in the immune system apoptotic Irradiation performed on resting or activated
pathways unaffected by bcl-2 expression, such as the lymphocytes;
CD-95-mediated pathway [S31].
Degree of differentiation;
168. Fuggetta et al. have shown impaired NK activity in Irradiation performed on sorted or unsorted
vitro after gamma irradiation (20Gy) [F6]. IFN- (200IU/ subpopulations;
mL) was able to completely reverse this inhibitory radiation- Influence of cytokines;
induced effect, but was not able to modify the number of
CD16+ and CD56+ cells that died by apoptosis after irradia- Spontaneous apoptosis exhibited by the subset
tion. Concerning in vivo radiation exposure, no changes under study;
in NK cell activity were found in 1,341 atomic bombing Age and sex of the donors
survivors residing in Hiroshima [B5].
172. B-lymphocytes (CD19+) seem to be the most radio-
169. The molecular basis of the differential radiation sensi- sensitive subset, both in vivo and in vitro. However, when
tivity among lymphocyte subpopulations remains unclear estimation of radiation-induced apoptosis is performed by
[M29]. It has been proposed that the higher radiosensitiv- subtracting spontaneous apoptosis, CD8+ T-cells exhibit
ity of B-lymphocytes is due to a lower activity of DNA- higher radiosensitivity. Most of the data show no difference
dependent protein kinase (DNA-PK) in these cells [M14]. in radiosensitivity between CD4+ and CD8+ T-cells. While
Also, the radiosensitivity of lymphocyte subsets has been NK cells are relatively radioresistant in vivo, particularly the
related to intrinsic differences in basal expression level of CD56+ CD16+ NK subset, data concerning in vitro irradia-
specific genes, particularly those related to Bcl-2 family tions are more controversial. The level of radiation-induced
genes such as Bax, Bcl-2 and Bcl-X [I11]. activation of apoptosis-related genes differs among these
subsets, probably reflecting their differential radiosensitiv-
170. However, a recent study using microarray analy- ity, as follows: NK cells < CD4+ T-cells < CD8+ T-cells <
sis demonstrated that basal gene expression does not CD19+ B-cells.
F. Alterations of the immune response a 40% reduction in the haematopoietic stem cell population
after prenatal irradiation (CFU-S), which persisted up to at least 6 months of age.
Spleen colony formation after sublethal doses of gamma
173. Radiation-induced impairment of both humoral anti- rays reflected this reduced complement of endogenous stem
body and cell-mediated responses have been reported in cells. The regulatory haematopoietic microenvironment,
numerous experimental and epidemiological studies. How- measured as fibroblastoid colony-forming cells (CFU-F),
ever, very few data are yet available concerning radiation was similarly depleted. The quality of the stem cell popula-
effects on the immune system following in utero exposure. tion in the offspring of irradiated mothers was not affected,
These data mainly concern numerical or structural changes, since normal growth of the CFU-S population was observed
and thus they cannot be directly related to effects on the after transplantation into standard recipients. In contrast,
immune function. The developing haematopoietic system is when used as recipients of a bone marrow transplant from
very sensitive to ionizing radiation. The mammalian embry- either normal or irradiated offspring, the offspring of irradi-
onic haematopoietic system becomes functional in the yolk ated mothers were unable to support normal growth. Com-
sac during organogenesis; in parallel, additional haematopoi- pared with normal offspring, there were 70% fewer CFU-F in
etic activity takes place in the aorta, gonads and mesone the femur 1 month after bone marrow transplantation when
phros. Later the function shifts to the foetal liver and spleen, the offspring of irradiated mothers were used as transplant
and finally to the bone marrow [T11, U16]. Foetal liver recipients. This confirmed a reduced capacity to host normal
haematopoiesis is first detectable at about the sixth week of stem cells and also indicated that CFU-F in the transplant
gestation in humans. Although the spleen has largely ceased were unable to compensate for the poor microenvironment
haematopoiesis in humans by the time of birth, it may regain in irradiated offspring hosts.
haematopoietic function in abnormal situations [H27].
176. The developing haematopoietic tissues are very sensi-
tive to 239Pu contamination. Mason et al. [M1] studied post-
1. Animal data natal haematopoietic function in the offspring of pregnant
mice injected with 30 kBq/kg of 239Pu at 13 days of ges-
174. Grande and Bueren irradiated mice at different stages tation. The maximum dose (1014 mGy) was absorbed in
of development with a single dose of 500mGy of X-rays. the liver. A long-term deficit in the number of haematopoi-
Mice irradiated on days 13 and 17 post-conception showed a etic colony-forming cells (CFU-S) in the spleen, liver and
significant reduction in the proportion of femoral bone mar- bone marrow was observed. The development of the stromal
row granulocytemacrophage colony-forming units (CFU- microenvironment was also deficient, suggesting sublethal
GM) one year after irradiation. This effect was manifested damage in those cells destined to become the precursors of
neither in mice irradiated on day 4 post-conception nor in the supportive haematopoietic microenvironment.
those irradiated in early post-natal life (2 days, 8 days and
12 weeks old) [G6]. The effects of ionizing radiation on the 177. Platteau et al. [P9] looked for medium-term effects in
embryo/foetus may differ according to the developmental the immune system of rats following 02Gy prenatal or early
stage at which the exposure takes place. In this study, the post-natal WBI. They did not find changes in the histology of
impairment in the CFU-GM population was observed when the spleen, profiles of lymphocyte subpopulations or serum
mice were irradiated after midgestation. As seen in figure VI, immunoglobulin levels. At an age of 10 weeks, rats were
this is the period of haematopoetic progenitor cell expansion immunized with a T-dependent or a T-independent dinitro-
(day 13) and bone marrow and thymus colonization (day 17) phenylated carrier antigen. T-dependent response was higher in
in rodents. This study indicates that, for most stages of devel- rats irradiated between days 6 and 20 of gestation; however, this
opment in the mouse, a single acute dose of X-irradiation of increase was significant only for IgM and IgG1 responses.
500 mGy is below the threshold dose capable of inducing
deterministic effects in the mouse haematopoietic system, 178. Nold et al. [N14] demonstrated that dogs irradiated
although it reveals the induction of a significant impairment prenatally with 1.5 Gy (60Co gamma irradiation) on day
in the CFU-GM population when irradiation is given at the 35 of gestation exhibited lower primary humoral antibody
late stages of embryonic development. responses to a T-dependent antigen (sheep red blood cells),
with a decrease in helper T-lymphocyte subpopulations in
175. Haematopoiesis is the product of two components: peripheral blood. Moreover, they found defects in epithelios-
the haematopoietic tissue and the regulatory stromal micro- tromal development of the thymus and concluded that the
environment in which it resides. The role of both compon- observed immune alterations could be related to radiation-
ents in radiation-induced haematopoietic effects remains induced prenatal thymic injury.
controversial. Yang et al. [Y3] proposed that irradiation at
midterm gestation damages the developing regulatory micro- 179. Thymocytes are either negatively selected as poten
environment but not the haematopoietic stem cell population tially autoreactive and deleted, or positively selected to
that it hosts. To demonstrate this, the authors used an experi- become mature cells. In addition to the signal mediated by
mental model of prenatal irradiation in combination with the T-cell receptor (TCR), other signalling pathways also
cross-transplantation experiments. They found that 1.8 Gy regulate this developmental selection. It has been demon-
of gamma irradiation given to mice at midgestation caused strated [N12] that the CD28 receptor, which plays a role in
enhancing the survival and expansion of peripheral T-cells, is in haematopoiesis in the growing foetus. Post-natal, the
also involved in negative selection in the thymus. Developing bone marrow becomes the main haematopoietic organ; the
thymocytes of CD28-deficient and wild-type mice displayed spleen and liver have ceased their function by the time of
similar radiosensitivity in terms of apoptosis, but nega- birth or soon after.
tive selection was significantly reduced in the former, thus
suggesting that CD28 receptor involvement in thymus 182. During the intrauterine ontogenesis of the immune
development is not related to regulation of cell survival. system, apoptosis plays a central role in thymus develop-
ment. A distinction should be made between developmental
180. Miller and Benjamin [M6] have studied radiation- and radiation-induced lymphocyte apoptosis. While apopto-
induced alterations in prenatal thymic development in the sis during T-cell maturation is p53-independent, p53 protein
beagle dog. They found that injury to both thymic cortices is a critical mediator of apoptosis in response to genotoxic
and medullas was greater following exposures earlier in ges- agents such as ionizing radiation. Immature cortical thymo-
tation. Damage to medullas was relatively more severe than cytes are characterized by a double-positive immunopheno-
in cortices following exposure at any given age. The degree type, CD4+ CD8+ TCRlow. The interaction between imma-
of reduction of medullar volume reflected thymic epithel- ture thymocytes and thymic reticuloendothelial cells induces
ial injury, which is surprising since the thymic epithelium is positive selection of T-lymphocytes that are not activated
considered in the adult to be radioresistant. Such injury may by self HLA molecules, thus promoting tolerance induc-
have serious post-natal consequences, as normal differentiation. T-lymphocytes that do not undergo positive selection
tion of T-cell subpopulations is dependent upon the integ- are killed by apoptosis. Immature thymocytes also undergo
rity of the thymic microenvironment. Damage to the thymic negative selection when thymic stromal cells eliminate self-
microenvironment could result in immunodeficiencies and reactive T-lymphocytes by apoptosis [K1].
defects in immunological regulation.
183. As seen in animals, the effects of ionizing radiation on
the human embryo/foetus may differ according to the develop-
2. Human data mental stage at which the exposure takes place. The definition
of critical windows in the development of the immune system
181. Human foetuses are thought to be highly sensitive may allow identification of periods of special vulnerability. On
to ionizing radiation. However, human data concerning the basis of known developmental changes occurring within
the effects of prenatal irradiation on the immune system the immune system, Dietert et al. proposed a relative timeline
are scarce. In humans, haematopoietic activity begins in for critical windows in the developing human immune system
the liver by six weeks of gestation and continues until one [D5]. A parallel approach for the development of rodent and
week of post-natal life. The spleen also plays a major role human immune systems is shown in figureVII.
Figure VII. Critical windows of toxic exposure for the developing immune system in rodents and humans.
Gestation: 21 days for rodents, 38 weeks for humans (adapted from reference [D5]).
Rodents
Days 79 Days 913 Day 13birth Birth30 days 3060 days
Humans
Weeks 810 Weeks 1016 Week 16birth Birth1 year 118 years
Stem cell Progenitor Bone marrow Perinatal Immune

formation cell expansion and thymus immune memory is
and tissue colonization maturation established
migration
Conception Birth Sexual

maturity
184. Prenatal events can affect the immune response at birth Prenatal radiation-induced damage in the thymus
and, depending on gestational timing, can result in widely is more severe for the medulla than for the cortex;
varied outcomes. The potential outcomes of toxic exposures Human foetal lymphoid progenitors include a
to the developing immune system may derive from suppres- major subpopulation that is relatively radioresis
sion, perturbation or up-regulation of the immune response, tant and a minor subpopulation that is very radio-
leading to immunodeficiencies, autoimmunity or hypersensitive to the induction of both translocations
sensitivity reactions, respectively. Moreover, prenatal dam- and cell killing.
age to the thymus would have a more profound effect than
post-maturational damage. Similarly, prenatal destruction of
abundant pluripotent stem cells may have a more harmful
outcome than destruction of single lineages or differentiated G. Immune dysfunction and hypersensitivity
cells, which predominate in adults [H14, H27]. to ionizing radiation
185. Ohtaki et al. evaluated the frequency of stable aberra- 187. As seen, DNA recombination processes not only
tions (translocations) in blood samples from 150 survivors of account for immune diversification but also constitute
the atomic bombings at Hiroshima and Nagasaki who were a major checkpoint in the development of lymphocytes
exposed in utero to doses of 5mSv and from 181controls [D26]. Defects in V(D)J recombination lead to immuno-
(dose <5mSv). Foetal doses were approximated by the dose deficiency, and a deregulation of this process may result in
to the maternal uterus. The mean age of subjects at the time higher sensitivity to genotoxic agents and increase the risk of
of sampling was 40 0.7 years. The investigators did not find malignancies.
a dose response but did find a small increase in transloca-
tion frequency at doses of <100mSv, with a peak response at 188. The understanding of the mechanisms involved in the
~30mSv, at which the net increase in translocation frequency development of human pathologies exhibiting immune dys-
was ~0.4%. There was no evidence for an effect of gesta- function and higher radiosensitivity may be relevant in the
tional age in the estimated coefficients. These findings were context of the effects of ionizing radiation on the immune
explained with the hypothesis that the human foetal lymphoid system. There exist a number of human genetic disorders char-
progenitor pool comprises two subpopulations with different acterized by chromosomal instability that are associated with
radiosensitivity. A major fraction exhibits radiation resistance. a higher incidence of cancer. Both the chromosomal instabili-
The other subpopulation, small in number, was considered ties and the neoplastic outcomes are related to abnormalities
sensitive to the induction of both translocations and cell killing, of DNA metabolism, DNA repair, cell cycle regulation or
and diminished rapidly following doses of >50mSv [O9]. control of apoptosis. Among them there are several disorders
associated with defects in the immune system and increased
susceptibility to radiation, including UV and ionizing radia-
3. Remarks concerning the effects of prenatal irradiation tion [B9]. These observations are especially relevant because
they are at the crossroads of basic cellular mechanisms,
186. On the basis of the preceding paragraphs, the follow-
combining immunodeficiency, increased rate of cancer, and
ing remarks may be made concerning the effects of prenatal
defects in DNA repair and pathways known to be associated
irradiation on the immune system:
with hypersensitivity to radiation. Other pathological condi-
The developing immune system is very sensitive tions involving immune dysfunction, such as autoimmune
to ionizing radiation; diseases and acquired immunodeficiency syndrome (AIDS),
There are critical windows of special vulnerabil- could be also associated with higher radiosensitivity. Because
ity of the prenatal immune system; of the double condition of hypersensitivity to radiation and
immunodeficiency, the radiation effects on the immune
The effects differ according to the developmen- system may be more severe in these patients.
tal stage at which the irradiation takes place; for
example, a dose of 500 mGy given to mice in
early pregnancy has no effect, whereas the same 1. Human genetic disorders
dose given after midgestation results in significant
depletion of bone marrow precursors 1 year later; 189. Abnormal DNA repair and cell death regulation may
Developing haematopoietic tissues are very sensi- result in higher vulnerability to ionizing radiation. Several
tive to 239Pu contamination: even doses of around human genetic disorders associated with defective DNA
10 mGy are capable of inducing a long-term repair present functional abnormalities in the immune system.
haematopoietic deficit; Some of them exhibit increased susceptibility to radiation. If
individuals with such disorders undergo radiotherapy, they
Radiation-induced impairment of the developing may develop adverse side effects in normal tissues, such as
stromal microenvironment accounts, at least in acute effects appearing during or shortly after treatment, or
part, for these long-lasting effects; late effects developed months or years later. Some of these
Prenatal thymic injury is greater following genetic disorders are reviewed below and are summarized in
irradiation in early pregnancy; table10.
Table 10 Human genetic disorders with immune system defects and increased susceptibility to radiation
Disease Defective Mutated gene Sensitivity tob

mechanisma
UV Ionizing radiation
Xeroderma pigmentosum NER XP-A, XP-B, XP-C, XP-D, XP-E, (+++) ?

(+/ TCR) XP-F, XP-F/ERCC1, XP-G
Trichothiodystrophy NER/TCR TFIIH-related XP-D and XP-B (++) ?
Xeroderma pigmentosum TLS hRAD30 (+) (+)

variant
Ataxia telangiectasia DSB cell signalling ATM (/) (++++)

homozygote
Ataxia telangiectasia DSB cell signalling ATM (+/) (+)

heterozygote
Ataxia-telangiectasia-like DSB cell signalling hMRE11 (++++)

disorder
Nijmegen breakage syndrome DSB cell signalling NBS1 (nibrin) (++++)
Fanconi anaemia Cross-linking repair and HR FANC-A, FANC-B, FANC-C, (++)

FANC-D1/BRCA2, FANC-D2,
FANC-E, FANC-F, FANC-G
Blooms syndrome HR/TLS BLM RecQ helicase (+) ?
WiedemannRautenstrauch Neonatal progeria WRS ?

syndrome
HutchinsonGilford syndrome Progeria infantum HGPS (lamin A) (++) (++)
Cockayne syndrome NER/TCR (youthful progeria) CS-A and CS-B (++) (?)
Werners syndrome HR/TLS (adult progeria) WRN RecQ helicase (+) (+)
Severe combined V(D)J/NHEJ Artemis (+++)

immunodeficiency (SCID) (SCID with increased
radiosensitivity)
Immunodeficiency with NHEJ Ligase IV (++++)

microcephaly Cernunnos/XLF
Seckel syndrome DSB cell signalling ATR (+++)
Dyskeratosis congenita Telomere metabolism Dyskerin/hTR (++)
Hyper-IgM syndromes Class switch recombination Uracil-N-glycosylase (UNG) (++)
a NER = nucleotide excision repair; TCR = transcription-coupled repair; DSB= b Increasing number of + symbols means increasing degree of radiosensitiv-
double-strand break; HR = homologous recombination; TLS = translesion ity. Query symbol (?) means probably radiosensitive but radiosensitivity not
synthesis; NHEJ = non-homologous end joining. demonstrated.
190. Xeroderma pigmentosum (XP) is an autosomal reces- delayed-type hypersensitivity reactions, decreased T-cell
sive disease with defective nucleotide excision repair (NER) proliferative responses to mitogens, decreased CD4/CD8
characterized by severe sensitivity to all types of UV radia- ratio and impairment of NK cell activity [G19, L6, N21,
tion. The NER pathway recognizes and removes UV-induced N22, W15]. XP is categorized in at least eight genetic sub-
DNA lesions. XP is characterized by cutaneous and ocular types labelled A to G, plus the F/ERCC1 group. While both
abnormalities, predominantly on sites exposed to sunlight, XP-A and XP-C can be attributed entirely to defects in
and in some cases by neurological features resulting from NER, the other complementation groups involve defects in
progressive neuronal loss. Expression in skin includes dis- other DNA repair mechanisms [L6]. Some XP patients in
position for sunburn, pigmentary abnormalities, telangiecta- complementation group E (XP-E) lack UV-damaged-DNA-
sia, dryness, scarring, and susceptibility to multiple benign binding protein (UV-DDB), which is present in healthy indi-
and malignant neoplasms, including basal and squamous viduals and in patients in other XP complementation groups.
cell carcinomas and melanomas [L7]. A variety of immune UV-DDB protein is composed of two subunits, DDB1 and
abnormalities have been described in XP patients: decreased DDB2. In vivo, UV-DDB protein plays an important role
in the p53-dependent response of mammalian cells to DNA as its main clinical features. AT patients are prone to cancer
damage. When cells are exposed to UV, the resulting accu- development and are unusually sensitive to ionizing radia-
mulation of p53 activates DDB2 transcription, which leads tion. They carry a mutation in a gene involved in DNA dam-
to increased levels of UV-DDB. A linear dose response for age signalling [J9], called the ataxia-telangiectasia-mutated
activation of DDB2 and XPC genes has been demonstrated (ATM) gene. Only homozygous AT patients present the typi-
following exposure of peripheral blood lymphocytes to doses cal clinical features described above. Homozygous AT is the
of gamma rays as low as 0.2Gy [A21]. most common cerebellar ataxia in children under 5 years
of age, with a prevalence of 1 in 100,000 live births [S48].
191. The cells of xeroderma pigmentosum variant (XP-V) Progressive cerebellar ataxia becomes apparent as early as
patients are only slightly more sensitive than normal cells the first year of life. Oculomotor abnormalities may also be
to the killing action of UV radiation. The XP-V cells are seen. Telangiectases appear after onset of the neurological
NER-proficient but present a deficit in translesion DNA syndrome and are progressive.
synthesis, with an increased probability of being blocked
at a DNA lesion [C31]. Defects in translesion synthesis 195. AT affects both TCR and Ig genes, thus explaining the
(TLS) due to mutations in the damage-specific polymer- immunodeficiency observed in AT patients. Moderate cellu-
ase hRAD30 (polymerase ) are responsible for the UV- lar and humoral immunodeficiency, with low levels of certain
hypermutability of XP-V cells leading to skin cancers Ig classes, in conjunction with difficulties in swallowing, lead
[K38]. It has been proposed that sunlight carcinogenesis in to frequent pulmonary infections in AT patients. Peripheral
XP-V patients may be associated with increased genomic lymphocytes from AT homozygotes show elevated chromo-
rearrangements that result from double-strand breaks and somal rearrangements, which preferentially involve chromo-
rejoining in cells of the skin in which p53 is inactivated by somal breakpoints within TCR genes, mainly at 14q11
UV-induced mutations [L12]. (TCR- and -), 7q14 (TCR-) and 7q35 (TCR-) [T2]. Telo-
mere shortening and fusions, with normal telomerase activity,
192. Trichothiodystrophy (TTD) refers to several auto- have been observed in peripheral blood lymphocytes of these
somal recessive diseases whose diagnostic hallmark is short, patients [T2]. AT patients show progeroid features, such as
brittle hair low in sulphur and cysteine because of impaired strands of grey hair or keratoses, which have been related to
synthesis of high-sulphur matrix protein [L7, S38]. The clin- accelerated telomere shortening [P2]. Endocrine defects typ-
ical symptoms associated with TTD, such as ichthyotic skin, ically result in gonadal abnormalities and retardation in som-
neurodegeneration and developmental disorders, represent a atic growth. Some patients develop insulin-resistant diabetes,
variable range of abnormalities in organs derived from the which has been attributed to antibodies directed against insu-
ectoderm [L7]. The majority of TTD patients exhibit photo- lin receptors [S48]. Many homozygous AT patients develop
sensitivity because their NER pathway does not remove UV- cancer, mostly lymphoid malignancies of both B-cell and
induced DNA lesions efficiently. Although their deficiencies T-cell origin, including Hodgkins lymphoma, non-Hodgkins
result mainly from mutations in either XP-B or XP-D, TTD lymphoma and leukaemias [B8].
patients do not present skin cancer susceptibility [C27, S38]
and also do not exhibit hypersensitivity to ionizing radia- 196. Solid tumours, mainly breast and stomach cancer,
tion. Although some abnormal immune parameters have occur more commonly as the AT patient matures, and are
been found in TTD patients [C19, N22, R10], immune defi- being seen in greater numbers as these patients are living
ciency is not a common feature of TTD. However, the find- longer [H23]. Although plausible, the hypothesis of a higher
ing of additional TTD patients combining features of XP and risk of radiogenic cancer in homozygous AT patients is not
Cockayne syndrome indicates that there may be consider- supported by solid data. In contrast, the hypersensitivity to
able clinical heterogeneity with phenotypic overlap. deterministic effects from ionizing radiation, around three
to fourfold compared with the general population, is well
193. Blooms syndrome belongs to a family of hereditary established. Indeed, the treatment of cancer in AT patients
diseases caused by defects in genes belonging to the RecQ with conventional doses of ionizing radiation may induce
family of DNA helicases, which play a role in regulating extremely high radiotoxicity, resulting in life-threatening
homologous recombination. Blooms syndrome patients, sequelae. The frequency of heterozygous ATM mutations
who exhibit a mutation in the BLM gene, are hypersensitive among the general population is around 1%. Heterozygous
to UV and exhibit abnormal replication patterns following carriers are neurologically normal. Although some authors
DNA damage. They present sun-induced rash, immuno have not found any evidence of abnormal radiotoxicity in
deficiency, subfertility and cancer predisposition [K4]. One heterozygous AT patients [W12], other epidemiological
of the defining features of cells from Blooms syndrome studies have suggested that heterozygous AT women have
individuals is chromosomal instability, characterized by a predisposition to breast cancer and may exhibit higher
chromosomal breaks, deletions and rearrangements, as well clinical radiosensitivity [A24].
as elevated levels of sister chromatid exchange.
197. Ataxia-telangiectasia-like disorder (ATLD) is due to
194. Ataxia telangiectasia (AT) is an autosomal recessive mutations in the hMre11a gene, involved in DNA double-
multisystem disorder with early-onset cerebellar ataxia, con- strand-break repair. ATLD shares many clinical features with
junctival and cutaneous telangiectasia, and immunodeficiency AT. While abnormalities in B-lymphocytes have not been
reported in ATLD, T-lymphocytes show an increased level hypoplasia, delayed tooth eruption, facial cyanosis, insulin-
of translocations involving the TCR. Both lymphocytes and dependent diabetes, accelerated ageing and early death, fre-
fibroblasts from these patients exhibit higher radiosensitivity quently from coronary artery disease. HGPS is caused by
in vitro [T2]. mutations in the lamin A gene, placing this syndrome within
the group of laminopathies [B29]. The main functions of
198. Nijmegen breakage syndrome (NBS) is a rare auto- A-type lamins include high-order chromatin organization,
somal recessive condition characterized by chromosomal nuclear structure maintenance and gene expression control.
instability, growth retardation, microcephaly, characteristic Hypersensitivity to gamma radiation has been described
facial features, radiosensitivity, immunodeficiency, gonadal in these patients [W7]. Concerning immune dysfunction,
dysgenesis and cancer predisposition. A high proportion of a decreased CD4/CD8 ratio and decreased T-cell response
NBS patients develop lymphoid malignancies, most of B-cell have been associated with HGPS [H19].
origin. Fibroblasts and lymphocytes from NBS patients are
35 times more sensitive to ionizing radiation and radio- 203. Youth progeria (Cockayne syndromeCS) patients
mimetic drugs than normal cells, and display radioresistant show many developmental defects, including mental retar-
DNA synthesis due to an inability to retard Sphase progres- dation, microcephaly, long limbs, birdlike face, pigmented
sion after exposure to ionizing radiation. NBS also involves retinopathy, gait defects and sun sensitivity due to a failure
inversions and translocations in peripheral T-cells affecting of RNA synthesis to recover following UV irradiation [L16],
the genes for the heavy chain of immunoglobulins and the but without an increased incidence of skin cancer. Two com-
TCR, thus accounting for the immunodeficiency character- plementation groups (A and B) have been identified in CS
istic of this syndrome [D6]. NBS patients carry a mutation depending on which gene is mutated (CS-A or CS-B); these
in the NBS1 gene, which codes for a protein called NBS-1/ genes encode proteins involved in the transcription-coupled
Nibrin, involved in DNA double-strand-break repair. repair pathway of NER [L16]. Cells from CS patients
accumulate oxidative-induced DNA lesions after exposure
199. Fanconi anaemia (FA) is a recessive disorder char- to ionizing radiation [T16]. Decreased T-cell proliferative
acterized by bone marrow failure, multiple congenital response and decreased serum levels of thymic hormone
abnormalities and predisposition to cancer, particularly have been observed in these patients [B22].
to acute myeloid leukaemia and squamous cell carcinoma
[R8,T2]. Although FA is considered a genetically and clin- 204. Adult progeria (Werners syndromeWS) patients
ically heterogeneous disorder, the genes mutated in FA are display age-related disorders, including greying and thinning
all involved in recruiting and organizing other proteins to of the hair, bilateral cataracts, type II diabetes, atherosclero-
cope with DNA damage and participate in the regulation sis, osteoporosis and increased incidence of sarcomas. The
of homologous recombination. FA patients are unusually incidence of epithelial cancer and mesenchymal sarcoma is
sensitive to a variety of clastogens, most prominently DNA 10times that of the general population. The incidence of WS
cross-linking agents such as mitomycinC. Moderate to high is extremely high in Japan compared with other countries
sensitivity to ionizing radiation and other oxidative stress [Y6]. WS patients carry a mutation in the WRN gene, which
inducers has been reported in FA patients [D10]. Djuzenova encodes a protein belonging to the RecQ family of DNA heli
et al. [D8] observed high initial and residual DNA damage cases. WS cells exhibit genomic instability, premature senes-
rates and elevated repair half-time in peripheral blood mono- cence, defects in telomere metabolism, and hypersensitivity
nuclear cells from FA patients exposed to X-rays. to DNA cross-linkers and to ionizing radiation [C25, M17].
The WRN protein is recruited in the radiation-induced DNA
200. Human progeria syndromes are rare disorders charac- double-strand breaks and collocalizes with the Mre11 and
terized by premature ageing. Some of these syndromes are H2AX complex via binding to NBS1. NBS1 is the gene
associated with defects in DNA repair pathways and with a mutated in the Nijmejen breakage syndrome, thus suggesting
higher susceptibility to DNA damage agents, such as ioniz- a functional link between these two genetic syndromes
ing radiation. According to the age at the onset of symptoms, with partially overlapping phenotypes [C24, C25]. Immune
human progeria syndromes may be classified as neonatal, dysfunction has been found in WS patients [G29, G30, N16].
infantum, youth and adult progeria.
205. Severe combined immune deficiency (SCID) is the
201. Neonatal progeria (WiedemannRautenstrauch syn- most severe inherited immunological disorder and is caused
drome) is a rare autosomal recessive disorder usually lethal by a variety of molecular defects, all affecting at least the
by 7 months. It is characterized by a triangular, aged-looking T-lymphocyte population [F16]. Human SCID is character-
face with prominent veins and sparse scalp hair, and nearly ized by the absence of the T- and B-lymphocytes owing to a
total absence of subcutaneous fat. These features are appar- defect in V(D)J rearrangement of TCR and Ig genes [D26].
ent at birth and therefore differ from congenital generalized Mutations in the Artemis gene, which encodes a protein
lipodystrophy. essential for V(D)J recombination and DNA double-strand-
break repair, cause a variant of human SCID with increased
202. Progeria infantum (HutchinsonGilford progeria radiosensitivity (RS-SCID) [L28, M19]. Hypomorphic
syndromeHGPS) is a rare genetic disorder characterized Artemis mutations are associated with the development of
by prominent scalp veins, the absence of hair, maxillary B-cell lymphomas [M13].
206. Immunodeficiency with microcephaly patients, pre- 2. Autoimmune diseases and radiation response
senting with various degrees of immunodeficiency and
growth delay, display mutations in the DNA ligase IV 210. DNA damage and its defective repair could be impor-
gene, which encodes a protein essential for DNA repair tant in the pathogenesis of autoimmune diseases. Impaired
through non-homologous end-joining (NHEJ) and V(D)J response to oxidative stress has been postulated as another
recombination [B33, O2]. This clinical phenotype closely condition found in autoimmune diseases [H17, K51]. Bhu-
resembles Nijmegen breakage syndrome, and cells from sate et al. demonstrated that the spontaneous number of DNA
the patients show pronounced radiosensitivity [O2]. A strand breaks in peripheral blood mononuclear cells from
new NHEJ factor, Cernunnos, was identified through the patients with rheumatoid arthritis is significantly increased
survey of similar patients with SCID and microcephaly compared with those from healthy donors [B24]. Neutrophils
[B34]. This resemblance is not surprising, given the inter- from systemic lupus erythematosus (SLE) patients display
actions of Cernunnos and DNA ligase IV in a same protein increased spontaneous DNA damage and defective repair
complex [A26]. of oxidative DNA damage [M20]. Higher sensitivity to oxi-
dative stress has been also described in lymphocytes from
207. Hyper-IgM syndromes are primary immunodeficien- patients with SLE, vasculitis and Behcets disease [B20].
cies characterized by normal or increased serum IgM levels
contrasting with low or absent IgG IgA, and IgE. They are 211. McCurdy et al. studied DNA repair of peripheral
caused by a defect in the class switch recombination [D31]. blood lymphocytes from patients with autoimmune diseases,
A subset of these patients display defects in DNA repair irradiated with 1.5Gy. By using single-cell alkaline gel elec-
genes such as Uracil-N-glycosylase [I12]. trophoresis (comet assay) they observed that lymphocytes
from patients with systemic lupus erythematosus, juvenile
rheumatoid arthritis and systemic sclerosis exhibited delayed
208. Seckel syndrome shares features with the above dis- repair of radiation-induced DNA damage compared with
orders involving impaired DNA damage repair and elevated lymphocytes from healthy donors [M21]. These findings
radiosensitivity. Seckel syndrome patients have a muta- were in accordance with a previous study by Harris et al.,
tion in ATR, the gene encoding ataxia telangiectasia and who evaluated the lymphocyte responsiveness to mitogens
Rad3-related protein, resulting in failed checkpoint arrest (Con A) following irradiation and found that lymphocytes
following exposure to genotoxic agents [A9, O3]. from patients with rheumatoid arthritis, systemic lupus ery-
thematosus and polymyositis were more radiosensitive than
209. Dyskeratosis congenita (DC) is a rare syndrome those from healthy volunteers or patients with conditions not
caused by defective telomere maintenance characterized associated with autoimmunity [H6].
by atrophy and reticular pigmentation of the skin, nail dys-
trophy, leucoplasia of mucosa membranes, hypotricosis, 212. Cossu et al. evaluated the proliferative responsiveness
dysphagia, skeletal abnormalities, mental retardation, bone following irradiation with doses of between 0 and 10 Gy
marrow failure and predisposition to malignancies [C29]. in peripheral blood lymphocytes from patients affected by
The major X-linked form of DC is due to mutations in a systemic lupus erythematosus in the active and remissive
nucleolar protein, dyskerin, found in the telomerase com- phases. They compared their results with those found in a
plex [D23]. An autosomal dominant form is due to muta- group of normal subjects. Patients in the clinically active
tions in the RNA component of telomerase (hTR) [S46]. phase of the disease exhibited a decreased responsiveness of
Patients with this form of the disease are more severely the total lymphocyte population as well as of the subpopula-
affected in later generations that carry the mutations, pos- tions of T- and B-cells. Responsiveness from patients in the
sibly owing to the inheritance of shortened telomeres, dis- remissive phase was similar to that of normal subjects. They
guising the inherited nature of the disease, which in some concluded that the lymphocytes of patients affected by this
cases is classified as aplastic anaemia. Increased sensitivity autoimmune disease in the active phase are more radiosen-
of DC cells to ionizing radiation and alkylating agents has sitive than those of patients in the remissive phase of these
been described [D24]. It was demonstrated that fibroblasts diseases [C15]. Greater toxicity from radiation therapy has
from DC patients are highly susceptible to X-irradiation- been described in patients with collagen diseases, such as
induced chromatid breakage [D18], and hypersensitivity to systemic lupus erythematosus, polymyositis, dermatomyos
radiation therapy has been described in these patients [C20]. itis and scleroderma, manifested as significant acute toxicity
A severe infantile variant of X-linked DC called Hoyeraal and severe late effects [M12].
Hreidarsson syndrome exhibits increased in vitro sensitivity
to radiation and alkylating agents in circulating lymphocytes
and fibroblasts. Accelerated telomere shortening was also 3. Ionizing radiation and acquired
reported in these patients [M24]. Severe B-lymphopenia immune deficiency syndrome
with decreased IgM levels and moderate T-lymphopenia
were observed in autosomal dominant form, probably as 213. A higher incidence of several cancers, e.g. Kaposis
a consequence of replicative failure and premature senes- sarcoma, non-Hodgkins lymphoma, conjunctival squamous
cence of lymphocytes, supporting a role of telomerase in carcinoma and Hodgkins disease, has been observed in
immune homeostasis [K41]. patients with acquired immunodeficiency syndrome (AIDS).
Since there is accumulating evidence that AIDS patients checkpoints may be involved in the higher radiosensitivity
exhibit higher radiosensitivity, the effects of ionizing radia- of AIDS patients [S53]. Decreased levels of major endog-
tion on the immune system may be relevant in medical prac- enous antioxidant systems have been seen in HIV-1 disease,
tice when radiotherapy is administrated to AIDS patients including lower levels of glutathione and decreased levels
with cancer [S53]. of superoxide dismutase and catalase [B13]. The state of
chronic immune activation secondary to HIV-1 infection and
214. Enhancement of the human immunodeficiency virus the frequent secondary or opportunistic infections (as well
type 1 (HIV-1) by heterologous viral, chemical and physical as reactions to other antigenic products) lead to a constant
agents has been shown both in vitro and in vivo. Exposure state of oxidative stress. ROS generated by ionizing radiation
of AIDS patients to ionizing radiation (for example dur- might trigger additional oxidative stress in these patients.
ing radiation therapy) could play a role in activating HIV-1
in vivo. Faure et al. demonstrated in lymphoid cell lines
that HIV long-terminal-repeat-directed gene expression is 4. Remarks concerning human pathologies with immune
activated by X-irradiation in a dose- and time-dependent dysfunction and hypersensitivity to ionizing radiation
manner [F2].
218. As described in the preceding paragraphs, the identi-
215. Stress agents such as ionizing radiation could directly fication of human pathologies in which immunodeficiency is
activate HIV-1 virus replication or reporter gene expres- associated with higher radiosensitivity is relevant, because
sion. The kappa B regulatory elements seem to be involved the effects of ionizing radiation on the immune system may
in this up-regulation [F1]. Antioxidant drugs inhibit this be more severe in these patients. Table10 summarized the
effect, which suggests that reactive oxygen species (ROS) main human genetic disorders in which immune dysfunction
are involved. Taher et al. found that ionizing radiation, at is associated with hypersensitivity to ionizing radiation. The
both low and high doses, stimulates HIV gene expression mutated genes and the defective mechanisms that account
to a lesser extent and with different kinetics than does UV for these disorders are also presented in this table. The data
radiation [T1]. While UV activation was completely blocked indicate that ataxia telangiectasia, ataxia telangiectasia-like-
by p38 MAP kinase inhibition, activation by ionizing radia- disorder, Nijmegen breakage syndrome, severe combined
tion was reversed by MAP kinase/MEK inhibition. This immune deficiency, ligase IV and Cerunnos deficiencies,
finding suggests that ionizing radiation modulates HIV gene and Seckel syndrome are the disorders exhibiting a very high
expression by this latter signalling pathway. radiosensitivity. To a lesser extent, higher radiosensitivity
has been proven for xeroderma pigmentosum variant, Fan-
216. Integrase-induced host DNA damage associated with coni anaemia, progeria infantum and adult, and dyskeratosis
HIV-1 infection elicits DNA damage signalling. Waninger et congenita. Concerning the other conditions described, their
al. have established that the DNA-PK is involved in HIV-1 probable hypersensitivity to ionizing radiation has not yet
replication, suggesting that the NHEJ pathway, involved in been demonstrated.
repair of radiation-induced DNA double-strand breakage,
is required to support efficient retroviral infection [W8]. In 219. Defective DNA damage repair and impaired response
addition to DNA-PK, Lau et al. have recently presented evi- to oxidative stress seem to be involved in the pathogenesis of
dence that ATM kinase activity has an important role in HIV-1 autoimmune diseases. Lymphocytes of patients in the active
infection. By using a specific ATM inhibitor (KU-55933), phase are more radiosensitive than those of patients in the
they demonstrated that ATM is required for HIV-1 replica- remissive phase of these diseases.
tion in NHEJ-proficient cells [D14, L24]. A direct correla-
tion exists between apoptosis and HIV gene expression in 220. Concerning AIDS, ionizing radiation activates human
T-cells in response to ionizing radiation exposure. Caspases immunodeficiency virus (HIV-1) replication. Higher radio-
seem to be involved in ionizing-radiation-induced activation toxicity is observed in AIDS patients, probably owing not
of HIV, since caspase inhibitors abolish both apoptosis and only to immune dysregulation but also to impairment of DNA
HIV gene expression [O1]. However, triggering of apopto- repair combined with a chronic state of oxidative stress.
sis is not sufficient to induce HIV gene expression, since in
other cell types (e.g. carcinoma cells), ionizing radiation
induces apoptosis but does not enhance HIV expression. H. Summary
217. Higher morbidity associated with radiation therapy 221. This section has summarized the influence of dose,
has been reported in HIV-1+ patients [S25], although the dose rate and radiation quality on radiation effects on the
mechanisms involved in this response remain controver- immune system. Data concerning the radiosensitivity of
sial. It has been postulated that the pattern of immune dys- lymphocyte subsets and the immune effects of prenatal
regulation present in these patients could play a role in their irradiation were reviewed. Human immune pathologies
abnormal response to ionizing radiation. Cells infected with associated with radiosensitivity were summarized.
HIV-1 exhibit down-regulation of the DNA repair gene DNA-
PKcs and other cell-cycle-related genes, suggesting that 222. Activation of the immune function by low-dose
impairment of DNA repair and dysregulation of cell cycle irradiation has been mainly demonstrated in splenic and
thymic lymphocytes from some strains of animals. Low- The RBE of high-LET radiation differs, depending on the
dose enhancement of the immune response is mainly seen end point considered. Some cell types exhibited differences
in T-lymphocytes, particularly in CD8+ T-cells. This effect, in the response to proton versus photon radiation, proton
which has not yet been demonstrated in humans, seems to irradiation inducing more significant immunosuppression.
take place within a very narrow dose range. While a dose Lymphoid cells and tissues are markedly affected by high-
of 20 mGy (acute exposure) induces immunoenhancement LET radiation at relatively low doses in terms of cell deple-
in rodents, changing the dose to 200 mGy induces a shift tion and organ size, whereas neutron RBE is close to unity
towards immunosuppression. The same dose (200 mGy) for the induction of lymphocyte apoptosis. Radon exposure
administered using a protracted schedule exhibits immuno induces marked changes in thymus subpopulations and alters
enhancing properties. However, this effect may vary accord- molecules involved in the migration and homing of immune
ing to the age and strain of the animal. The suppressive effect cells.
of low-dose irradiation on tumour growth has been reported
in animal models. An adaptive response to radiation in the 225. Although the radiosensitivity of lymphocyte subsets
immune system seems to be related to a reduction of apop- depends on several factors related to the experimental con-
tosis and an enhanced capacity to repair DNA damage. Even ditions, the data reviewed indicate that B-lymphocytes are
at very low doses, tritium incorporation appears to have the most radiosensitive subset and that NK cells are more
a higher RBE. The long-term impact of low doses on the radioresistant.
immune functions related to human health remains to be
determined. 226. There are critical windows of special vulnerability for
prenatal irradiation of the immune system, and the effects
223. Concerning high doses, minimal depression of leu- differ according to the developmental stage at which the irra-
cocyte counts may be observed following acute WBI in the diation takes place. Radiation-induced damage to the devel-
range 0.51Gy. Acute radiation syndrome occurs after acute oping thymus and haematopoietic stromal microenvironment
whole-body or significant partial-body exposure of >1 Gy. account, at least in part, for the observed effects.
The kinetics and severity of immunosuppression depend on
the whole-body dose. In non-uniform exposures, temporal 227. The identification of human pathologies in which
blood cell parameters are more relevant for dose estimation immunodeficiency is associated with higher radiosensitivity
than the magnitude of cytopenia. Reconstitution of innate is relevant, because the effects of ionizing radiation on the
immunity is more rapid than that of acquired immunity. immune system may be more severe in patients with these
Humoral recovery precedes T-cell reconstitution, which disorders. Delayed repair of radiation-induced DNA damage
includes both thymus-dependent and thymus-independent and increased lymphocyte radiosensitivity have been found
pathways. in patients with autoimmune diseases. AIDS patients exhibit
higher radiotoxicity. Ionizing radiation activates HIV-1 rep-
224. Radiation-induced changes in immune parameters lication, and bystander effects involving reactive oxygen
seem to be more dependent on total dose than on dose rate. species seem to be involved in this activation.
III. possible MECHANISMS INVOLVED AND IMPLICATIONS
228. In order to better understand the findings described in during which the morphological and biochemical features of
section IV (Epidemiological studies), this section summarizes apoptosis become apparent [K20].
some mechanisms that are probably involved in radiation-
induced alterations of the immune system. Mechanisms of 231. There are at least two pathways for radiation-induced
cancer development and the possible roles of the immune apoptosis: one is mediated by mitochondrial factors and is
system are also discussed. p53-dependent, and the other is mediated by cell surface
receptors (Fas/CD95) [S16]. The latter pathway may be
229. The pathways activated by ionizing radiation that acidic-sphingomyelinase-dependent and ceramide-mediated
have been investigated in the greatest depth are those dealing [K46]. ROS generated by ionizing radiation result in oxi-
with the responses to DNA damage. These pathways involve dative damage to the cell membrane, and lymphocytes are
sensor molecules linked to primary downstream components known to be sensitive to oxidative stress because of their
that integrate and process the signals. As a result of this high mitotic potential and the content of polyunsaturated
response to DNA damage, the cell cycle arrests, DNA repair fatty acids in their cell membranes [S51]. In recent years,
takes place and the cell may survive or die. However, not evidence has accumulated suggesting that the damage to the
all the effects of ionizing radiation on the immune system cell membrane contributes to radiation cell killing [R14]. It
can be ascribed to cytotoxicity. An additional outcome of has been demonstrated that activation of membrane-bound
radiation exposure, which is not often considered, concerns sphingomyelinase after irradiation produces ceramide,
the production of danger signals that may also influence which strongly induces expression of Fas ligand (FasL/
the classical cellular responses normally related to DNA CD95L), cleavage of caspases and apoptosis [D22]. These
damage [M2]. The following possible mechanisms involved data demonstrate that ceramide links cellular stress responses
in radiation-induced alterations of the immune system will induced by gamma irradiation or anticancer drugs to the Fas
be summarized: pathway of apoptosis.
Lymphocyte apoptosis; 232. Radiation-induced apoptosis in lymphocytes may
TCR mutations; be initiated by the Fas/FasL system. Radiation induces the
Modification of Th1 and Th2 balance; synthesis of the death ligand FasL. Ligand-mediated cross-
linking of the Fas receptor initiates signalling pathways to
Bystander effects and genomic instability; apoptosis. Anti-Fas or anti-FasL antibodies reduced the level
Shift towards an inflammatory profile; of radiation-mediated cell killing [B3]. Furthermore, ion-
Acceleration of immunological ageing; izing radiation up-regulates the surface expression of Fas,
thus increasing the sensitivity of those cells to FasL. The Fas
Modification of antigen presentation; receptor stimulates a variety of molecules, including several
Autoimmune reactions; members of the caspase family and the acidic sphingomye
Perturbation of the immunological homeostasis; linase. Brenner et al. [B10] described a signalling cascade
from the Fas receptor via caspases to acidic sphingomye
Other possible mechanisms involved. linase, release of ceramide and activation of Jun N-terminal
kinase (JNK) and p38-K kinases (phospho-p38 mitogen-
activated protein kinase). Fas-mediated apoptosis could be
A. Lymphocyte apoptosis prevented in CD4+ or CD8+ T-cells by several protease
antagonists, suggesting the involvement of the interleukin-
1. Review of published data 1-converting-enzyme-related cysteine protease in CD4+
T-cell death, and of both a CPP32-related cysteine protease
230. Apoptosis plays a crucial role within the immune sys- and a calpaine protease in CD8+ T-cell death triggered by
tem, in particular in negative regulation, and is a key mech- Fas [E5].
anism in the response to ionizing radiation. Lymphocytes die
by apoptosis immediately after exposure (interphase death) 233. In contrast, Ogawa et al. [O4] demonstrated that
[J5] or by reproductive cell death [M22]. The apoptotic peripheral blood mononuclear cells irradiated with 5 or
process can be divided into three phases: a death-stimulus- 10 Gy of gamma radiation showed positivity to apop-
dependent induction phase; an effector phase during which tosis markers but displayed no increase in surface Fas
the decision to die is taken; and a degradation phase, expression or caspase-3 activity relative to non-irradiated
133
cells, suggesting a Fas-independent mechanism. A Fas- recently described the possible existence of a new apoptotic
independent mechanism was also reported by Kuida et al. cascade involving early lysosomal membrane destabiliza-
[K35] in thymocytes from ICE mice that were sensitive to tion. Therefore possible involvement of lysosomal protease
apoptosis induced by dexamethasone or ionizing radiation leakage caused by hydroxyl radical formation in lysosomes
but resistant to apoptosis induced by Fas antibody. In addi- (possibly resulting in mitochondrial membrane dysfunction)
tion, TCR stimulation of CD8+ T-cells led to a different is considered to play an important role in radiation-induced
Fas-independent death process [E5]. T-cell apoptosis [O6]. Moreover, in a recent study, Sharma
et al. [S51] investigated the immunomodulatory effect of
234. A p53-dependent, mitochondria-mediated apop- chlorophyllin (CHL), a water-soluble mixture of salts of
totic pathway was proposed. The p53 molecule is a key chlorophyll that had earlier been shown to reduce the level of
modulator of radiation-induced apoptosis in several cell intracellular ROS. CHL significantly inhibited apoptosis in
types [L22]; however, it has also been shown that ion- Con-A-stimulated spleen cells from BALB/c mice, whereas
izing radiation can induce apoptosis in human lympho- the expression of anti-apoptotic genes bcl-2 and bcl-xL was
cytes independently of p53 status. Radiation-induced up-regulated in lymphocytes of CHL-treated mice compared
up-regulation of FasL protein defines a p53-independent to controls.
pathway to apoptosis, since apoptosis induced by FasL
does not require p53. In fact, radiation-induced p53- 238. Down-regulation of mitochondrial transmembrane
dependent and p53-independent apoptotic pathways are potential by inhibitors of electron transport and adenosine
both present in different cell types of the immune system. triphosphate (ATP) synthesis prevented stress-induced p53
Seki et al. [S10] demonstrated that p53 protein was indu- protein accumulation and eliminated p53-dependent apop-
cible in TCR T-cells (CD4 and CD8 cells) and B-cells, tosis in a wild-type p53 leukaemia cell line (MOLT-3) and
but not in TCR T- and NK cells after gamma irradia- in normal T-lymphocytes, identifying mitochondrial activity
tion. Cycloheximide was able to inhibit radiation-induced and ROS levels as critical intracellular determinants of the
cell death in TCR T-cells and B-cells, indicating a p53 activity [K7]. On the other hand, Chen et al. [C8] demon
requirement for protein synthesis, including p53 protein. strated that nitric oxide, a key RNS, protects thymocytes
from gamma-irradiation-induced apoptosis. The mechanism
235. Mitochondria serve to integrate and amplify upstream may involve inhibition of p53 up-regulation and reduction of
cell death signals, clarifying the cellular reaction to a go/ mitochondrial damage, with subsequent inhibition of down-
no-go response. These signals include proteins, reactive spe- stream caspase activation.
cies and divalent cations. The protein signals include the
proapoptotic members of the Bcl-2 family, such as Bax, Bad 239. The apoptotic response of lymphocytes may differ fol-
and Bak. Anti-apoptotic members of the Bcl-2 family include lowing low-dose irradiation. Data recently communicated by
bcl-2 and bcl-xL. Reactive compounds include reactive oxy- Shankar and Sainis in whole-body gamma-irradiated mice
gen species (ROS) and reactive nitrogen species (RNS). If (cumulative dose 200 mGy at 40 mGy/day) demonstrated
the stress is sufficient, mitochondria respond by releasing a that such very low doses enhanced the mitogen responsive-
series of protein factors. These factors include cytochromec ness to Con A of spleen lymphocytes, reduced expression of
and Smac/DIABLO, which act to initiate and facilitate the p53 and down-regulated apoptosis. This anti-apoptotic effect
downstream stages of the caspase-dependent cascade. Other was associated with a higher expression of cyclin D1 and
factors released include apoptosis-inducing factors and proliferating cell nuclear antigen (PCNA), two critical pro-
endonuclease G, which then initiate the downstream stages teins for cell cycle transition and cell proliferation. Interest-
of the caspase-independent cascade [K20, S29]. ingly, these authors also demonstrated that down-regulation
of apoptosis was not mediated by the Fas/FasL pathway
236. Cui et al. [C13, C18] found an increased expression but rather through the mitochondrial pathway [S16]. These
of Bax protein in thymic lymphocytes of mice 3 hours after findings suggest that those apparently opposite effects of
exposure to lethal doses of gamma radiation. On the other ionizing radiation on some immune responses observed fol-
hand, the expression of bcl-2 and bcl-xL proteins was reduced lowing moderate to high doses compared with low doses,
at 3 hours after irradiation, reaching their lowest level at 24 e.g. immunosuppression versus immunostimulation, may be
hours. However, a Fas-mediated pathway unaffected by bcl-2 related to signal transduction pathways involving cell cycle
has been described [S31]. regulatory proteins such as p53, cyclins and PCNA.
237. The role of ROS in radiation-induced apoptosis of

human peripheral T-cells was studied by Ogawa et al. [O5]. 2. Remarks concerning lymphocyte apoptosis
They found that ROS formation occurred immediately after
irradiation, continued for several hours and resulted in oxi- 240. The preceding paragraphs indicate that apoptosis plays
dative DNA damage. Early (13 hours post-irradiation) and a crucial role within the immune system, in particular in neg-
late (23 hours post-irradiation) apoptotic changes were cor- ative regulation, and is also a key mechanism in the response
related. Therefore the origin of the hyperradiosensitivity of to ionizing radiation. It is accepted that there are at least two
T-lymphocytes seems to be the high production of ROS in pathways for radiation-induced apoptosis: DNA-damage-
the mitochondrial DNA following irradiation. Ogawa et al. mediated and p53-dependent, and ceramide-mediated.
241. Radiation-induced apoptosis in lymphocytes may be exposed to effluents of the Techa River in the Russian
initiated by the Fas/FasL system. Radiation induces the syn- Federation [A17].
thesis of the death ligand FasL and up-regulates the surface
expression of the Fas receptor, which stimulates the release 246. On the other hand, a positive correlation has been
of ceramides and members of the caspase family. Radiation- found between TCR mutation frequencies and dicentric
induced up-regulation of FasL protein is a p53-independent chromosome frequencies in lymphocytes from patients who
pathway to apoptosis. had previously received a full course of radiation therapy for
gynaecological disorders. By comparing mutation frequen-
242. A p53-dependent, mitochondria-mediated apoptotic cies of hypoxanthine-guanine phosphoribosyltransferase
pathway has been proposed. Radiation-induced p53 apop- (HPRT) and TCR using flow cytometry, it was possible to
tosis and p53-independent pathways are both present in dif- demonstrate that the frequency of TCR mutants correlated
ferent cell types of the immune system. Mitochondria inte- well with that of dicentric chromosomes [I4].
grate and amplify upstream cell death signals. These signals
include proteins, reactive species and divalent cations. The 247. Although the TCR in vivo somatic mutation assay has
proteins include proapoptotic and anti-apoptotic members been proposed as a sensitive indicator of ionizing radiation
of the Bcl-2 family, and mitochondria respond by releasing exposure, this assay cannot be applied immediately, since
protein factors that initiate the caspase-dependent cascade. the mutant phenotype may require as long as several months
Reactive compounds include ROS and RNS, and divalent to express. Ishioka et al. [I3], using IL-2 after PHA pulse
cations are mainly Ca2+ and Mg2+. stimulation, demonstrated a dose-dependent increase of
mutation frequency in CD4+ cells during the first seven days
243. The apoptotic response may differ following low-dose post-irradiation.
irradiation. Protracted exposure to radiations at low dose rate
reduces the expression of p53 and down-regulates apoptosis. 248. In 2002, Smirnova et al. described the mutation fre-
This effect was associated with a higher expression of cyclin quency of TCR genes in lymphocytes from 165 individuals
D1 and PCNA, two critical proteins for cell cycle transition exposed to ionizing radiation [S24]. The cohort was divided
and cell proliferation. These findings suggest that the appar- into three groups depending on the type of irradiation and
ently opposite effects observed in the immune system at time elapsed since exposure: group 1, analysis performed
high and low doses might be related to signalling pathways 1640 years after acute irradiation; group 2, 13 years after
involving cell cycle regulatory proteins such as p53, cyclins acute irradiation; and group 3, 913 years after prolonged
and PCNA. irradiation. Elevated frequencies of TCR mutant cells were
detected in all three groups: 36%, 25% and 15% in the first,
second and third group, respectively. The same authors have
B. TCR mutations recently found elevated frequencies of TCR mutant cells in
nuclear chemical plant workers chronically exposed to low
1. Review of published data doses of external and internal irradiation [S44]. In both stud-
ies, the frequency of mutant cells was significantly higher
244. It has been well established that ionizing radiation than in control groups.
induces somatic mutations in a dose-dependent manner both
in vivo and in vitro. Radiation-induced mutations in TCR 249. Although several papers have provided strong evi-
genes could result in the phenotypic expression of TCR- dence for mutation of the TCR, the question concerning
defective T-cells. Since the TCR/CD3 complex is involved in the lifespan of human memory cells in the absence of TCR
the first step of a variety of other T-cell-dependent immune signalling remained open. The long-term kinetics of TCR/
functions, loss or alteration of TCR expression in surviving CD3 mutation between CD4+ CD45RA+ naive and CD4+
cells may contribute to radiation-induced impairment of the CD45RA memory T-cell fractions was studied in cancer
T-cell response [K34]. patients receiving radiotherapy [U17]. Both the proportion
and the number of mutant cells decayed exponentially with
245. A considerable volume of literature is available time following radiotherapy. The results indicated that the
describing the defective expression of TCR gene or . lifespan of mature CD4+ T-cells is limited regardless of their
A marginally significant (p = 0.051) dose-related increase memory or naive phenotype, suggesting that continued cell
in the TCR mutation frequency has been detected among receptor signalling is required for lifetime maintenance of
survivors of the atomic bombings in Japan. The presence human memory cells.
of TCR mutation is dependent on the in vivo selection that
occurred soon after exposure, and TCR mutants were almost 250. Moreover, in vivo models to establish the spontaneous
completely eliminated in vivo during the first decades fol- and radiation-induced TCR mutation frequency showed that
lowing the exposure to radiation from the atomic bombings. the TCR mutation frequency dose response fitted a linear
The half-life of TCR mutants is quite short, between two and quadratic or quadratic function. The general trend was
three years. Similar results were found in patients treated that radiation-induced TCR mutation frequency started to
with Thorotrast and with 131I [A7, K34, U19]. An increased increase 3 days after WBI with Xrays, reached a peak at
frequency of TCR mutations was found among persons 23 weeks and then gradually decreased, with a half-life
of about 2 weeks. The coefficients of the quadratic term in C. Modification of Th1/Th2 balance
BALB/c mice were significantly higher than for C57BL/6 or
C3H/He mice, suggesting that genetic factors may control 1. Review of published data
the susceptibility of somatic genes to both spontaneous and
radiation-induced mutagenesis [U18]. 256. As described earlier, two distinct functional cyto-
kine secretion patterns, designated Th1 and Th2, have been
251. Studies involving TCR mutation frequencies in p53- defined for helper T-cells. While Th1 cytokines promote
deficient mice have clarified the important role of the p53 cell-mediated immunity, Th2 cytokines favour humoral
protein in the repair of radiation-induced mutagenic damage immunity, providing B-cell assistance for antibody produc-
to the immune system. In p53 (-/-) mice, the TCR mutation tion. Controversial results have been published concerning
frequency did not decline significantly with time. It was the effects of ionizing radiation on the Th1/Th2 balance and
concluded that complete repair of mutagenic damage in its impact on human health. Th1 and Th2 helper T-cells are
irradiated tissues requires the integration of DNA repair and cross-regulatory in vitro, and the balance of these cells in
p53-dependent apoptotic mechanisms [K8, S32]. vivo determines the character of the cell-mediated immune
and inflammatory response [N10]. An imbalance between
252. In order to explore the ability of ionizing radiation to Th1 and Th2 may be responsible both for the progression of
induce rearrangements in TCR leading to TCR variants several diseases and their resultant complications. Patients
(hybrids) in human lymphocytes, peripheral blood lympho- with advanced cancer often have impaired cell-mediated
cytes from healthy donors were exposed in vitro to 3Gy of immunity associated with a switch from Th1 to Th2. While
either X- or gamma rays. The TCR frequency was not organ-specific autoimmune diseases have been related to an
significantly different in irradiated versus control samples up overreactive Th1 pathway, the Th2 pathway may underlie
to 55 days after PHA stimulation, suggesting that low-LET allergy and systemic autoimmune diseases [G13, K11]. On
radiation is not able to induce this type of TCR rearrangement the other hand, shifting from one cytokine pattern to another
in vitro [M4]. may be highly beneficial in certain physiological condi-
tions; for instance, IL-10 (a Th2-type cytokine) may play a
role in pregnancy-associated immune tolerance through the
2. Remarks concerning TCR mutations establishment of a Th2 cytokine bias at the maternalfoetal
interface [S20].
253. Some remarks may be made on the basis of the
information presented in the preceding paragraphs. 257. The impairment of cell-mediated immunity associ-
Radiation-induced mutations in TCR genes could result ated with the increase in the B-cell component and humoral
in the phenotypic expression of TCR-defective T-cells immunity observed in atomic bombing survivors led to the
and thus contribute to radiation-induced impairment of hypothesis that radiation exposure could induce an imbal-
the T-cell response. A significantly increased frequency of ance towards a Th2 profile. The observed increase in per-
TCR mutation has been detected among survivors of the centage of CD4 CD8 + double-negative T-cells, known
atomic bombings, in patients treated with Thorotrast and to produce primarily Th2-type cytokines, supported the idea
131
I, and among the Techa River cohort. It must be empha- that ionizing radiation could induce a shift from a Th1 to a
sized that the presence of mutation is dependent on the Th2 response [K23]. Reduced IL-2 production in response to
in vivo selection, and that the half-life of TCR mutants is Con A in survivors was reported to be caused by a reduced
between two and three years. Elevated frequencies of TCR number of naive CD4+ T-cells [K31]. However, a dose-
mutant cells were also observed in chronically exposed dependent increase in TNF- and IFN- production was
workers at nuclear plants. observed in atomic bombing survivors, suggesting that Th2
does not dominate over Th1 [N3].
254. In vivo models to establish the spontaneous and
radiation-induced TCR mutation frequency showed that 258. Interaction between cytokines and their receptors
the doseresponse function fitted a linearquadratic or leads to the activation of multiple signalling molecules,
quadratic function. The coefficients were dependent on including the family of signal transducer and activator of
the strain of mouse studied, suggesting that genetic fac- transcription (STAT) proteins. Different STAT proteins
tors may control the susceptibility of somatic genes to both are capable of regulating the activity of diverse types of
spontaneous and radiation-induced mutagenesis. Likewise, cytokine. It has been reported that mice with a disrupted
in a p53 (-/-) mouse model it was observed that the TCR STAT gene have impaired IL-12 responsiveness of NK
mutation frequency did not decline significantly with time, and T-cells, a lack of Th1 responsiveness and enhanced
leading to the conclusion that repair of mutagenic damage Th2 function [K5]. Gamma radiation has been shown to
in irradiated tissues requires the integration of DNA repair reduce STAT1 phosphorylation. In contrast, mRNA levels
and p53-dependent apoptotic mechanisms. for IL-5 were only slightly increased by gamma radiation
compared with non-irradiated samples, suggesting that ion-
255. To date, there are no definitive data demonstrating izing radiation induces a polarized Th2 response by inter-
that low levels of TCR mutation frequency have induced fering with STAT signals, thereby causing suppression of
immunodeficiency. the Th1response [H4].
259. In addition to the STAT protein family, the transcrip- 262. Pharmacological improvement of the impaired Th1
tion factor NF-B is one of the key regulators of the genes function after irradiation has been used as an indirect way
implicated in the immune inflammatory response. In a rat to investigate the radiation-induced enhancement of Th2
abdominal gamma irradiation model, Linard et al. [L26] have response. Ginsan (an acidic polysaccharide from Panex gin-
shown that genesis of the inflammatory process involved the seng) is able to induce proliferation of lymphokine-activated
translocation/activation of the NF-B/Rel p65 subunit in the killer cells, to increase the mitogen activity in different sys-
intestine. This activation was inhibited by a specific NF-B tems and to induce the production of several cytokines (such
inhibitor (caffeic acid phenethyl ester) that contributed to a as IL-1, IL-6, IFN- and IL-12) that are required for haema-
reduction in the expression of TNF-, IL-6 and IL-6 recep- topoietic recovery. In an experimental model of WBI, ginsan
tors. The cytokine signalling is under negative feedback was injected in vivo and its action was evaluated by measur-
regulation by intracellular proteins such as the suppressor ing its effect on CFU-S bone marrow cells and cytokine gen-
of cytokine signalling (SOCS) gene. The differentiation into eration. Ginsan was shown to enhance Th1 function while
Th1 and Th2 is accompanied by a preferential expression of interfering with the radiation-induced Th2 response [S27].
distinct SOCS (SOCS1 is highly expressed by Th1, whereas
Th2 expresses high levels of SOCS3). Reports indicated 263. Interestingly, the cytokines characteristically expressed
that Th1 responses are likely to be negatively regulated by in Th1 cells seem to be regulated by cell-mediated suppres-
SOCS3 in vivo, rather than Th2 responses being attenuated sion. The induction of TNF- mRNA in lymphoid cells is
by SOCS1 [I7]. Irradiation induced an intestinal overexpres- greatly enhanced by gamma radiation. However, the level of
sion of SOCS3 and a repression of SOCS1 in the first week. TNF- mRNA expressed in response to radiation and other
The inhibition of NF-B activation reduced the SOCS3 stimuli, whether by mitogen or antigen, is strongly reduced by
expression [L27]. These data suggested that the polarized concomitant activation of suppressive cell subsets. Removal
Th2 response induced by ionizing radiation involved the of CD8+ or CD11b+ cells leads to a substantial induction of
transcription factor NF-B. TNF- mRNA in the depleted cell population; this induction
precedes the appearance of suppressive cell activity, allowing
260. Bass et al. [B2] studied the ratio of Th1 and Th2 clones for temporary suppression. TNF-, as well as other Th1
in the spleens of mice 46 weeks following total lymphoid cytokines such as IFN- and IL-2, is suppressed by CD8+ or
irradiation by high-dose Xrays (5.5 and 8.5Gy). The Th1/ CD11b+ cells [A1].
Th2 ratio was 1/0.6 in control mice, whereas the ratio in
total lymphoid irradiated mice was approximately 1:7, sup- 264. IL-4 and IL-5 synthesis in lymph node cells primed
porting a conclusion that radiation exposure enhances Th2- by keyhole limpet haemocyanin (KLH) was greatly dimin-
type cytokine production [B2]. In contrast, it has been shown ished after irradiation. In addition, the capacity of irradiated
that low-dose WBI with 0.075Gy Xrays is able to generate KLH-primed lymph node cells to induce IgG, IgM and IgE
changes in IL-12 p35/p40 mRNA and IL-12 p70 protein lev- synthesis in hapten-primed cells was studied. Irradiation was
els, while IL-10 decreased significantly in splenocytes, and not able to modify IgG synthesis in these cells, but their cap-
mRNA levels for both IL-12 p35 and p40 subunits increased acity to induce IgE was significantly reduced. Thus irradia-
in macrophages following WBI. The suppression of IL-10 tion greatly inhibited the capacity of Th2 clones, but only
expression and stimulation of IL-12 expression were inter- minimally inhibited the capacity of Th1 clones, to induce
preted as representing a shift of the immune response in IgG synthesis in primed B-cells. By adding IL-4 and IL-5,
favour of Th1 differentiation [L19]. the capacity of Th2 cells to produce IgE was completely
restored [D2].
261. The prevalence of a radiation-induced Th2 response
has been verified in irradiated lung. Enhanced lymphocyte
reactivity, dominated by Th2 cells, was shown in radiation- 2. Remarks concerning modification of Th1/Th2 balance
induced pneumonitis and subsequent pulmonary fibrosis.
The kinetics was studied in T-cell lymphocytes isolated from 265. As discussed in the preceding paragraphs, two distinct
lungs irradiated with 20Gy. A selective increase of CD4+ functional cytokine secretion patterns have been defined for
T-cells was observed, peaking four weeks after irradiation helper T-cells: Th1 and Th2. While Th1 cytokines promote
of the lungs. When the rats were depleted in CD4+ T-cells, cell-mediated immunity, Th2 cytokines favour humoral
post-irradiation thickening of the parenchyma was signifi- immunity. The balance of Th1 and Th2 helper cells in vivo
cantly reduced, as determined by morphometric analysis. determines the character of cell-mediated immunity and
The CD4+ cell subtype of the T-lymphocyte population inflammatory response, the imbalance being responsible
was analysed by measuring different cytokine mRNAs by for the progression of several diseases and their resultant
RT-PCR (reverse transcription polymerase chain reaction). complications.
It was found that IL-4 mRNA was selectively increased in
the CD4+ cells isolated from irradiated lungs, which indi- 266. The results concerning the effects of ionizing radia-
cates a lymphocyte reactivity by Th2 cells. The authors tion on Th1/Th2 balance are controversial. In survivors
suggested a critical role for Th2 CD4+ cells in the patho- of the atomic bombings, the impairment of cell-mediated
genesis of radiation-induced pneumonitis preceding lung immunity associated with the increase in the B-cell compo-
fibrosis [W3]. nent and humoral immunity suggests an imbalance towards a
Th2 profile induced by the radiation exposure. The observed These various end points have all been demonstrated as non-
increase in the percentage of CD4 CD8 + T-cells, targeted effects of ionizing radiation. Many properties of
known to produce mainly Th2-type cytokines, supports the activated macrophages are consistent with in vitro studies
hypothesis of a shift from Th1 to Th2. Nevertheless, a dose- that implicate free radical generation in non-targeted radia-
dependent increase in TNF- and IFN- secretion suggests tion effects [N5], and with other studies in which oxidative
that Th2 does not dominate over Th1. processes and nitric oxide have been implicated as having
roles in the mechanisms [C12, G4, L11]. Nitric oxide can
267. The prevalence of a radiation-induced Th2 response be either proapoptotic or anti-apoptotic, can either down-
has been verified in experimental studies, for example of the regulate or up-regulate p53 activity [B11], and can be either
spleens of mice irradiated with high-dose X-rays and the pro-inflammatory or weakly anti-inflammatory [G13, N6],
lungs of rats irradiated with 20Gy, where it was found that depending on context.
Th2CD4+ cells might play a critical role in the pathogenesis
of radiation-induced pneumonitis. In contrast, after low-dose 272. A stimulatory bystander effect can be induced in
WBI, 0.075Gy, the changes observed might contribute to a immune cells by low-dose irradiation. When a mouse mac-
shift in favour of Th1 differentiation. rophage cell line (J774A.1) was exposed to a low dose
(0.075 Gy) and co-cultured with a non-irradiated mouse
268. STAT proteins are key molecules in the regulation T-lymphocyte cell line (EL-4), the irradiated macrophages
of the activity of different types of cytokine, and mice with exerted a stimulatory effect on the EL-4 cells, as shown by
disrupted STAT genes have a lack of Th1 responsiveness increased proliferation. At a high dose (2 Gy), irradiated
and enhanced Th2 function. It has been shown that radia- J774A-1 cells exerted an inhibitory effect on the prolifera-
tion reduces STAT phosphorylation, inducing suppression tion of the non-irradiated EL-4 cells. Preliminary mechanis-
of Th1 response. The transcription factor NFB is another tic studies show that changes in CD48 expression and nitric
key regulator of the genes implicated in the immune inflam- oxide production by the J774A.1 cells after high- and low-
matory response, and the action of specific NFB inhibitors dose irradiation might be important factors underlying the
after irradiation in a rat model contributed to a reduction differential bystander effects elicited by different doses of
of Th2 cytokine expression. In addition, the cytokines radiation [L13].
expressed in Th1 cells seem to be regulated by cell-mediated
suppression. 273. There are few data on bystander effects in whole ani-
mals. However, prior to the recent interest in non-targeted
effects, there were numerous reports that a transferable clas-
D. Bystander effects and genomic instability togenic activity capable of causing chromosome breaks in
non-irradiated lymphocytes was present in the plasma of
1. Review of published data patients after radiotherapy, though with considerable inter-
individual variation in both production and response [M15].
269. Bystander effects and genomic instability are two Clastogenic factors in plasma have also been obtained from
general mechanisms possibly involved in the effects of ion- atomic bombing survivors and Chernobyl liquidators [P3,
izing radiation on the immune system. The general features W6], and from patients with a variety of chromosomal
of these two mechanisms are reviewed in annex C, Non instability syndromes and inflammatory disorders. The
targeted and delayed effects of exposure to ionizing radia- chromosome-damaging effects of clastogenic factors are
tion. Thus this section reviews only observations of these mediated by the superoxide anion. Their clastogenic activity
non-targeted and delayed effects that relate to the immune may be related to the formation of lipid peroxidation prod-
system. ucts and cytotoxic cytokines, which are possible agents for
mediating radiation-induced bystander effects. A body of
270. Irradiation has been shown to induce leukaemic trans- clinical and experimental radiotherapy data exists concern-
formation of non-irradiated stem cells transplanted into syn- ing the abscopal effects of radiation, where responses are
geneic mice [D13]. These findings may reflect the altered noted in unrelated organs or tissues that had not been irradi-
characteristics of the stem cell microenvironment after ated [C2]. However, it is far from clear whether bystander
irradiation, since irradiated haematopoietic stromal cells killing contributes to the curative potential of radiotherapy
release mutagenic ROS, produce different sets of adhesion and whether inducible instability is an important component
molecules and growth factors, and alter the overall growth of late adverse effects.
and phenotypic characteristics of co-cultured non-irradiated
stem cells [G7]. 274. Xu et al. demonstrated that low doses of radiation
(0.2510 mGy) stimulate expression of IL-2 receptors
271. Haematopoietic tissues exposed to ionizing radiation (CD25) on the surface of peripheral blood lymphocytes
have been shown to exhibit increased macrophage activation taken from normal human donors [X1]. Clastogenic factors
[L8]. Activated macrophages are able to induce apoptosis in can also stimulate CD25 surface expression in non-irradiated
neighbouring cells [B12, D12] and produce gene mutations cells, suggesting that this radiation-stimulated surface
[W2], DNA base modifications [D7], DNA strand breaks expression is a bystander effect resulting from the secretion
[S14] and cytogenetic damage [W1] in neighbouring cells. into the medium of a soluble factor from the irradiated cells.
Stimulation of CD25 expression by ionizing radiation shows 2. Remarks concerning bystander

a triggered-type response rather than being proportional to effects and genomic instability
dose.
279. Some remarks may be made on the basis of the data
275. Persistent subclinical inflammation has recently been presented above. Delayed effects and genomic instabil-
reported among survivors of the atomic bombings in Japan ity in the immune system have been demonstrated in vitro
[N7], and it was suggested that radiation-induced enhance- and in vivo after exposure to ionizing radiation. Chromo-
ment of inflammatory reactions might contribute, as an somal instability in haematopoietic cells can be induced by
epigenetic and/or bystander effect, to the development of a bystander-type mechanism, providing a link between these
several radiation-induced disorders. two untargeted effects, as well as other radiation responses
that are consistent with the microenvironment contributing to
276. Thymic stromal cell cultures are able to sup- cell damage as a consequence of an inflammatory response
port T-cell precursor proliferation and differentiation in to radiation-induced injury.
the presence of IL-7 and stem cell factor. By exposing
thymic stromal cell cultures to 10Gy of gamma irradia- 280. Activated macrophages after irradiation are able to
tion before the seeding of T-cell precursors, it was pos- induce apoptosis, gene mutations, DNA base modifications,
sible to demonstrate a reduction of these T-cell precursors DNA strand breaks and chromosome-damaging effects in
without changes in their differentiation. The effect could neighbouring cells. Intercellular signalling and free radical
be reproduced by the addition of supernatants from irradi- generation are implicated in these non-targeted effects of
ated stromal cell cultures on to sham-irradiated cultures, ionizing radiation. Nitric oxide emerges as a key mediator in
which suggests that gamma irradiation induces the pro- the bystander effects elicited by high- and low-dose irradia-
duction of soluble factors by thymic stromal cells, which tion. Likewise, the superoxide anion has been described as
in turn modify their ability to support proliferation of a mediator of clastogenic factors in chromosome-damaging
T-cell precursors [B4]. effects.
277. Radiation-induced overexpression of IL-7 from 281. Long-lasting inflammation has been reported among
thymic stromal cells is key to understanding the radiation- the atomic bombing survivors, and it was suggested that
induced differentiation of CD8+ TCR T-cells. When radiation-induced enhancement of inflammatory reactions
double-negative foetal thymocytes were co-cultured with might contribute as an epigenetic and/or bystander effect to
foetal thymus irradiated with 25Gy of low-LET radiation the development of several disorders. However, the potential
in the absence of direct contact or mitogen stimulation, impact of such delayed effects in humans is not known.
induction of TCR T-cells was observed, reaching 50%
after 4 days of co-culture. Supernatants of the irradiated
foetal thymus were also able to induce the differentiation E. Shift towards an inflammatory profile
from double-negative thymocytes to CD8+ TCR T-cells
after 3 days of culture, suggesting a radiation-induced pro- 1. Review of published data
duction of soluble factors by thymic cells. It was possible
using RT-PCR to detect an increased expression of IL-7 282. Ionizing radiation may induce a persistent inflamma-
mRNA in the foetal thymus 24hours after irradiation, and tory status that could increase the risks of both cancer and
antibodies against IL-7 inhibited the radiation-induced non-cancer diseases [N3]. Higher risks of hepatic, cardio-
differentiation [T7]. vascular and thyroid pathologies have been observed among
atomic bombing survivors, and several authors have inves-
278. Shankar et al. studied bystander effects and adap- tigated the relationship between these chronic diseases and
tive response induced by gamma radiation in murine lym- impairment of the immune system.
phocytes, using irradiated conditioned medium (ICM)
from lymphocytes exposed to 0.1 Gy, 0.5 Gy and 1 Gy. 283. One of the main functions of cytokines is to medi-
They found that ICM enhanced the proliferation response ate interactions between the immune and the inflammatory
of non-irradiated lymphocytes to Con A, with increased response. Chronic immune inflammatory diseases might be
expression of IL-2 receptor and cyclin D, two proteins caused in part by dysregulation of cytokine production [B14].
that drive progression through the cell cycle. ICM also TNF-, IFN-, IL-6 and IL-10 coordinate the inflammatory
enhanced intracellular ROS content and nitric oxide gen- response [H10]. The stimulus for production of acute phase
eration in non-irradiated lymphocytes. Apoptosis was sig- proteins in response to tissue injury is likely to be mediated
nificantly lower in lymphocytes exposed to a challenge by these inflammatory cytokines. Thus the cytokine profile
dose of 1 Gy when they were preincubated with ICM. as well as the level of acute phase proteins may be useful
The results of these authors suggest that soluble factors markers of inflammation.
released by irradiated lymphocytes trigger signalling
pathways that result in increased response to mitogens 284. Exposure to high doses of ionizing radiation, such as
and resistance to radiation exposure in non-irradiated those delivered during radiotherapy or in cases of accidental
lymphocytes [S50]. irradiation, can induce fibrosis in many tissues as a late effect.
Formation of the fibrotic tissue requires chronic activation of some way to a decrease in CD4+ T-cells, suggesting that
several cell types, including myofibroblasts, that secrete the radiation-associated immunological changes may cause
collagenous matrix. The origin of the chronic activation of long-lasting inflammation [K36]. This T-cell impairment
these cells is still a matter of debate. TGF-1 has been pro- may generate age-associated chronic inflammation, which
posed as a master switch for the fibrotic programme [M18]. may be responsible for an increased risk of various lifestyle-
This cytokine can be secreted by the inflammatory cells that associated diseases, such as atherosclerosis, coronary heart
chronically invade the irradiated tissue and locally by the disease, diabetes and several cancers [K36, N3].
myofibroblasts. Antioxidant treatment that reduces estab-
lished fibrotic tissues in patients can act on both of these cell
populations [D19, D20]. 2. Remarks concerning the shift
towards an inflammatory profile
285. Neriishi et al. [N7] investigated the status of several
inflammation parameters in atomic bombing survivors. They 289. As reviewed in the paragraphs above, a persistent
demonstrated a positive association between radiation dose inflammatory status induced by ionizing radiation has been
and erythrocyte sedimentation rate, total leucocyte counts, associated with impairment of the immune system and
alpha-1 and alpha-2 globulin, and sialic acid. with cancer and non-cancer diseases. Since TNF-, IFN-,
IL-6 and IL-10 coordinate the inflammatory response,
286. Hayashi et al. [H8] found increased plasma levels of immune inflammatory diseases might be attributed in part to
C-reactive protein (CRP) and IL-6 in atomic bombing sur- dysregulation of cytokine production.
vivors. This increase was significantly related to radiation
dose, by about 30%Gy1 for CRP and 10%Gy1 for IL-6, 290. Significant dose-dependent increases of TNF-,
and was associated with a decrease in the percentage of IFN- and IL-10 in parallel with the erythrocyte sedimenta-
peripheral CD4+ T-cells. tion rate as a biomarker of inflammation were observed from
blood analysis of atomic bombing survivors. Total immuno
287. Inflammatory parameters were analysed in blood globulin levels were also enhanced in a dose-dependent
samples from atomic bombing survivors, including 180 non- manner. On the other hand, increased serum levels of TNF-
exposed subjects and 90 subjects from each of the follow- and IgM with higher functional complement activity were
ing dose groups: low dose (0.00050.7 Gy), medium dose reported in Chernobyl emergency and clean-up workers.
(0.71.5Gy) and high dose (>1.5Gy). The levels of TNF-,
IFN- and IL-10 were significantly increased with radiation 291. Preclinical inflammatory status may be linked to
dose, as was the erythrocyte sedimentation rate. There was impairment of cellular immunity, e.g. a decrease in CD4+
a radiation-dose-dependent increase in plasma levels of IL-6 T-cells observed after radiation exposure, suggesting that
and CRP. IL-6 stimulates the synthesis of acute phase pro- radiation-associated immunological changes could account
teins (such as CRP) involved in complement activation. A for long-lasting inflammation.
dose-dependent increase was also observed in total immuno-
globulin levels. While the levels of IgA and IgM increased
significantly with radiation dose, those of IgG and IgE did F. Acceleration of immunological ageing
not [H10]. Increased serum levels of TNF- [S13] and IgM
[K21, S13] with higher functional complement activity 1. Review of published data
[K21] were reported in Chernobyl emergency and clean-
up workers. Higher serum levels of both IgG and IgM were 292. It has been proposed that acceleration of immuno-
found in children resident in contaminated areas around the logical ageing may be associated with radiation effects in
Chernobyl nuclear power plant [K15, T5]. humans. Immunosenescence has been described in sectionII
above. As illustrated in table 11, comparison of the main
288. These observations provide evidence of a persis- features of immunosenescence with the experimental and
tent inflammatory profile as a long-term effect after radia- epidemiological findings concerning radiation effects on the
tion exposure. Preclinical inflammatory status is linked in immune system supports this hypothesis.
Table 11 Comparison between the main features of normal immunosenescence and observed radiation effects on
the immune system
Parameter Normal ageing Irradiation
Renewal capacity of stem cells and haematopoietic Decreased [H1, L1] Decreased [G5]
progenitor cells
Total CD4+ T-cells Decreased, about 4% per 10 years [K29] Decreased [C7, C9, G9, K21, K33, P5, S8, T6, Y4],
about 2% Gy1 [K29] Increased [T9, V9]
CD4+ naive T-cells Decreased [H16], about 7.5% per 10years [K36] Decreased [K25, K29, K37, Y2], about 4.5% Gy1
[K36]
CD4+ memory T-cells No significant changes [K36] No significant changes [K36, Y2]
CD4+ naive/memory T-cell ratio Decreased [H1, L5, V2, V4] Decreased [K24, K25, K37, Y2]
Total CD8+ T-cells No significant changes [K36] No significant changes [K36]
CD8+ naive T-cells Decreased, more than 40% per 10 years [K36] Decreased [Y2], about 7.7% Gy1 [K36]
CD8+ memory T-cells Increased, about 7.3% per 10 years [K36] Increased [Y2], about 5.6% Gy1 [K36]
CD8+ naive/memory T-cell ratio Decreased [U21] Decreased [Y2]
Double-negative CD4 CD8 + T-cells Increased [H15] Increased [A6, K37, N1]
Available TCR repertoire Reduced [H1, V2, V4] Reduced [K25]
CD8+ CD28 (effector) T-cells Increased proportion of CD8+ CD28 T-cells [E2, CD28 expression: up-regulation
H16] (low doses) and down-regulation
(high doses) [L14]
T-cell responsiveness to mitogens Lower [B6, B15, V2] High doses: lower [A4, A5, K26, K31, P5]
Low doses: higher [J6, L17, L18, N20, P11, S16,
S17, Y1]
Thymus mass and cellularity Decreased [H16] Decreased [G8, N1, P6]
B-lymphocytes Decreased, about 7.3% per 10 years [K36]; less ability Increased [K29, Y1], about 8.5%
to generate antibody responses [B15, F3, H1, L5] Gy1 [K36]
Decreased [G9, K24, P6]
Hyporesponsiveness to LPS [C10, P6]
Lymphocyte oxidative status Oxidative stress [V2] Oxidative stress [C10]
IL-2 production Decreased [E1, H16] High doses: decreased [A2, B5, G8, K31]
Low doses: increased [J8, L18]
TNF- release Increased [B6, E1], about 15% per 10 years [N3] Increased [S13], about 7% Gy1 [H10, N3]
IL-10 Increased, about 8% per 10 years [N3] Increased, about 6% Gy1 [H10, N3]
IL-6 release Increased [B6, E1], about 24% per Increased [H5], about 13% Gy1 [H10, N3]
10 years [H10, N3]
C-reactive protein level Increased, about 25% per 10 years [H10, N3] Increased [H5], about 39% Gy1 [H10, N3]
IgA Increased, about 5% per 10 years [H10, N3] Increased [T5], about 8% Gy1 [H10, N3]
Increased in females [F4]
No change [K21]
IgG Decreased [K21]

Increased [K15, T5]
No change [F4, H10]
IgM Increased [F4, H10, K15, K21, T5]
IgE Increased [K15]

No change [F4, H10]
Total Ig Increased, about 3% per 10 years [H10] Increased [K14], about 3% Gy1 [H10]
Erythrocyte sedimentation rate Increased, about 15% per 10 years [H10, N3] Increased [N7], about 17% Gy1 [H10, N3]
Th1/Th2 imbalance Shift from Th1 to Th2 [R1, S7] Shift to Th2 [A1, B2, H4, K23, S27, T5, W3]
Shift to Th1 [D2, L19, N3]
Production of autoantibodies Increased [H13] Increased [T6, Y1, Y4]

No change [F4]
Neutrophils Impaired function [G25] Impaired function [K21]
Monocytes/macrophages Impaired function [B15, H1] Impaired function [G18, K33]

Macrophage activation [C21, I6, L8, N24, P11]
Increased proportion of peripheral monocytes [S13]
Absolute number of NK cells Increased [B15], about 20% per 10 years [K36] Increased [K24, K33]
No significant change [K29, K36]
NK cell function Impaired [H1] Impaired [K15]

Enhanced [C21, K18, Y1]
No significant change [B5, P6]
CD3+ CD56+ CD16+ (NKT) cells Increased [M9] Increased [K33]
Immunoproteasome function Impaired [M8] Impaired [L10]
293. Kusunoki et al. [K29] tested the hypothesis that ioniz- [H10, N3] found that both age and radiation expos-
ing radiation may accelerate ageing by using the proportion of ure were associated with increases in selected plasma
CD4+ T-cells as an index. They reported that the normal age- inflammation markers. Their findings indicated that the
related decrease of CD4+ T-cells was about 4% per 10years r adiation effect might be estimated in terms of accelera-
and that the radiation-induced decrease of CD4+ T-cells was tion of ageing by applying a multivariate model (table 12).
about 2%Gy1. These findings suggest that exposure to 1Gy The per cent increments in TNF-, IL-10, IL-6, CRP,
is equivalent to about a 5-year increase in age. IgA and erythrocyte sedimentation rate observed in
atomic bombing survivors ranged from 6% Gy 1 to
294. In 442 atomic bombing survivors without a hist- 39% Gy 1, corresponding on average to an increase in
ory of cancer or inflammatory diseases, Nakachis group age of 10 a/Gy.
Table 12 Multivariable model of the effects of age at time of irradiation and of radiation dose on inflammatory biomarkers
and ageinga
Adapted from reference [N3]
Variableb Change in per cent (95% CI)
TNF- IL-10 IL-6 CRP ESR IgA
Age at time of irradiation (per cent 15 (9, 20) 8 (4, 13) 24 (19, 30) 25 (13, 38) 15 (9, 20) 5 (2, 9)
per 10 years)
Radiation dose 7 (1, 15) 6 (0, 12) 13 (6, 20) 39 (20, 62) 17 (9, 24) 8 (3, 13)
(% Gy1)
Estimated ageing effect of radiation 5 (0, 10) 6 (1, 14)c 5 (2, 8) 14 (4, 24) 11 (5, 17) 15 (1, 29)
(a Gy1)
a Subjects were a total of 442 atomic bombing survivors who did not have a b TNF- = tumour necrosis factor ; CRP = C-reactive protein; ESR = erythro-
history of cancer or inflammatory-associated disease (e.g. chronic bronchitis, cyte sedimentation rate.
collagen disease, arthritis, myocardial infarction). c Estimated by the -method.
2. Remarks concerning the acceleration and experimental findings on radiation effects on the immune
of immunological ageing system supports the hypothesis that acceleration of immuno-
logical ageing may be involved in radiation effects in humans.
295. The preceding paragraphs indicate that comparison of the No demonstrable relationship with cancer or inflammatory
main features of immunosenescence with the epidemiological diseases in atomic bombing survivors has been found.
G. Modification of antigen presentation activated by ionizing radiation in different cell types as well
as to different dose protraction and total doses.
1. Review of published data
300. HLA mutant lymphocytes are induced by radiation
296. Danger signals affect antigen-presenting cells exposure and eliminated by NK cells [K30]. Autologous
(APCs), and the dendritic cells are the most powerful. Func- NK cells are responsible for the elimination of mutant lym-
tional antigen presentation by dendritic cells requires that phocytes that have lost the ability to express self class I HLA
the cells mature under the influence of different danger sig- molecules in vivo [K27], and therefore may explain why it
nals. However, in addition to the maturation of dendritic has not been possible to detect increased frequencies of HLA
cells being essential for lymphocyte activation, immature mutants in blood samples from atomic bombing survivors.
dendritic cells themselves maintain a state of immunological
tolerance. Cells dying by necrosis are more potent at induc-
ing dendritic cell maturation than cells dying by apoptosis 2. Remarks concerning modification of antigen presentation
(the latter may even block maturation). However, cells that
have undergone apoptosis in response to stressors such as 301. The data reviewed indicate that dendritic cells, the
heat or ionizing radiation may be more effective for induc- most powerful APCs, are relatively radioresistant, but that
ing dendritic cell maturation than cells that have undergone radiation may affect their function. Down-regulation of
natural physiological apoptosis. immunoproteasome activity has been reported. Immunopro-
teasomes are responsible for the processing of antigens for
297. Although dendritic cells are relatively radioresistant, presentation by the class I HLA pathway; consequently, ion-
ionizing radiation affects their functions. Liao et al. dem- izing radiation could impair immune function by modifica-
onstrated that non-cytotoxic effects of ionizing radiation tion of antigen processing at the immunoproteasome level.
might account for the impairment of antigen processing and This was also proposed as a sign of immunosenescence.
presentation following irradiation of dendritic cells. Cell
viability was not significantly affected over a 24 h culture 302. Concerning the effects of ionizing radiation on
period following 10Gy of gamma irradiation at 4.5Gy/min. HLA molecules, controversial results are presented. Non-
However, immunoproteasome activity was down-regulated significant changes were found in the expression of class I
in irradiated cells by 5060% [L10]. and class II HLA molecules following irradiation of dendritic
cells. Enhancement in the expression of class I HLA mole-
298. It has been reported that ionizing radiation may cause cules after fractionated irradiation of a murine melanoma cell
a generalized decrease in proteasome functions in mamma- line, as well as down-regulation of their expression following
lian cells [M3]. Immunoproteasomes are responsible for the acute irradiation of a human melanoma cell line, have been
processing of antigens for presentation by the class I HLA reported. Different dose protraction and total doses, as well
pathway. Alterations of immunoproteasome function have as different cell types, may account for the discrepancies.
been proposed as a signal of immunosenescence [M8]. Pro-
teasomes are direct redox-sensitive targets for the action of
ionizing radiation [M2]. Using microarray analysis, Snyder H. Autoimmune reactions
[S26] has studied gene expression profiles of cells exhibiting
radiation-induced genomic instability. Two of the genes that 1. Review of published data
were underexpressed belonged to the proteasome/ubiquitin
pathway. These findings suggest that ionizing radiation could 303. Ionizing radiation can produce functional alteration
impair immune function by altering antigen processing at the immune system and break self tolerance. Autoimmune
the immunoproteasome level. diseases are characterized by the activity of autoreactive
lymphocytes that produce antibodies targeting self tissues or
299. Findings concerning the effect of ionizing radiation organs for destruction. Autoimmunity may be seen as a case
on HLA molecules are controversial. Liao et al. did not find of mistaken identity, in which the immune system mistakes
significant changes in the expression of class I and class II part of the body for a foreign invader. One explanation for
HLA molecules on dendritic cells following gamma irradia- why the immune system attacks self tissues in some people
tion with a single dose of 10Gy [L10]. Reits et al. found that is molecular mimicry, which means that a part of a mole
cell surface expression of class I HLA molecules increased cule of a given protein closely resembles a part of another,
in a radiation-dose-dependent manner on murine colon totally different protein. It has been shown that peptides in
adenocarcinoma cells [R19]. Radiation-induced enhance- various infectious agents resemble parts of various self pro-
ment in the expression of class I HLA molecules has been teins. Therefore, if these protein fragments are presented to
reported by Hauser et al. in a murine melanoma cell line T-cells, the activated immune system will not only attack all
following fractionated gamma irradiation (50Gy in 25 frac- foreign invaders with the same pattern but could also attack
tions) [H7]. In contrast, a decrease in the expression of class a very similar pattern in a self protein [O10]. The significant
I HLA molecules was found in a human melanoma cell line dose-dependent impairment of the immune system demon-
following gamma irradiation with a single dose of 20 Gy strated in irradiated populations [K14, K21, K29, K31, V9]
[G35]. These discrepancies may be due to the pathways could lead to many of these persons being less responsive to
infectious agents. These individuals are at a higher risk for from fractionated total lymphoid irradiation showed that the
viral or microbial infection, and are therefore more prone to development of autoimmunity was related to the alteration
developing autoimmune diseases by molecular mimicry. of T-cell-dependent control of self-reactive T-cells.
304. It was not proved that autoimmune reactions were

involved in the pathogenesis of thyroid diseases in atomic I. Perturbation of immunological homeostasis
bombing survivors [I8]. However, the immune system has
been demonstrated to be involved in the pathogenesis of thy- 1. Review of published data
roid diseases in victims of the Chernobyl accident. These
apparently contradictory results may be due to the differ- 308. Immunological homeostasis is the mechanism by
ent thyroid exposure conditions (acute external irradiation which the immune system responds to foreign antigens (e.g.
versus internal exposure from radioiodine). It is possible an infectious organism) and then returns to its original state,
that thyroid damage induced by internal exposure from although retaining memory cells that will protect the host
radioiodine sets into motion antigenic mechanisms that lead against subsequent infection by the same organism. This
to autoimmune responses. Epidemiological data from chil- homeostasis is achieved in the T-cell system by the balance
dren exposed to radioiodine during the Chernobyl accident between renewal and death of naive and memory T-cells.
indicate signs of autoimmune thyroid disorder and impaired The ability to maintain both naive and memory T-cell pools,
NK-related elimination of tumour cells, both of which may which declines with age, is critical for immune function. An
be contributing to the promotion of thyroid neoplasia in this immunostatic mechanism exists that controls the proportions
population. of immune cell types, the production of cytokines and the
level of expression of functional immune cell molecules.
305. Sakaguchi et al. [S6] demonstrated that high-dose
fractionated total lymphoid irradiation (42.5Gy in 17 frac- 309. Exposure to ionizing radiation is thought to affect T-cell
tions) caused various organ-specific autoimmune diseases in homeostasis. Both experimental and epidemiological data
mice. Irradiation of the target organs alone failed to elicit have demonstrated that ionizing radiation may perturb T-cell
the autoimmunity, and shielding the organs from irradiation homeostasis by reducing the ability of the immune system to
failed to prevent it, suggesting that radiation-induced tissue produce new naive T-cells and by disturbing the regulation
damage is not the primary cause of the autoimmune disease. and maintenance of memory T-cell pools. A diverse pool of
A significant decrease in mature thymocytes and peripheral naive T-cells is necessary to produce immune responses to
T-cells was observed for one month post-irradiation. These new antigens. Exposed atomic bombing survivors showed
findings suggest that high-dose fractionated total lymphoid lower numbers of naive CD4+ and CD8+ T-cells. Although
irradiation can cause autoimmune disease by affecting the memory T-cell pools were either normal (CD4+) or even
T-cell immune system (rather than the target self antigens), larger (CD8+) in size [Y2], their TCR repertoire was sig-
presumably by altering T-cell-dependent control of self- nificantly reduced with radiation dose [K25], probably due
reactive T-cells. to clonal expansion of memory T-cells. Alterations in T-cell
subpopulations were also described in Chernobyl clean-up
306. In a further paper, Sakaguchi [S3] demonstrated that workers [T6, Y4].
elimination of CD4+ CD25+ T-regulatory cells (Treg) led
to the development of various organ-specific autoimmune 310. Radiation-induced perturbation of T-cell homeostasis
diseases in mice. Reconstitution of the Treg population pre- may have important health implications. The reduction of
vented the development of autoimmunity. Moreover, elimi- the naive T-cell pool may lead to reduced ability of the host
nation or reduction of the Treg population by environmental to defend against new pathogens, and the clonal expansion
agents also induced autoimmune diseases in normal mice, of memory T-cells associated with TCR repertoire deviation
suggesting that radiation-induced CD4+ T-cell alterations may compromise the ability of the host to control recurrent
may cause autoimmunity without altering the antigenicity of and latent infections [K36].
the host organs concerned [K23].
2. Remarks concerning perturbation

2. Remarks concerning autoimmune reactions of immunological homeostasis
307. As discussed in the preceding paragraphs, self toler- 311. The data reviewed indicate that immunological
ance breaking may be among the alterations on the immune homeostasis is the mechanism by which the immune sys-
system induced by radiation. No radiation-induced auto tem responds to foreign antigens and returns to its original
immune reactions were involved in the pathogenesis of state, but retaining memory cells to protect against subse-
thyroid diseases observed in atomic bombing survivors. In quent infection by the same agent. This homeostasis is
contrast, the immune system was involved in the pathogen- achieved by the balance between renewal and death of naive
esis of thyroid diseases in people exposed to radiation from and memory T-cells. Experimental and epidemiological data
the Chernobyl accident. This may be due to the different have demonstrated that radiation alters T-cell homeostasis by
thyroid exposure conditions. Experimental data obtained reducing the ability of the immune system to produce new
naive T-cells and by disturbing the maintenance of memory 316. In a recent paper, Van der Meeren et al. [V3] inves-
T-cells. The perturbation of T-cell homeostasis may have tigated the radiation-induced inflammatory response after
health implications in terms of decreased defences against total-abdominal or whole-body irradiation of mice at a
new pathogens and compromised ability to control recurrent dose of 15 Gy. A comparison with WBI was used to take
and latent infections. into account haematopoietic involvement in the inflamma-
tory process. The authors found a systemic inflammatory
reaction after both abdominal irradiation and WBI, with an
J. Other possible mechanisms involved increased cytokine and chemokine production at the intes-
tinal and lung levels, indicating a possible abscopal effect
1. Review of published data of radiation. They postulated that the effects observed in the
lungs after irradiation of the abdominopelvic region may be
312. Liu et al. [L16] proposed that catecholamines medi- caused by circulating inflammatory mediators due to the gut
ate the increase in proliferative reactivity of splenic and inflammatory response.
thymic lymphocytes that has been observed in mice irradi-
ated at a low dose (75 mGy). In a similar model, they 317. One question that remains unanswered is whether the
demonstrated the involvement of intracellular calcium and immunogenetic background may be involved in disease risks
protein kinaseC in the facilitation of signal transduction of irradiated subjects. There are large individual variations
in lymphocytes and suggested that this facilitation was in the level of immunological parameters and inflamma-
implicated in the mechanism of immune enhancement tory markers. Only some individuals with reduced immune
after low-dose irradiation [L17]. function and/or elevated inflammatory biomarkers develop
particular diseases [K36]. Thus it may be postulated that indi-
313. Modulation of oxidative status has been postulated vidual immunogenetic background may determine individual
as another mechanism for radiation-induced immune stimu- susceptibility to certain diseases. One particularly important
lation following low-dose irradiation. Kojima et al. [K16] genetic factor that can affect host immune response appears
found an increase of immune function in mouse splenocytes to be the HLA gene. Higher risks of type 2 diabetes were
that correlated with endogenous glutathione (GSH) accumu- found between heavily exposed atomic bombing survivors
lation within the first six hours after irradiation. This effect with different class II HLA DQA1 and DRB1 alleles [H12],
was enhanced by exogenous addition of precursors of GSH suggesting that certain class II HLA genes regulate one or
synthesis and was completely blocked by inhibition of GSH more components of the immune system that are related with
synthesis, suggesting that low-dose exposure to ionizing the risk of diabetes development in irradiated people.
radiation enhances immune function through the induction
of GSH [K16, K17, K18]. 318. Ionizing radiation exhibits immunomodulatory prop-
erties. The danger model of immunity describes antigen-
314. Indirect effects of local radiotherapy on tumour specific cellular immunity engendered by an inflammatory
cells outside the radiation field have been reported in milieu, where an important role is played by dendritic cells.
many malignancies [A14, C2, E3, K13, N11, O7, R2, S15, Ionizing radiation may create an inflammatory setting via
U20]. It has been proposed that this phenomenon, origin- induction of apoptosis, necrosis, cell surface molecules and
ally described as the abscopal effect, may be related to secretory molecules. Radiation may influence the expres-
radiation-induced effects on the immune system. Several sion of immunomodulatory surface molecules (MHC,
factors could influence this effect, such as the immuno- co-stimulatory molecules, adhesion molecules, death recep-
logical state of the tumour-bearing host and the immuno- tors, heat shock proteins) as well as secretory molecules
genicity of the tumour cells, as well as the schedule and (cytokines, inflammatory mediators), in both tumour and
overall dose of radiotherapy. normal cells. Experimental data indicate possible radiation-
mediated modulation of tumour antigen-specific immun-
315. In an experimental mammary carcinoma model, ity [F5]. Radiation-mediated immunomodulation currently
Demara et al. [D3] demonstrated that the growth of tumours remains unquantified and poorly understood. A major
outside the radiotherapy field was impaired by the com- research effort will be required to better elucidate the
bination of radiotherapy and Flt3 ligand, a haematopoietic mechanisms involved.
cytokine that has been shown to facilitate the expansion of
dendritic cells and the generation of an antitumour immune
2. Remarks concerning other
response. Importantly, in this experimental model Flt3 ligand
possible mechanisms involved
alone had no effect on the growth of primary or secondary
tumours, indicating that ionizing radiation was involved in
319. Other possible mechanisms involved are:
the abscopal phenomenon. In addition, this abscopal effect
was absent in nude mice (i.e. in mice lacking T-cells). In Involvement of catecholamines in the prolifera-
contrast to immunocompetent mice, the addition of Flt3 lig- tive activity of splenic and thymic lymphocytes,
and did not result in any abscopal effect in nude mice. These as well as intracellular calcium and protein kinase
findings indicate that the abscopal effect triggered by local C in the signalling of immunoenhancement after
irradiation was T-cell dependent [D3]. low-dose irradiation;
Modulation of oxidative status following low- premalignant tissues may actually promote tumour develop-
dose irradiation; ment. In cancers, the abundance of infiltrating lymphocytes,
Indirect effects of local radiotherapy, outside the which are the predominant cells involved in the acquired
radiation field, described originally as abscopal response, correlates with a favourable prognosis. On the
effects; other hand, an abundance of infiltrating innate immune cells,
such as macrophages, mast cells and neutrophils, correlates
Possible involvement of immunogenetic back- with increased angiogenesis and/or a poor prognosis [D17],
ground in disease risks of irradiated subjects. although clusters of macrophages around tumours are often
associated with tumour regression [G27].
K. Immune mechanisms and cancer 324. Therefore, with regard to the role of the immune sys-
tem in cancer development, it could be inferred that ioniz-
1. General considerations ing radiation might modify cancer risk not only by acting
as a carcinogen per se but also by modulating host immune
320. That cancer may result as a stochastic effect from response. Genotoxic stress and stalled DNA replication
exposure to ionizing radiations has been well known for a forks induce the expression of ligands for the NKG2D
long time, and mechanisms of radiation carcinogenesis have receptor found in NK and certain T-cells, cell types that are
been extensively reviewed [U2, U4, U5, U6]. In the context able to attack tumour cells [G36]. This activation depends
of this annex, it is most important to understand the mecha- on proteins involved in DNA damage-sensing pathways and
nisms of cancer development and especially to investigate cell cycle regulation. This might explain how DNA damage
the possible roles of the immune system. response participates in altering the immune response to the
presence of potentially dangerous cells.
321. Cancer is a multifactorial disease for which a genetic
susceptibility and environmental factorschemical, physi-
cal or viralcan be responsible. It is worth noting that some 2. Immune surveillance theory
specific cancers are usually linked to specific exposures to
environmental or infectious factors [N3, W18]. Some evi- 325. The fact that so many persons die each year of cancer
dence has been recorded of a possible connection between suggests that their immune response to tumour cells is ineffi-
haematological malignancies and exposure to ionizing radia- cient. Indeed the immune system may respond only if novel
tion, although nitrates, pesticides, HTLV1 or EpsteinBarr antigens are expressed on the cell surface by tumour cells and
virus infections, and immunodeficiency are other possible are subsequently recognized as non-self neoantigens [L29].
risk factors [D27]. The increased cancer incidence observed A number of alterations occur in the cell during tumori
in organ transplant recipients has been related to immuno- genesis: depression of some genes, expression of others
suppressive treatments that must be maintained to prevent or alteration of genes via mutations. Thus genetic changes
and treat acute rejection [A11, A30, O11]. related with carcinogenesis may result in the expression of
aberrant molecules by transformed cells (reappearance of
322. Cancers are not merely autonomous masses of mutant embryonic proteins not expressed in adult life, expression of
cells, but are composed of multiple cell types such as fibro unique antigens not expressed by normal cells). However,
blast and epithelial cells, cells that form blood and lymphatic the prevalence of an antigen expression can vary, meaning
vasculature, specialized mesenchymal cells that are unique that not all tumours of a particular type may express the anti-
to each tissue environment, and indeed innate and acquired gen at all. Many antigens have heterogeneous expression,
immune cells [C35]. While tissue homeostasis is maintained with the result that the proportion of cells that express the
by collaborative interactions between these diverse cell antigen within each tumour may vary from patient to patient.
types, cancer development is enhanced when mutant cells Indeed, antigen expression depends on the status of the cel-
neutralize homeostatic growth constraints and hijack the lular machinery; for example, antigen expression would
normal physiological processes to favour their own survival. be reduced in the case of proteasome deficiency [D28].
Furthermore, tumours can develop an angiogenic pheno- It is worth noting that most tumours induced by physical,
type which gives them a potential of growth and metastatic chemical or viral agents express neoantigens [S52], while
migration [F14]. in contrast, spontaneously occurring tumours are only often
weakly immunogenic or are non-immunogenic.
323. It is recognized that each stage of cancer development
can be exquisitely susceptible to modulation by immune 326. In the immune surveillance theory of cancer, tumours
cells. In essence, there is a complex relationship between can develop only when cancer cells can escape from the
immune cells and developing tumours with the following immune surveillance either by reducing the expression of
paradox: full activation of immune cells in response to the tumour antigens or by modifying immune recognition and
tumour may result in eradication of malignant cells and con- activation [Z3]. As an example, the down-regulation of the
versely an inefficient immune response may leave tumour synthesis of class I HLA molecules in tumours and meta
cells with the possibility to grow, whereas chronic activa- stases is a potential mechanism by which cancer cells can
tion of various types of innate immune cell in or around escape from class I HLA restricted lysis by cytotoxic T-cells.
In addition, the expression of the non-classical class I HLA This is the case in nude mice with no thymus, which do not
molecule HLA-G on the cell surfaces of various cancers develop more cancers than normal mice though this would
(melanomas, kidney cancers, breast cancers) inhibits both be expected given the lack of T-cells. On the other hand, it
the cytotoxic activity of NK lymphocytes and the antigen- has been observed in some tumour grafting experiments that
specific cytotoxic lymphocyte response [R22]. the tumour does not develop after injection of intermediate
doses of cancer cells, while tumour development is observed
327. In support of the immune surveillance theory is the after injection of low and high doses of cancer cells; this
fact that the incidence of cancers is significantly increased finding is difficult to reconcile with the immune surveillance
in immunodepressed patients whatever the cause of their theory.
immunodepression. This is well documented in patients
with AIDS due to viruses of the HIV family. These patients,
who present with an unusually high frequency of Kaposi sar- 3. Immune response against tumours
coma, are also more sensitive to radiation. Unlike the clas-
sical Kaposi sarcoma, where radiation therapy is associated 333. Cancer immune surveillance involves innate and
with minimal toxicity, radiotherapy treatment of this tumour acquired responses. Innate responses for transformed cells
in AIDS patients is associated with very high morbidity are associated mainly with NK cells, and the function is
[C32, H30, R11]. balanced between activating and inhibitory receptors. This
balance significantly influences the efficacy of the immune
328. A higher incidence of cancers is also observed in response and consequently of tumour progression [S12].
transplant patients who receive immunosuppressive treat- Activating NK receptors may respond to stress-inducible
ments [A11, O11]. This higher incidence concerns not only proteins overexpressed by tumour cells. Conversely, the lost
tumours associated with latent infections [N3], but also or down-regulated expression of class I HLA molecules in
tumours commonly observed in the general population, such transformed cells (missing self) may suppress the inhibi-
as digestive, respiratory, endocrine and breast cancers. The tory signalling in other NK receptors. NK cells can protect
increased incidence of these tumours can be associated with against experimental tumour growth, in part by produc-
the immunosuppressive treatment [L3], although some con- ing mediators with anti-angiogenic properties [H22, S45].
founding factors such as tobacco and alcohol certainly play NK cell deficiency as observed in the ChediakHigashi
a role [C28, F13, H26]. syndrome in humans and in Beige mice results in some
circumstances in an excess of cancers.
329. The immune system can produce significant anti
tumour effects, for example after allogenic bone marrow 334. Tumour cells may express HLA-G, a non-classical
grafting. T-cells from the donor recognize the tumour as class I HLA molecule involved in immunotolerance. The
non-self and develop impressive antitumour effects (graft- expression of HLA-G by malignant cells prevents their
against-tumour effects). elimination, and constitutes a newly described mecha-
nism by which tumour cells may evade immune surveil-
330. Natural antibodies are not very efficient at destroying lance [C4]. Through the interaction with specific inhibitory
tumour cells. However, it has been suggested that the immune receptors, HLA-G can protect tumour cells lacking classical
system may eliminate tumour cells that carry tumour-specific class I HLA expression from cytotoxicity mediated by
antigens, leaving room for the tumour to grow cells with a NK and T-cells [S12]. Through the inhibition of MICA
low level of these antigens or with antigens that differ only signals, HLA-G may lead to tumour escape from immune
very slightly from those of normal cells [G27]. On the other surveillance [R9].
hand, monoclonal antibodies can be successful in control-
ling tumours when they have a high affinity for the tumour 335. Genotoxic stress and stalled DNA replication forks
and can be used in large quantities. The most successful induce the expression of ligands for the NKG2D receptor
examples are the treatments of B-lymphoma with anti- found in NK and certain T-cells, cell types that are able
CD20 monoclonal antibodies and of some breast cancers to attack tumour cells [G36]. This activation depends on
with anti-human epidermal growth factor receptor 2 (HER2) proteins involved in DNA damage-sensing pathways and
monoclonal antibodies. cell cycle regulation. This may explain how DNA damage
response participates in altering the immune response to
331. Against the immune surveillance theory, it has been potentially dangerous cells.
observed that the relative risk for some common non-virus-
associated solid tumours of epithelial origin (breast, pros- 336. Activated macrophages can play a significant role
tate and bladder) is decreased in some immune-suppressed in the immune response against tumours. Their antitumour
patients [F12, G17]. This finding has not yet been completely activity is probably linked to lytic enzymes and the gen-
explained, although it has been suggested that immuno eration of free radicals. Furthermore, macrophages produce
suppressive drugs could have a direct antitumour effect. TNF-, a cytotoxin with a powerful antitumour activity.
332. In order to test the validity of the immune surveil- 337. Acquired immunity involves the recognition by
lance theory, experiments can be carried out in animals. T-cells of the products of mutated genes, oncogenic virus
products or normal proteins aberrantly expressed. Moreover, induction of genetic instability. During chronic inflamma-
interactions between T- and B-cells mediated by cytokines, tory processes there is an excess production of free radi-
as well as minor T-cell subsets such as NKT cells and cals, which deregulate cellular homeostasis and can drive
T-cells, may act in eliminating transformed cells. normal cells to malignancy [B1]. Recent findings have
provided evidence suggesting that persistent inflammation
involving repeated infection could be a key step in car-
4. Immunologic promotion of tumours cinogenesis. Indeed, the long-term inhibition of chronic
inflammation by aspirin and selective cyclooxygenase-2
338. Exposure to ionizing radiation may impair the (COX-2) inhibitors in patients with premalignant disease,
immune system and, on some occasions, result in low- or who are predisposed to cancer development, has sig-
grade chronic inflammation. It has been proposed that per- nificantly reduced cancer risk [D15]. Figure VIII shows
sistent inflammation could play a role in promoting the a model proposed by de Visser et al. [D17] for explain-
proliferation of initiated cells through the generation of ing innate and acquired immune cell functions during
ROS, the production of inflammatory cytokines and the inflammation-associated cancer.
Figure VIII. Model of innate and acquired immune cell functions during inflammation-associated cancer.
Tumour antigens are presented by dendritic cells (DCs) to activate acquired immune responses, which may result in both antitumour (direct)
effects and tumour-promoting effects (via innate immune response) [D17].
Neoplastic progession
Initiation
Pro-inflammatory
cytokines
Tumour-promoting
Pro-growth
DC migration and Tissue expansion
antigen presentation Malignant conversion
Innate immune
response Cell-death inhibition
Genomic instability
Fibroblast activation
Serum proteins Matrix metabolism
T- and B- Angiogenesis
lymphocyte
activation Anti-tumour
T-cell-mediated cytotoxicity
(FAS, perforin and/or cytokine pathways)
Secondary lymphoid organs Antibody-dependent cell-mediated cytotoxicity
Adaptive immune response Antibody-induced complement-mediated lysis
339. Chronically activated innate immune cells can also 340. Immunological activation of tumour growth by tumour
contribute indirectly to cancer development through sup- cells has been observed in experimental animals. In many
pression of antitumour escape from immune surveillance. circumstances, attempts to protect animals against tumour
For example, myeloid suppressor GR+CD11b+ cells, e.g. growth by active immunization by tumour-specific antigens
a subset of innate immune cells, induce T-lymphocyte or by passive immunization by specific tumour antibodies
dysfunction by direct cellcell contact and by production have, surprisingly, yielded tumour growth. This is interpreted
of immunosuppressive mediators, and therefore actively as being due to the existence of blocking factors. either the
inhibit antitumour acquired immunity [G16, S42, Z3]. antibody itself, which after binding the antigen hides it from
cytotoxic T-cells, or the antibodyantigen complex, which L. Summary

inhibits the antibody-dependent cell-mediated cytotoxicity
by binding to the Fc receptors on the surface of NK cells or 346. There are many mechanisms potentially involved in
macrophages and blocking their activity. radiation-induced alterations of the immune system:
Radiation-induced apoptosis is a key mechanism,
well established for blood-circulating white cells,
5. Remarks concerning immune mechanisms mostly lymphocytes.
and cancer
Mutations of TCR genes is a radiation-dose-
341. On the basis of the preceding paragraphs, some dependent mechanism which can produce defec-
remarks may be made concerning immune mechanisms and tive TCRs and alter the discrimination between
cancer. A complex relationship giving rise to a paradox is self and non-self.
observed between immune cells and developing tumours: There is still some controversy regarding the func-
full activation of immune cells in response to the tumour tional cytokine secretion pattern of helper T-cells
may result in the elimination of tumour cells, whereas an following exposure to ionizing radiation, although
inefficient immune response allows their growth. In addi- it is likely that the homeostatic balance between
tion, chronic activation of various types of innate immune Th1 pattern (cell-mediated immunity) and Th2
cells in or around premalignant tissues may actually promote pattern (humoral immunity) is shifted towards a
tumour development. pro-inflammatory profile.
Delayed effects, e.g. bystander effects and genomic
342. The immune surveillance theory suggests that instability, have been demonstrated after exposure
tumours can develop only when cancer cells can escape of the immune system to ionizing radiation. How-
from the immune surveillance either by reducing the tumour ever, the potential impact of such delayed effects
antigens or by modifying the immune response to them. A in humans is not known.
large body of evidence in favour of the immune surveil-
lance theory comes from immunodepressed patients, who Inflammation resulting from the effects of ioniz-
present a higher incidence of cancer. Evidence has also been ing radiation can be observed at the microscopic
seen in transplant patients who receive an immunosuppres- level and involves immune cells within and around
sive treatment. In contrast to these observations, it has been tumours, but inflammation may be large enough
reported that the relative risk for some common non-virus- to produce significant alterations of parameters in
associated solid tumours of epithelial origin is decreased in blood samples. Inflammation may be associated
some immunodepressed patients. An antitumour effect of with chronic diseases.
the immunosuppressive drugs was suggested in these cases. There is a vast literature showing that immune
cells after exposure to ionizing radiation show
343. The capability of the immune system to develop abnormalities that are quite similar to those
antitumour effects involves innate and acquired responses. observed in normal ageing. These observations at
The innate response is mainly associated with NK cells. the biological level have so far not been linked to
Its function is balanced between activating and inhibi- diseases.
tory receptors. NK cell deficiency as observed in human Alterations of the process of antigen presenta-
and mice syndromes results in some circumstances in tion at the level of the immunoproteasome have
an excess of cancers. A newly described mechanism by been demonstrated and are possibly a signal of
which malignant cells avoid their elimination is through immunosenescence after exposure to ionizing
the expression of HLA-G, a non-classical class I HLA radiation.
molecule that can protect tumour cells lacking classical
class I HLA expression from cytotoxicity mediated by NK Ionizing radiation can contribute to a disturbance
and T-cells. Similarly, activated macrophages play an anti- of self tolerance and consequently can pave the
tumour role linked to lytic enzymes and the generation of way towards autoimmunity.
free radicals along with the release of cytokines with a Finally, the immunological response against
powerful antitumour activity. foreign antigens implies T-cell homeostasis, which
is disturbed after exposure to ionizing radiation.
344. Acquired immunity involves the recognition by
T-cells of the products of mutated genes, oncogenic virus 347. Besides apoptosis, which is a key mechanism within
products and normal proteins aberrantly expressed. the immune system, it is rather difficult to classify the other
mechanisms according to their importance after exposure
345. Finally, long-lasting inflammation could play a role to ionizing radiation. It likely that these mechanisms are
in promoting the proliferation of initiated cells through interlinked, e.g. microscopic inflammation, propagated by a
the generation of free radicals, the release of inflammatory type of bystander mechanism and contributing to the age-
cytokines and the induction of genetic instability, because of ing of tissues and promotion of cancer. Three hypotheses
alterations of immune cells. to further explore the mechanisms involved in the effects of
ionizing radiation on the immune system and their impact in 348. Immune surveillance is different for the various cancer
human health have been postulated by the Radiation Effects entities and has not been reported for all of them. The immune
Research Foundation (RERF) (see section IV): surveillance theory of cancer development remains contro-
versial. Although the immune system has the capability to
Ionizing radiation may accelerate immunological develop impressive antitumour effects, it is not very clear that
ageing by perturbing T-cell homeostasis; cancer results from a deficiency of the immune system, and
Ionizing radiation may induce long-lasting inflam- tumours can be promoted through low-level chronic inflam-
mation that may lead to disease development; mation because of alterations of immune cells. The poten-
tial effects of low doses of ionizing radiation on the critical
Individual immunogenetic background may deter- balance existing in the immunological network (promoting or
mine individual susceptibility to succumbing to suppressing antitumour immunological response arising in the
disease. tumour microenvironment) has been insufficiently studied.
IV. EPIDEMIOLOGICAL STUDIES
A. Atomic bombing survivors 3. Long-term effects
1. General considerations 352. In an early paper investigating T-cell immunity among

the atomic bombing survivors, Akiyama et al. [A5] looked
349. Epidemiological studies of the survivors of the atomic at the responsiveness of peripheral blood lymphocytes
bombings in Japan are currently the most important single to allogenic antigens in mixed lymphocyte cultures from
source of radiation risk estimates for humans. Most of the 139 atomic bombing survivors. This study revealed a sig-
information on the health effects of ionizing radiation avail- nificant decrease in mixed lymphocyte culture response with
able to date comes from long-term studies of survivors of the increasing radiation dose. The decline was most marked in
atomic bombings in Hiroshima and Nagasaki. Almost sixty the survivors who were more than 15 years old at the time
years after exposure to radiation, survivors of the atomic of the initial exposure. These results were interpreted as an
bombings still exhibit increased risks of developing solid impaired thymic function.
tumours. Immune mechanisms have consistently been asso-
ciated with either resistance to or development of numerous 353. In 1983 Akiyama et al. [A4] described functional
tumours. Also, an association between non-cancer mortal- defects in T-cell response to mitogens such as PHA. IL-2 is
ity and radiation dose has been observed among survivors, known to have different actions regarding T-cell prolifera-
cardiovascular, thyroid and liver diseases being the more tion and T-cell development. CD4+ T-cells are those primar-
frequently reported causes. Long-lasting inflammation may ily responsible for producing IL-2 in response to mitogens
be considered an important contributory factor for the devel- such as concanavalin A (Con A). Decreased production of
opment of some of these diseases [K36]. Knowledge of the IL-2 has been implicated as a potential factor in radiation-
impact of radiation on the immune system is therefore criti- induced impaired immunity [B5]. To elucidate the biological
cal to assessing radiation-induced effects on the long-term significance of the T-cell abnormalities observed in atomic
health of survivors [K23, K36]. bombing survivors long after exposure, Kusunoki et al.
investigated the percentage of T-cells capable of responding
to PHA or Con A or that could produce IL-2. The study used
a limiting dilution assay method to evaluate the responsive-
2. Short-term effects ness of the T-cell population to these mitogens. The subjects
in this study were 251 atomic bombing survivors exposed
350. It has been estimated that around 114,000 people to <0.005 Gy and 159 survivors exposed to >1.5 Gy.
in Hiroshima (an additional 20,000 military personnel not The percentage of CD2+ cells (activated T-lymphocytes)
included) and 74,000 people in Nagasaki died before the capable of proliferating in response to PHA in the pres-
end of 1945, in total about 210,000 deaths, as a direct result ence of exogenous IL-2 did not differ substantially between
of the bombings. These deaths are referred to as acute distally and more heavily exposed survivors. In contrast,
deaths. The short-term effects of the bombings have been T-cell capacity in response to Con A was lower in the more
extensively described, and include thermal, mechanical exposed individuals. Moreover, heavily exposed survivors
and radiation injuries (in particular radiation-induced bone possessed fewer T-cells with the capability of producing
marrow depletion). IL-2. It was concluded that peripheral blood samples from
heavily exposed survivors contained significantly fewer
351. At the time of the bombings, the haematopoietic sys- IL-2-producing CD4+ T-cells than did similar samples from
tems of survivors underwent a level of damage for which those distally exposed to radiation from the atomic bomb-
the severity and persistence were dose-dependent. The most ings. Radiation might have a long-lasting negative effect
serious effects were those related to radiation-induced cell on the capacity of the CD4+ T-cell populations involved in
death resulting in the development of symptoms of acute IL-2 production [K31].
radiation syndrome. Several months after exposure, the
haematolymphoid function of many survivors had almost 354. A decreased proportion of mature CD3+ T-cells was
completely recovered [O8]. Studies initiated soon after the found in peripheral blood lymphocytes among the atomic
bombings showed little evident dose-dependent effects on bombing survivors exposed to >1.5 Gy, particularly in the
the immune system [A6]. However, even several decades proportion of the CD4+ CD45RA+ naive T-cell subset. The
later, it was still possible to detect long-term alterations in frequency of a rare T-lymphocyte subpopulation bearing
the immune system of exposed survivors. CD3 surface antigen and TCR ( and chains), but lacking
151
both CD4 and CD8 (double-negative CD4 CD8 +), was 358. The T-cells of survivors with a history of myocardial
studied in 409 atomic bombing survivors (160 who had been infarction responded poorly to Staphylococcus aureus tox-
exposed to 1.5 Gy and 249 controls). The frequency of ins, and these individuals had proportionally fewer CD4+
CD4CD8 + T-cells was significantly elevated in indi- CD45RA+ (naive) T-cell populations than survivors with no
viduals exposed to >1.5Gy [K37]. The authors interpreted myocardial infarction in their history [K26]. It had previ-
this finding as a result of altered differentiation and develop- ously been reported that among 1,006 survivors uniformly
ment of T-cells. This rare T-cell population may be differen- distributed with respect to age, sex and dose, 18 persons had
tiated through a pathway different from that of conventional a history of myocardial infarction; the proportion of CD4+
CD4+ or CD8+ + T-cells [K32]. cells was significantly decreased with increased dose and
history of this disease. Further, the prevalence of myocardial
355. Alterations of T-cell population subsets were con- infarction was significantly greater in those individuals who
firmed in further studies. The proportions of subsets of T-, had a lower proportion of CD4+ helper T-cells [K28].
B- and NK cells in peripheral blood lymphocytes of atomic
bombing survivors were studied by flow cytometry analysis 359. Kusunoki et al. suggested that myocardial infarc-
[K29]. Blood samples from 159 survivors estimated to have tion in atomic bombing survivors may be due at least in
received >1.5 Gy and from 252 controls were evaluated part to their having diminished ability to mount an immune
using multiple combinations of monoclonal antibodies to response against certain infections that may be implicated in
lymphocyte differentiation antigens. The findings revealed the aetiology of cardiovascular disease [K36]. However, this
that the proportion of CD4+ T-cells was decreased signifi- inference may be premature. Blood samples for determina-
cantly in the heavily exposed survivors and that a similar tion of the proportion of CD4+ and CD8+ T-cells were taken
tendency was apparent for the CD4+ CD45RA+ naive T-cell between 1992 and 1995, while histories of myocardial infarc-
subset. No significant changes were found in the proportion tion were recorded from 1958 to 1990. Although Kusunoki
of CD8+ T-cell subsets between exposed individuals and et al. assumed that measurements of T-cell subsets before
controls. Also, a dose-dependent increase in the frequency disease onset would have shown similar values to those
of PHA-stimulated lymphocytes bearing chromosome obtained in their study, in order to demonstrate a causal rela-
aberrations was reported in 1975 [A15]. tionship they had to carry out a prospective study to record
newly diagnosed cases and compare the incidence between
356. The high sensitivity of CD4+ CD45RA+ naive subjects exhibiting low and normal CD4+ T-cell propor-
T-cells to ionizing radiation in long-term studies appears tions. Changes in the proportion of CD4+ T-cells have been
to involve functional defects in T-cell response or demon- described in patients with acute myocardial infarction and
strable impairment in CD4+ T-cell immunity. In T-cells post-myocardial-infarction syndrome without antecedents of
from 723 atomic bombing survivors, almost uniformly radiation exposure [A19, B26, K53, T15]. Although some
distributed with respect to age, sex and dose, the ability of of these changes were exhibited only temporarily, long-term
T-cells to proliferate in vitro was tested after a challenge effects may also exist. It is thus possible that CD4+ T-cell
by each of the Staphylococcus aureus toxins SEB, SEC-2, deficiencies in survivors with myocardial infarction history
SEC-3, SEE and TSST-1. The results revealed that the are, at least in part, of a fundamental nature rather than being
proliferative responses of the T-cells of the atomic bomb- totally attributable to radiation exposure.
ing survivors became progressively weaker as the radia-
tion dose increased, and that they did so in a manner that 360. Kusunokis observation is reminiscent of an earlier
correlated with the decrease in the percentage of CD4+ report by Roberts-Thomson et al. [R7], who examined the
CD45RA+ (naive) T-cells, but not with that of CD4+ number of positive delayed-type hypersensitivity reactions
CD45RA (memory) T-cells. These findings indicated and the number of deaths among study participants aged
that irradiation from the atomic bombings led to impair- over 80 years. They found that those who manifested fewer
ment of the ability of exposed individuals to maintain their than two positive reactions had significantly greater mortal-
naive T-cell pools, explaining why they responded poorly ity over the two-year period of study than those who showed
to toxins encoded by common pathogens [K26]. two to five positive reactions. Bronchopneumonia, cerebro-
vascular accidents and cardiac failure were the most com-
357. A dose-dependent increase in the relative risk of myo- monly recorded causes of death; no deaths were attributed
cardial infarction has been observed in RERFs Adult Health to cancer, suggesting that reduced T-cell-mediated immune
Study cohort of atomic bombing survivors [K43]. The effects responsiveness resulting from earlier exposure to radiation
of ionizing radiation on conditions other than cancer have could cause diseases other than cancer related to old age by
previously been reviewed in the UNSCEAR 1982 [U8] and as yet unknown mechanisms.
1993 [U5] Reports. This subject is now extensively reviewed
in annex B, Epidemiological evaluation of cardiovascu- 361. No doseresponse relationship was found between
lar disease and other non-cancer diseases following radia- anti-hepatitis-C-virus (HCV) seropositivity and radiation
tion exposure. However, some data will be discussed here dose in atomic bombing survivors. The relative risk of
concerning the hypothesis of a causal relationship between chronic liver diseases among anti-HCV-positive individuals
immune dysfunction and myocardial infarction in atomic was marginally increased with radiation dose. The authors
bombing survivors. interpreted their findings with the hypothesis that radiation
exposure may accelerate the progress of chronic liver disease significant dose-dependent decreases in the percentages of
associated with HCV infection [F8]. The rates of seropositiv- naive CD4+ and CD8+ T-cells were found in the peripheral
ity for hepatitis B surface antigen (HBsAg), which indicates blood lymphocyte populations of 533 Hiroshima atomic
current hepatitis B virus (HBV) infections, and anti-HBV bombing survivors. In contrast, while the percentages of
core antibody, which indicates either cured or current infec- memory CD8+ T-cell subsets were found to increase with
tions, increased with radiation dose among 6,121 atomic radiation dose, no changes were observed in the percentages
bombing survivors. However, no relationship was observed of memory CD4+ T-cell subsets [Y2].
between radiation and anti-HBV surface antibody, indicat-
ing cured infection, suggesting a lower likelihood of clear- 365. The numbers of peripheral blood lymphocytes
ance after HBV infection among those who were more likely belonging to different subsets were studied in 1,328 atomic
to have been infected with HBV as adults after irradiation bombing survivors using immunocytochemistry (fluorescent
from the atomic bombings [F7]. Taking into account that antibodies) [K24]. A decreasing trend in the numbers of
Th1 responses are able to clear hepatitis virus infections CD4+ and CD8+ T-cells and in CD19+ B-cells was observed
very efficiently, these findings could be interpreted to be the with increasing age. The CD5 molecule has an import-
result of a persisting radiation-induced Th1/Th2 imbalance ant role in T-cell/B-cell interactions [B25]. The number of
promoting chronic infection [K23]. CD5+ B-lymphocytes was significantly lower in those per-
sons exposed to >1Gy within the group exposed at the age
362. As discussed earlier, a large and diverse TCR rep- of 30 years or later. A similar tendency towards decreased
ertoire, necessary for recognition of the many antigenic numbers of CD4+, CD8+ and CD19+ cells was observed in
peptides possible, is a critical feature of T-cell populations. these older survivors, although the differences were not sta-
Kusunoki et al. [K25] evaluated whether the recovery of tistically significant. These results suggest that ageing of the
CD4+ T-cell populations in atomic bombing survivors was T-cell-related immune system is accelerated in people irradi-
associated with a long-term reduction in the diversity of the ated at an advanced age. Owing to the age-related decrease
TCR repertoire. Using a panel of monoclonal antibodies in thymic function, subjects who were older at the time of
against 13 TCR V families, they employed flow cyto the bombing may have decreased functional capability of the
metry to analyse peripheral blood samples from 710surviv- immune system for recovery after radiation injury.
ors, distributed almost uniformly with respect to age, sex
and dose (controls, <0.0005 Gy; exposed, 0.0005 Gy). 366. In a further paper reporting flow cytometric analyses
They defined a parameter referred to as repertoire devia- of the lymphocyte subsets from atomic bombing survivors,
tion, which expressed the extent to which the TCR V Kusunoki et al. [K29] demonstrated a significant increase
repertoires of T-cells from a given individual deviated from in the proportion of B-lymphocytes in heavily exposed sur-
the mean for the whole population. The naive helper T-cell vivors. The increase was evident in both positive and nega-
pools (CD4+ CD45RA+) of exposed individuals showed tive cells for CD5 antigen (a marker of mature B-cells), as
a dose-dependent decline without changes in their TCR well as in both positive and negative cells for CD23 antigen
V repertoires. In contrast, the percentages of memory (a marker of stimulated B-cells). The discrepancy between
helper T-cells (CD4+ CD45RA) did not decline, but their these results and those from earlier studies [K24] may be due
TCR V repertoires were skewed in a dose-dependent to a difference in the measurement method.
manner among individuals who were at least 20 years of
age at the time of the bombings. 367. NK cell numbers were studied in atomic bombing sur-
vivors using immunocytochemistry. The NK cell population
363. Normally, since fewer new T-cells emerge from the was found to be increased significantly in the older compared
thymus in the elderly, naive T-cell pools gradually become with the younger age group, but there was little dependence
smaller with age. In contrast, memory T-cells that are lost on dose [K24]. These results are in good agreement with a
tend to be replaced through clonal expansion. Thus the mem- further study carried out using flow cytometry that did not
ory T-cell pool remains almost constant in size but gradually find any effect of radiation dose on the proportion of NK cell
loses the diversity of TCR repertoire with age. Recovery of subsets [K29]. Concerning NK cell activity, no significant
T-cell populations after radiation-induced depletion involves changes were observed in a study of 1,341atomic bombing
two different pathways: the production of new T-cells from survivors [B5].
thymus stem cells and the proliferation of peripheral mature
cells that have managed to survive. The observations by 368. Several studies have been carried out since 1968 con-
Kusunoki et al. [K25] lead to the conclusion that restora- cerning serum immunoglobulin levels. Data published by
tion of the peripheral T-cell pools of atomic bombing sur- Hall et al. [H2] and by King et al. [K12] in 1973 showed
vivors involved these two different pathways, and suggest no relationship between radiation dose and serum immuno-
that ionizing radiation accelerated the normal processes of globulin levels in the cohort of atomic bombing survivors
immunological ageing. at that time. Fujiwara et al. [F4] determined the levels of
autoantibodies and immunoglobulins among 2,061 individ-
364. Radiation exposure from the atomic bombings was uals exposed to radiation from the atomic bombings in Hiro-
demonstrated to be associated with long-lasting deficits in shima and Nagasaki for whom dose estimates ranged from
both naive CD4+ and CD8+ T-cell populations. Statistically 0 to 5.6Gy. They found: a significant increase in IgA levels
in females, a significant increase in IgM levels in both sexes, type has been addressed. To investigate the possibility of
and no changes in the prevalence of antinuclear antibody, differing frequency distributions of HLA type in the Hiro-
antithyroglobulin antibody and antithyroid microsomal anti- shima cohorts, HLA-DQA1 alleles and HLA-DR antigens
body, or in levels of IgG and IgE. These results were recently were typed for 201 survivors exposed to >1.5 Gy, 339
confirmed by Hayashi et al. [H10]. exposed to between 0.005 and 1.5Gy, and 388 in a distally
exposed group (<0.005Gy). Although no dose-related dif-
369. In 1994 Nagataki et al. reported an increase in the ferences were found, when the subjects were grouped by
prevalence of antibody-positive hypothyroidism among the presence of a specific allele or antigen, males carrying
atomic bombing survivors in Nagasaki [N2]. In contrast, the DQA1*0103 in at least one of their two HLA-DQA1 loci
Adult Health Study by the Atomic Bomb Casualty Commis- exhibited frequency distributions that decreased as radiation
sion/RERF reported a lack of doseeffect relationship on dose increased [H9].
the prevalence of autoantibodies [F4]. Imaizumi et al. have
recently re-evaluated these observations and found that the 373. In earlier work, Kusunoki et al. [K27] had demon-
prevalence of hypothyroidism with autoantibodies margin- strated that mutant lymphocytes lacking expression of class
ally increased among moderately exposed survivors but not I HLA molecules were eliminated by autologous NK cells.
among highly exposed survivors in Nagasaki. They concluded In an attempt to explain the inability to detect any increase
that there is no statistically significant dose response in the in HLA-A2 negative cell number in HLA-A2 heterozygous
prevalence of antithyroid autoantibodies or hypothyroidism individuals exposed to irradiation from the atomic bombings,
with autoantibodies in atomic bombing survivors [I8]. the hypothesis was tested that HLA mutant lymphocytes
might well have been induced by radiation exposure but
370. In their studies of somatic mutations, Kushiro et al. eliminated by strong negative selection associated with their
[K22] used a flow cytometric assay to identify both gene almost inevitable exposure to autologous NK cells [K30].
mutation and somatic recombination. In 168 Adult Health The results strongly supported the hypothesis that autolo-
Study participants and 58 employees of RERF, the frequency gous NK cells are responsible for the elimination of mutant
of variant lymphocytes lacking expression of HLA-A2 or lymphocytes that have lost the ability to express self class
HLA-A24 allele products was about 10-4 in heterozygous I HLA molecules in vivo, and therefore might explain why
donors and increased with donor age. Possible mutant cells it has not been possible to detect increased frequencies of
lacking expression of HLA-A2 or HLA-A24 were isolated HLA-A2 mutants in samples from any of the 164 atomic
and clonally propagated. Molecular analysis of 164 clones bombing survivors whose HLA-A2 heterozygote status
derived from six donors revealed that 71100% were defec- made their lymphocytes suitable for such a test.
tive in expression of the selected HLA-A alleles. On the
other hand, 80% of the clones consisted of CD4+ T-cells, 374. Kodama et al. wanted to investigate whether radiation
and the remainder were CD8+ T-cells. The effect of expo- exposure had induced chromosomal instability in periph-
sure to radiation from the atomic bombings was not statis- eral lymphocytes. Ordinary cytogenetics was not expected
tically significant. However, while 1 out of 50 mutants in to help them solve this problem, as lymphocyte stable aber-
vivo derived showed a possible small deletion at the HLA- rations (mainly translocations) induced at the time of the
locus without any chromosomal abnormality, the majority of bombings would not be distinguishable from those that may
mutants derived from in vitro X-irradiated peripheral blood have arisen later as a result of the instability. Therefore they
mononuclear cells bore important deletions [K22]. studied clonally expanded T-cell populations, e.g. cells bear-
ing identical translocations, because they are descendants
371. As already discussed, the HLA gene seems to be a par- of a single progenitor cell which acquired aberrations as a
ticularly important genetic factor that can affect host immune result of radiation exposure. By determining the frequency
response. Significant differences in type 2 diabetes prevalence of additional translocations among clonal cells, the authors
were found between heavily exposed (>1.5Gy) and low-dose found that clonally expanded T-cell populations of atomic
or non-exposed Hiroshima atomic bombing survivors with bombing survivors do not exhibit increased chromosomal
different class II HLA DQA1 and DRB1 alleles [H12]. The instability [K44].
prevalence was higher for heavily exposed individuals who
were less than 20 years old at the time of the bombing and who 375. It has been argued that chronic low-level inflamma-
presented DQA1*0401 and DRB1*08alleles or DQA1*0301 tory responses induced by radiation could be a significant
and DRB1*09. These results suggest that certain class II HLA risk factor in the well-documented increase of non-cancer
genes regulate one or more components of the immune sys- disease occurring in atomic bombing survivors. Hayashi et
tem related with the risk of diabetes development among the al. investigated the long-term effects of ionizing radiation
younger and more heavily exposed survivors. This was the on the levels of two markers of inflammatory response,
first report suggesting that the development of a particular C-reactive protein (CRP) and IL-6, in blood samples from
disease can be affected by radiation exposure in individuals 453 participants in an epidemiological cohort of atomic
with different genetic backgrounds. bombing survivors [H8]. Blood lymphocyte subpopulations
were identified by flow cytometry, using monoclonal anti-
372. The possibility of various degrees of radiation- bodies to CD3, CD4 and CD8. CRP levels were significantly
associated immune suppression being dependent on HLA increased, by about 35%Gy1 (p = 0.0001). After adjustment
for confounding factors (sex, age, etc.), CRP levels were still Functional defects in T-cell responses to mitogens
increased significantly with dose, by 28%Gy1 (p = 0.0002). and alloantigens.
IL-6 levels also increased with radiation dose, by 9.3%Gy1
(p = 0.0003) and, after multiple adjustments, by 9.8% at 379. Effects on B-cell immunity:
1Gy (p = 0.0007). Elevated CRP and IL-6 levels were asso-
Significant increase in the proportion of B-cells;
ciated with decreases in the percentages of CD4+ T-cells in
the peripheral blood lymphocyte population [H8]. Hayashi Increase in serum IgA levels in females;
et al. recently reported long-term effects of radiation dose Increase in IgM levels in both sexes;
on inflammatory markers in atomic bombing survivors. They
No changes in IgG and IgE levels.
found that erythrocyte sedimentation rate, IFN-, TNF- and
IL-10 increased significantly with radiation dose [H10].
380. Effects on innate immunity:
In contrast with acquired immunity, significant
4. Remarks concerning data on survivors dose effects were not observed on the number
of the atomic bombings and function of NK cells. However, some studies
showed an increase in the proportion of NK
376. The preceding review of data concerning atomic cells in the peripheral blood of atomic bombing
bombing survivors shows that short-term effects of survivors.
radiation on the immune system were expressed mainly
as dose-dependent acute bone marrow depletion due to 381. Other findings:
radiation-induced cell death. These effects were reversed
Increased frequencies of somatic mutations (TCR
over several months, and studies initiated shortly after
and HLA) and chromosome aberrations;
the bombings showed few dose-dependent effects on the
immune system [A6]. Marginal increase with radiation dose in the prev-
alence of chronic liver diseases and hepatocellular
377. Studies of the late effects of radiation on the immune carcinoma among anti-HCV-positive individuals;
system commenced about 20 years after the atomic bomb- Decreased cellular immunity and enhanced
ings. The most remarkable late effects of radiation were humoral immunity may have led to long-term
functional and quantitative abnormalities of T- and B-cells in imbalance in Th1/Th2 responses, resulting in
survivors exposed to high doses (1Gy). The main findings altered cytokine expression profiles;
observed up to 1995 have been reviewed and summarized
Qualitative and quantitative changes suggesting
by Akiyama [A6]. With respect to data published thereafter,
a radiation-induced acceleration of the normal
the most remarkable late effects of radiation on the immune
process of immunological ageing;
system of atomic bombing survivors are summarized in the
following paragraphs. Radiation-associated chronic inflammatory
responses;
378. Effects on T-cell immunity: Decreased proportion of CD4+ cells with
Decreased proportion of CD3+ CD4+ TCR + increased dose and history of myocardial
T-cells; infarction, and higher prevalence of myocardial
infarction in those survivors who had a lower
Decreased proportion of CD3+ CD8+ TCR +
proportion of CD4+ cells;
T-cells;
Differences in type 2 diabetes prevalence in heav-
Decreased proportion of CD3+ CD4+ CD45RA+
ily exposed individuals with two particular class
naive T-cells;
II HLA DQA1 and DRB1 alleles.
Non-significant changes in the proportion of
CD3+ CD4+ CD45RA memory T-cells;
Skewed TCR repertoires of CD3+ CD4+ B. Chernobyl workers and residents
CD45RA memory T-cells in individuals exposed
in adult life; 1. General considerations
Decreased proportion of CD3+ CD8+ CD45RA+
naive T-cells; 382. The accident at the Chernobyl nuclear power plant
Increased proportion of CD3+ CD8+ CD45RA (NPP) on 26 April 1986 resulted in both acute and long-
memory T-cells; lasting health effects. Early and late immune system changes
were among the key points studied after the accident. Acute
Increased frequency of CD4 and CD8 (double- radiation effects in victims were extensively described in an
negative) + T-cells; appendix to the UNSCEAR 1988 Report [U6]. Further infor-
No change in the proportion of CD3+ TCR + mation about the immunological effects of exposure to radi-
T-cells; ation from the Chernobyl accident as they were known up to
the year 2000 was provided by the Committee in reference workers without manifestations of acute radiation syndrome
[U2]. The Committee is currently updating its assessment of (ARS), for which total doses from external irradiation were
the health consequences of the accident. However, some data 0.10.5Gy (group 1), and the second being individuals who
concerning immunological issues will be discussed here. A survived ARS, for which total doses from external irradia-
broad spectrum of immune abnormalities had been reported tion were 0.59Gy (group 2). Decreases in the percentage
among Chernobyl victims; however, it has not been possi- and absolute number of CD3+ T-cells were observed in both
ble to interpret these results, since it was unclear whether all groups. A decrease in the percentage and absolute number of
possible confounding factors (such as heavy metal contami- CD8+ T-cells was observed only in group 1 (which had lower
nation, infections and diet) had been taken into account. doses). A decrease in the percentage and absolute number of
CD4+ T-cells was evident only in heavily exposed people
383. Early changes in immune parameters were character- from group2.
ized by alteration of the amount or function of peripheral
lymphocytes and changes in serum immunoglobulins. The 387. Titova et al. found that the mean number of CD8+
data indicate that radiation-induced effects on the immune T-cells was decreased in personnel working in the 30 km
system remained detectable for a considerable period after control zone around the NPP [T6]. The absolute number
the accident. The available data vary widely, according to the of CD4+ T-cells was also decreased, but their percentage
characteristics of the populations studied, the dose received remained higher. Kurjane et al. characterized the immune
and its protraction in time, the mode of exposure (exter- status of a group of Latvian workers who received exter-
nal irradiation and/or internal contamination) and the time nal radiation doses of 0.010.5 Gy [K21]; this study was
elapsed since the accident. performed 1014 years after the accident. A significant
decrease was observed in the number of CD3+ T-cells. This
384. Immunological monitoring of persons affected by the study also demonstrated that both CD4+ and CD8+ T-cells
Chernobyl accident comprised two main groups: were decreased. A study performed by Kuzmenok et al.
[K33] 1114 years after the accident did not, however, find
Individuals who worked at the NPP during the
significant changes in the phenotypic characterization of the
emergency and/or participated in further clean-up
main subpopulations of peripheral lymphocytes in a group
activities;
of Belarussian clean-up workers who received mean doses
Residents of contaminated areas, particularly of 0.150.5Gy.
children living in several settlements around
the NPP, who were included in the Children of 388. Other lines of evidence point to the role of serum
Chernobyl Project, as requested by the Ukrainian inhibitory factors that down-regulate T-cell surface antigen
Government. expression and that could regulate T-cell differentiation in
vitro. It has been reported that the decreased percentage of
Different parameters have been evaluated and several
CD4+ helperinducer T-lymphocytes of recovery operations
phases may be identified in these two groups concerning the
workers returned to normal values after 3 days of culture
temporal behaviour of the immunological effects.
without activation, suggesting that the phenotype may be
under the control of suppressive soluble factors in the blood
of these individuals [K33]. The fact that the percentage of
2. Emergency and clean-up workers CD4+ T-cells in control samples did not change after culture
reinforces this hypothesis.
385. The workers involved in the recovery and clean-up
after the Chernobyl accident were subjected not only to 389. A decline in the number of CD3+ and CD4+ T-cells,
external and internal radiation exposure but also to other with augmentation of the percentages of CD8+ T-cells and
non-radiation factors that may have affected their health. CD16+ CD56+/NK cells, was observed after 3 days of
As a consequence of the accident, different heavy metals culture with the polyclonal activator PHA at optimal con-
were deposited at the reactor site, with a significant amount centration (10 g mL1). This activation-induced deviation
being vaporized and distributed in rain clouds. Higher blood in the maturation of T-cell subpopulations may be a consist-
concentrations of iron, zinc and lead have been found in ent characteristic of impaired T-cell immunity in clean-up
workers who took part in cleaning up after the accident [N9]. workers [K33].
It could be hypothesized that some of the observed changes
in the immune status of clean-up workers might be due to a 390. The functional status of T-cells plays a key role in
combined action of ionizing radiation and heavy metal con- the immune regulation of human pathology. The prolifera-
tamination. [B19, G10]. Moreover, these workers suffered tive response of lymphoid cells to mitogens was also altered
strong psychological stress, which may significantly affect in recovery operations workers. Kuzmenok et al. [K33]
the immune system [G21]. reported a significant decrease of the response of periph-
eral blood mononuclear cells to PHA and the phorbol ester
386. Yarilin et al. [Y4] evaluated disorders in T-cell sub- PMA. Neither the TCR-restricted proliferative response of
populations 5 years after the accident in two groups of T-cells nor the level of Con-A-induced proliferation was
workers from the Chernobyl NPP accident, the first being significantly decreased.
391. The proliferative response of peripheral blood mono- 396. Yarilins results are in good agreement with those of
nuclear cells to exogenous IL-2 was higher in recovery oper- Titova et al. [T6], who also found lower levels of thymosin
ations workers, which may indicate an up-regulation of the alpha-1 and an increased serum level of antithymic epithel-
IL-2 receptor CD25 in their cells [K33]. Interleukin-2 (IL-2) ium autoantibodies in personnel from the 30 km control zone
is a cytokine responsible for a variety of immune stimulatory around the Chernobyl NPP. The dose-dependent decrease
and regulatory functions, including activation and stimu- of the serum level of thymosin alpha-1 and STA observed
lation of cytotoxic cells able to recognize and kill human 5years after the accident indicates late impairment of thymic
tumour cells, and T-cell proliferation and differentiation. function, which could be a result of a disturbance of thymic
Similar results had previously been obtained by Xu et al. in epithelial cell renewal. Thymus dysfunction after low doses
an experimental model of low-dose (0.2510mGy) in vitro could be due to the action of anti-epithelial autoantibodies
irradiation [X1]. induced by the release of antigenic material from the cells
damaged, even minimally, by ionizing radiation.
392. Changes in cell subpopulations have been reported
as evidence of radiation-induced disturbance of the T-cell 397. Thomas et al. [T4] performed a multiple end point
system [W5]. An increase in peripheral blood CD3+ CD16+ study comparing hypoxantine phosphoribosyltransferase
CD56+ NKT cells, a small subpopulation of lymphocytes (HPRT) mutation frequency with chromosome transloca-
that exhibits certain characteristics of both T-cells and NK tions in peripheral blood lymphocytes of clean-up workers.
cells and that can be the source of an abnormal pattern of When adjusted for age, smoking status and year of sampling,
cytokines, was observed in Belarussian clean-up workers the authors demonstrated a significant increase in HPRT
[K33]. mutation frequency in clean-up workers, with a depend-
ence on time elapsed since radiation exposure (a decline of
393. One of the best described effects of the Chernobyl 4.4% per year). They found little difference in the overall
accident on the immune system was the increased level of deletion spectra. However, they observed a decline in the
monocytes in peripheral blood. Senyuk et al. evaluated the average size of deletions of clean-up workers as time after
long-term effects of ionizing radiation in Chernobyl recov- exposure increased from 6 to 13 years. Jones et al. found an
ery operations workers [S13]. In many cases, the cumula- increase, more than 5 years after the accident, of chromo-
tive gamma radiation dose was >0.5Gy. The authors found a some translocations and in HPRT mutation frequency in
high number of monocytes with an increase in plasma levels peripheral lymphocytes of clean-up workers with absorbed
of cytokines IFN- and TNF. doses of below 0.25Gy [J4].
394. Functional changes have been reported in the mono- 398. Chumak et al. demonstrated an accumulation of autoxi
cytes and macrophages of clean-up workers. T-cell activa- dized lipoxygenase products of polyunsaturated fatty acids in
tion implies cooperation between the APCs and T-cells. the peripheral blood mononuclear cells of 23 clean-up workers
The functions of monocytes as APCs were compared in with absorbed doses of below 0.3Gy [C10]. They observed
clean-up workers and control individuals. Impaired func- higher levels of free and esterified fatty acids, with a positive
tion of monocytes as APCs was found in the T-cell prolif- correlation between the absolute number of CD4+ T-cells and
eration assay. Indeed, allogenic monocytes purified from the amount of 15-hydroxyeicosatetraenoic acid (15-HETE)
clean-up workers significantly augmented the prolifera- in the phospholipid fraction. The percentage of CD4+ T-cells
tive response to mitogens of T-cells from control individ- was higher in heavily irradiated workers, and the percentage
uals but inhibited proliferation of T-cells from clean-up of CD8+ T-cells tended to decrease with dose.
workers. In contrast, allogenic monocytes purified from
healthy donors marginally augmented the proliferative
response to mitogens from both clean-up workers and 3. Residents of contaminated areas
control individuals [K33].
399. Titov et al. investigated the production of immuno
395. Yarilin et al. evaluated the effect of ionizing radia- globulins in children living around the Chernobyl NPP. They
tion on the thymus and its role in radiation-induced T-cell found a decrease in B-cell numbers, a transient decrease of
disorders in victims of the Chernobyl NPP accident. A IgM and IgG and an increase of IgA levels (in both serum
decrease in serum concentration of thymosin alpha-1 and and saliva) during the first months following the accident.
serum thymic activity (STA) level was found with increased Over a six-year period of living in contaminated areas,
titres of autoantibodies to epithelial cells of the thymus children exhibited increasing production of IgG and IgM.
[Y4]. This titre was higher in persons with lower levels A correlation was found between the changes in B-system
of thymosin alpha-1. The dynamics of post-irradiation immunity and the levels of 137Cs contamination. There was
recovery of CD4+ and CD8+ cells were different. It had also a strong correlation between the production of natu-
been suggested previously that preferential CD4+ cell defi- ral (heterophilic) antibodies and dose to the thyroid due to
ciency might result from radiation-induced damage to the incorporation of 131I (in the range 0.11Gy). Higher accu-
thymus [A12]. The good correlation observed by Yarilin et mulation of 131I resulted in decreased titres of these anti
al. between thymic hormone and CD4+ cell levels would bodies. High levels of heterophilic antibodies correlated
confirm this hypothesis [Y4]. with high levels of IgE. Altered production of subclasses
of IgG associated with the increasing biosynthesis of IgE 402. The same group of researchers published further
suggests that T-cells may have been driven towards the Th2 results that confirmed previous findings and showed in addi-
profile [T5]. However, trying to find a causal association tion that children with RRD from contaminated areas had
between radiation exposure and these changes in Th2 pro- higher levels of CD3 CD56+ CD16+ NK cells than did
file would be speculative, because no data about confound- RRD children living in non-contaminated regions [V8]. It is
ing factors such as parasite infections in these children were interesting to note that children examined 810 years after
taken into account. the accident exhibited a more marked decrease in CD4+ cells
than those with the same dose but who were examined at
400. Chernyshov et al. examined peripheral blood lympho- 5years after the accident. This finding shows that long-term
cyte subsets eight years after the accident in children living exposure to low doses (i.e. a time effect) rather than low-dose
around the Chernobyl NPP [C9]. They evaluated children radiation exposure itself (i.e. a dose effect) altered the com-
living in 15 contaminated settlements in Ukraine, with and position of peripheral blood lymphocyte subsets in children
without recurrent respiratory disease (RRD), and a control with RRD living in contaminated areas. Although it has been
group of children living in non-contaminated areas, again suggested that CD4+ T-cells are relatively radioresistant in
with and without RRD. The average dose (internal plus vitro [S8], it may be that the combination of repeated expos-
external contributions: 0.573.09 mSv) was calculated ure to antigenic stimuli together with long-term exposure to
on the basis of the average density of contamination with low doses of ionizing radiation leads to CD4+ T-cell deple-
137
Cs and 90Sr; no data were included concerning thyroid tion. Considering that NK cells have a lower in vivo radio
doses due to 131I incorporation. Lower percentages of CD3+ sensitivity [C11, L21], their relative increase in children
T-cells were observed in RRD children from contaminated with RRD from contaminated areas could also be an effect
areas than in control RRD children. Lower percentages of of long-term low-dose exposure. The different responses of
CD3+ CD4+ (helper) T-cells were observed in RRD children blood lymphocyte subsets could contribute to the lower risk
from contaminated areas than in control RRD children. RRD of developing autoimmune thyroid abnormalities in children
children from contaminated areas exhibited lower percent- with RRD living in contaminated areas.
ages of CD3+ T-cells and CD3+ CD4+ (helper) T-cells than
healthy children. Healthy children (no RRD) from contam- 403. Koike et al. compared NK activity in children living
inated areas had the same mean values for lymphocyte sub- in Gomel, a highly contaminated area, with that of children
sets as control healthy children. However, a wider range of living in non-contaminated areas [K15]. While children
percentage levels of CD3+ CD4+ T-cells was found among living in non-contaminated areas exhibited a narrow range
healthy children from contaminated areas, which allowed of NK cell cytotoxicity percentages, a wider range of NK
them to be divided into three subpopulations: children with cell cytotoxicity (from 8.9% to 76%) was found in child
very low, normal or very high percentage levels of CD3+ ren from contaminated areas. The NK cell cytotoxicity of
CD4+ T-cells. The other lymphocyte subsets studied did not these children was correlated neither with NK cell number
differ among groups. nor with the amount of internal contamination by 137Cs. The
authors interpreted these findings as a loss of the normal
401. Children from contaminated areas had a healthy regulatory mechanisms that maintain a correlation between
population (non-RRD) without major lymphocytic mani- cytotoxic activity and NK cell number. It seems a rather
festations of immune disorders and an RRD population speculative conclusion. Even if such dysregulation exists, it
that exhibited lower percentages of total T-cells and helper cannot be attributed to ionizing radiation. The lack of cor-
T-cells than RRD controls. This decrease was more marked relation between these abnormalities and the levels of inter-
in RRD children with higher doses [C9]. This dose depend- nal contamination suggests that related factors, other than
ence provided strong evidence for a radiation-induced direct internal exposure to 137Cs, may be responsible. Diet
effect. The question is what accounts for the difference in and/or environmental exposure to some agent (such as heavy
immune response observed between exposed children who metals) might be proposed. The effect of external ionizing
are healthy and those with RRD. It may be that repeated radiation from contaminated ground and the effect from
exposure to pathogenic or antigenic stimuli is necessary for radionuclides other than 137Cs remain to be determined.
the development of radiation-induced immune disturbances.
Moreover, individual features (including genetic factors) 404. Mikhalevich et al. investigated cytogenetic and muta-
are involved in the sensitivity of immunocompetent cells to tional effects in the lymphocytes of children living in a con-
ionizing radiation. It could be proposed that children pre- taminated region of Belarus nine years after the accident
disposed to RRD have an impaired immune response and [M5]. Their results indicated a doubling of the percentage of
may exhibit greater radiosensitivity. Although this study did micronuclei in the mononucleated lymphocytes of exposed
not consider thyroid doses, it is well known that the region children, while the same parameter studied in binucleated
where the study was performed (northern Ukraine) had a lymphocytes showed no differences. No evidence was found
high level of 131I contamination. It could be hypothesized for induction of HPRT mutations.
that healthy children from contaminated areas exhibited a
higher percentage of CD3+ CD4+ T-cells owing to clinical 405. An adaptive response of lymphocytes to radiation has
and subclinical autoimmune disorders related to radioiodine been suggested by a number of in vitro studies indicating
incorporation. that cells can become less susceptible to radiation-induced
damage when a challenge exposure to ionizing radiation Complement split product C3d was higher in both groups
is preceded by a very low priming dose. Padovani et al. (i.e. with and without thyroid disease) of clean-up workers.
[P1] administered a challenge dose of 1.5Gy to stimulated Thyroid follicular cells are protected from lysis by locally
peripheral lymphocytes of children chronically exposed in activated complement. Although the underlying mechanism
contaminated areas around Chernobyl. They did not find of the complement activation in clean-up workers is unclear,
any decreased susceptibility for the two end points exam- it may reflect a secondary radiation-induced inflammatory
ined (chromosome and chromatid aberrations). An important response. The question of whether this mechanism is also
consideration relates to the dose rate at which the priming involved in the development of thyroid abnormalities among
dose is delivered. Assuming a constant intake for 1 year, the these workers remains unanswered.
average value of committed effective dose equivalent was
450Sv (range 502,000 Sv); this dose rate is lower than 408. Considering that the immune system is a vulnerable
that used in most published studies. Another point of concern target for the effect of lead contamination [B19], the results
is that the priming dose in this study took place in resting presented for Kurjane et al. should be interpreted cautiously.
lymphocytes, and it has been reported that a radio-adaptive It has been reported that CD16+ NK cells and CD4+ T-cells
response cannot be induced in the G0 stage of the cell cycle. are vulnerable targets for the effects of lead [G10]. Elevated
blood and urine lead concentrations were found in Kurjanes
group of clean-up workers. It could be concluded that even
4. Radioiodine contamination, immune 1014 years after exposure, a combined impact of both
status and thyroid diseases radiological and non-radiological factors could be observed
on the immune system of Latvian workers: impairment of
406. A higher incidence of goitre has been reported among phagocytic activity, reduction of cell-mediated immunity
the Chernobyl clean-up workers. Kurjane et al. [K21] ana- parameters and a shift towards an inflammatory profile.
lysed several parameters of the immune system in 385 male
Latvian residents who participated in the clean-up work at 409. Kiseleva et al. reported an increase in serum levels of
the Chernobyl site. The results were compared with those antithyroglobulin and microsomal fraction autoantibodies,
from 47 healthy age- and sex-matched controls. This group with higher levels of circulating immune complexes in
of clean-up workers received external doses of 10500mGy. liquidators 11 years after the Chernobyl accident [K14].
No data were provided in this paper concerning thyroid doses Vykhovanets et al. investigated the involvement of auto-
due to radioiodine incorporation. Workers were exposed immune mechanisms in the development of thyroid abnor-
during 26 months, while working at Chernobyl, and then malities in the context of radioiodine exposure of children
they lived in uncontaminated territories after they returned living around the Chernobyl NPP [V9]. The study, which was
to Latvia. The prevalence of non-cancer thyroid diseases carried out 8 years after the accident, included children living
as determined in January 2000 was higher among clean-up in 15 contaminated settlements and control children living
workers (47 cases among 385 workers; 121/1,000), than in in non-contaminated areas. Individual absorbed doses to the
a non-exposed Latvian population (30/100,000), with goitre thyroid due to radioiodine (<1Gy, 12Gy and >2Gy) and
being the most frequent disorder. Diminished acquired cel- average doses (internal plus external; range 0.573.09mSv)
lular immunity (total CD3+ cells, CD4+ and CD8+ T-cells) due to 137Cs and 90Sr were estimated. A positive correlation
was found among the Latvian clean-up workers. The phago- was found between thyroid 131I dose and serum AbTg lev-
cyte activity of neutrophils was significant decreased. Lower els, content of CD4+ T and CD4+/CD8+ ratio. In contrast,
levels of IgG and higher levels of IgM, without changes in a negative correlation was observed between thyroid 131I
IgA were also found in this group. The observed decrease in dose and CD8+ T-cells and NK cells. The lack of correlation
the percentage of CD16+ NK cells contrasts with previous between thyroid-stimulating hormone (TSH) levels and thy-
reports suggesting that NK cells display radioresistance. It is roid dose suggests that the higher levels of TSH found among
important to note that blood lead concentration was six times children living in contaminated areas may be due to iodine
higher in clean-up workers [K21]. deprivation in areas of endemic goitre. Children with individ-
ual absorbed doses of >2Gy due to radioiodine have several
407. Kurjane et al. [K21] also reported that some immune signs of autoimmune disorder: abnormal thyroid echogen-
parameters of workers with thyroid diseases differed from icity, positive sera for AbTg, higher levels of CD4+ T-cells
those observed in workers without thyroid disease: a lower (which play a central role in immune response and are able to
number of NK cells, higher IgG plasma concentrations and increase immunoglobulin production by B-cells), lower lev-
higher activation of the classical pathway of complement.2 els of CD8+ T-cells and higher CD4+/CD8+ T-cell ratios, a
frequent finding in autoimmune thyroid diseases [V9].
2
Note: These results are presented here as discussed by Kurjane et al. [K21]
in the text of their paper. However, the Committee found a lack of correla- 410. Two further studies [P10, V12] also reported a higher
tion between these comments and the values presented by the authors in prevalence of antithyroglobulin or antithyroperoxidase
table 2 of their paper, which seem to be contradictory: a higher number of antibodies in children living in contaminated areas; this
NK cells, lower IgG plasma concentrations and lower functional activity
of the classical pathway of complement in clean-up workers with thyroid
was already apparent in individuals who were in utero or
diseases. The Committee considered that this discrepancy might be due to a newborn at the time of the accident. Autoimmune pheno
mistake in typing column headings. mena were limited to an increased prevalence of circulating
thyroid autoantibodies, without evidence of significant thy- to be necessary for the development of radiation-induced
roid dysfunction. It should be taken into account that children immune disturbances. Individual features, including genetic
involved in these geographical correlation (ecological) factors, are involved in the sensitivity of immunocompetent
studies may present a combined effect of iodine deficiency cells to ionizing radiation. Illnesses associated with both
and internal contamination with short-lived iodine isotopes. radiation exposure and genetic factors could be determinants
of the immune status after the accident.
411. Koike et al. evaluated the immune status in children
with goitre living in the highly contaminated area of Gomel. 414. The immunological effects of exposure to ionizing
They found increased serum levels of IgG, IgM and IgE, and radiation from the Chernobyl accident were mainly related
depressed NK cell activity [K15]. Although IFN- and IL-2 to changes in the amounts or function of peripheral lym-
enhanced the cytotoxicity of these NK cells, the response to phocytes and serum immunoglobulin levels. These effects
IFN- was still below control values. The other parameters were detectable long after the accident. The immune system
were within normal values. seems to be involved in the pathogenesis of thyroid diseases
in victims of the Chernobyl accident, probably owing to
antigenic mechanisms being triggered by radiation-induced
5. Remarks concerning data on Chernobyl thyroid damage, leading to autoimmune responses. Neuro
workers and residents endocrine and other stress-related factors, respiratory
diseases, chronic infections, chemical contamination and
412. Some remarks may be made on the basis of the pub- autoimmune dysbalance could also be factors in some of the
lications on the Chernobyl accident reviewed above. Even immune disorders found in this population.
many years after the accident, the impacts of both radio-
logical and non-radiological factors on the immune system
were observed in Chernobyl recovery operations (clean-up) C. Techa River study
workers. Ionizing radiation accelerated the natural ageing of
the immune system due to a progressively declining thymic 1. General considerations
function. The dynamics of post-irradiation recovery are dif-
ferent for CD4+ and CD8+ cells, and it has been suggested 415. The Techa River study is seen as an excellent oppor-
that preferential CD4+ cell deficiency may result from tunity to obtain more reliable risk estimates for a general
radiation-induced damage to the thymus. population exposed over an extended period to low-dose-
rate gamma rays. More than 25,000 inhabitants of Techa
413. Short-term as well as long-term effects were detect- riverside villages were exposed, predominantly during
able in B-cell and T-cell function profiles, as well as in the the early 1950s, to external gamma radiation from fission
biosynthesis of immunoglobulins in both serum and saliva, products associated with discharges of high- and medium-
of children living in contaminated areas around the Cher- level wastes into the river from the Mayak nuclear facility.
nobyl NPP. Some of these changes were dose-dependent In addition, residents incorporated, via drinking water and
and were characterized by phases. Indeed, immune profiles through the food chain, large activities of short-lived fission
were different several months as opposed to several years products such as 89Sr, and subsequently long-lived activity,
after the accident. The NK cell system of these children may especially from 90Sr and 137Cs. Mean and median doses to soft
have lost the normal regulatory mechanisms that maintain a tissue and bone marrow according to the earlier Techa River
correlation between cytotoxic activity and NK cell number. Dosimetry System (TRDS-1996) and the revised dosimetry
Repeated exposure to pathogenic or antigenic stimuli seems system (TRDS-2000) are shown in table13.
Table 13 Mean and median doses to soft tissue and bone marrow in inhabitants residing near the Techa River [K9]
Dosimetry system Soft tissue dose (mGy) Bone marrow dose (mGy)
TRDS-1996
Mean 99 405
Median 17 267
TRDS-2000
Mean 35 353
Median 7 253
2. Epidemiological data CRS was based on the occurrence of the following signs:
changes in blood parameters (leucopenia, thrombocyto-
416. In the early period, cases of chronic radiation sickness penia, granulocytopenia); nervous system disorders; oste
(CRS; 940 cases in total) were diagnosed. The diagnosis of algia; cardiovascular syndrome; and changes in immunity
(inhibition of innate immunity, autoimmunity). At dose rates values disappear (figure IX). The dynamics of segmented
in excess of 300500mSv/a to red bone marrow, a portion neutrophils correlated with leucocyte dynamics, indirectly
of the irradiated population developed post-irradiation reac- corroborating the decrease in leucocyte counts as associated
tions of the haematopoietic and immunological systems with the decreased number of granulocytes (figure X) [K19].
[A8]. Some of the residents exposed did not develop CRS, According to the data for individuals with CRS, there was
but in the early years they manifested isolated reactions most an increase in the fractions of myelocytes and metamyelo-
commonly represented by haematological changes in periph- cytes in the bone marrow, corresponding to the occurrence of
eral blood studies. The dynamics of blood parameters clearly leucopenia and granulocytopenia in peripheral blood. Such
manifested a reduction in the number of cellular elements at findings can be interpreted as delayed maturation and dif-
the highest dose rates and a subsequent normalization with a ferentiation of granulocytes at the final stage of cell develop-
decrease in dose rate. The average leucocyte counts for CRS ment. The subjects who were initially exposed in utero or at
patients persisted at lower than 90% confidence intervals age 12 years showed the greatest changes in the immune
of the reference value for three decades after the beginning system parameters already mentioned. Haematopoietic
of exposure. Only after 1970 did the difference in leuco disturbances developed almost at the same time as the signs
cyte counts between followed-up patients and reference of immune insufficiency [K19].
Figure IX. Mean leucocyte counts at different times after Figure X. Mean neutrophil counts at different times after
the beginning of exposure [K19]. the beginning of exposure [K19].
7 4.0
SEGMENTED NEUTROPHIL COUNT (103 L-1)
LEUCOCYTE COUNT (103 L-1)
3.5
6
3.0
5
2.5
Normal Normal
90% confidence intervals 90% confidence intervals
4 2.0
1950 1960 1970 1980 1950 1960 1970 1980
CALENDAR YEAR CALENDAR YEAR
417. Recovery from these symptoms depended on exposure processes developed more slowly in children and teenagers
rates, with greater exposure leading to longer recovery times. who received the highest doses, since a close dependence
Even after the cessation of external exposure and intakes of exposure dose on age was observed. The age depend-
of radionuclides, leucopenia and neutropenia persisted for ence of the duration of CRS is shown in figure XI [K19].
a long period; this may have been due to incorporation of Immunity disorders persisted for 30 years and longer after
long-lived strontium, which contributed to irradiation and the exposures began. Long-term immunity changes involved
maintained a certain level of dose rate. The average dura- cellular immunity (decreased expression of differentiating
tion of the disease was 7.35 years, but at doses in excess of antigens of T-lymphocytes, T-lymphocyte blast transforma-
700mSv to the red bone marrow, the repair process lasted tion), natural toxicity (reduced counts of NK cells) and signs
for more than 9 years [K19]. Complete recovery from the of immunological imbalance. At long times (4348 years)
haematological and neurological effects occurred within after the beginning of exposure, the status of haematopoiesis
1316 and 1420 years, respectively, following the begin- and immunity was normal among most of the exposed sub-
ning of exposure. The duration of the disease was presum- jects. However, the proportions of the exposed persons still
ably dependent on the patients age at exposure. Recovery showed an increased frequency of chromosomal aberrations
and CD3CD4+ mutant T-lymphocytes in the periph- have since died, mainly owing to infectious and respiratory
eral blood [A18]. An increased frequency of TCR mutant diseases and trauma [K49]. A total of 75 cases of cancer
lymphocytes was also noted [A17]. were detected. The most frequent cancer types were found
to be respiratory tract, malignant lymphoma and leukaemia.
The overall cancer incidence rate was 24.3 per 100,000, this
Figure XI. Dependence of CRS duration on age at time of comparatively low morbidity rate being attributed to the fact
exposure [K19]. that the highest age attained was 45 years, with only 26% of
the cohort being over 40 years of age [K50].
14
3. Remarks on the Techa River study

12
420. Some remarks may be made concerning the informa-
DURATION OF CRS (YEARS)
10 tion reviewed above. Residents of Techa riverside villages

were exposed to external gamma radiation and internal
8 contamination with both short-lived and long-lived fission
products. Early effects on the immune system included
6 leucopenia, neutropenia, inhibition of innate immunity and
autoimmune disorders. Long-term effects include impaired
4 cellular immunity and a decrease of NK cells. A long-lasting
delayed maturation and differentiation of granulocytes was
2
observed. Leucopenia and neutropenia persisted for around
three decades after the beginning of the exposure. Continuous
exposure from long-lived incorporated radionuclides may
0
account for this long-lasting effect. Greater exposures were
correlated with longer recovery times. Subjects exposed in
utero or during the first two years of post-natal life presented
-1 20 40 60 80
more severe effects. Five decades after the beginning of the
exposure, immunological parameters had normalized, but an
AGE (YEARS)
increase in the frequency of chromosomal aberrations and
mutations was found in the peripheral lymphocytes of resi-
dents of Techa riverside villages. Manifestations of immuno
418. CRS diagnosed in a number of residents of Techa river deficiency occurred more frequently among residents who
side villages was found to be associated with higher death developed tumours.
rates from cancer and leukaemia. The Extended Techa River
Cohort (ETRC) includes 29,873 people born before 1950
who lived near the river sometime between 1950 and 1960. D. Hanford nuclear site
Between the years 1950 and 1999, 1,842 solid cancer deaths
and 61 leukaemia deaths occurred. The maximum incidence 1. General considerations
of leukaemia was observed 1519 years after the exposure
began. The excess relative risk per unit dose for solid can- 421. As previously described, there is no statistically sig-
cer was 0.92 (95% CI: 0.2, 1.7) Gy1, while the values for nificant dose response in the prevalence of autoimmune
leukaemia, including and excluding chronic lymphocytic leu- hypothyroidism or thyroid autoantibodies in atomic bomb-
kaemia, were 4.2 (95% CI: 1.2, 13) Gy1 and 6.5 (95% CI: ing survivors. On the other hand, it was suggested that the
1.8, 24) Gy1, respectively. It is estimated that about 2.5% of immune system might be involved in the pathogenesis of
the solid cancer deaths and 63% of the leukaemia deaths were thyroid diseases in Chernobyl accident victims. It is thus
associated with the radiation exposure [K52]. Clinical mani- interesting to present here another epidemiological study
festations of immune insufficiency with respect to certain developed for evaluating thyroid diseases in people exposed
infectious diseases (such as chronic pneumonia, pulmonary to ionizing radiation.
tuberculosis and non-traumatic osteomyelitis) occurred with
higher frequency among exposed patients with tumours than 422. Approximately 2.73 1016 Bq of 131I were released to
in exposed individuals without tumours [A8]. the atmosphere from the Hanford nuclear site between the
years 1944 and 1957. This facility manufactured plutonium
419. The Techa River Offspring Cohort (TROC) comprises for early nuclear weapons. This production process caused
10,459 children at least one of whose parents lived along the the release of a variety of radioisotopes, which drifted on the
Techa River during the period 19501992. Of these children, wind and the river, settled on vegetation and were consumed
3,897 were born during the period of highest release, i.e. by grazing animals. The vast majority of radioactive releases
between 1950 and 1956, and might thus have been exposed came in a single year. A study was recommended to estimate
in utero or during childhood. A total of 1,103 individuals radiation doses to area residents and another to examine the
feasibility of potential health effects of 131I, the radioisotope expansion of the number of elderly individuals in the world
that accounted for most of the exposures [R12]. population will lead to a substantial increase in the prevalence
of cancer and hence in the number of individuals undergoing
radiotherapy. Second primary malignancies among cancer
2. Hanford Thyroid Disease Study patients account for 16% of all cancer incidences [T13]. An
extensive body of literature concerning second cancers in
423. The Hanford Thyroid Disease Study was conducted patients undergoing radiotherapy has recently been published
as a retrospective cohort study (19921997) to determine [A20, D25, G33, R15, R16, R17]. However, papers concern-
if thyroid disease had increased among persons exposed as ing changes of immunological parameters after radiotherapy
children to these atmospheric releases of 131I. The cohort are scarce, and the actual impact of these changes on health
included a sample of all births between the years 1940 and has not been well established.
1946 to mothers whose usual residence was in one of seven
counties near the Hanford site. The thyroid doses ranged
from 0.0029 to 2,823mGy (mean 174mGy, median 97mGy) 2. Review of published data
[K47]. Assessments of thyroid disease, including a thyroid
ultrasound, a physical examination, and a fine needle biopsy 427. Nakayama et al. investigated changes in peripheral
if required to evaluate thyroid nodularity, were carried out in blood lymphocyte subsets of 15 lung cancer patients who
3,440 individuals. had undergone thoracic irradiation [N17]. After radia-
tion therapy, the percentage and the absolute number of
424. There was no evidence of a relationship between CD4+CD45RA+ cells (naive T-cells) and CD56+ and/or
radiation dose and the cumulative incidence of any of the CD16+ cells (NK cells) decreased. The percentage of HLA-
following outcomes: total neoplasia, thyroid cancer, benign DR+ CD4+ cells (activated CD4+ T-cells) and HLA-DR+
thyroid nodules, autoimmune thyroiditis and hypothy- CD8+ cells (activated CD8+ T-cells) increased, although the
roidism. Although ultrasound abnormalities were observed absolute number did not change significantly. Changes in
in 55.5% of women and 37.4% of men, they were not sig- local inflammatory cells in bronchoalveolar lavage fluid were
nificantly associated with the dose. The Hanford Thyroid analysed by the same authors in a similar group of patients
Disease Study has sufficient statistical power to test for [N18]. The percentage of lymphocytes and eosinophils, the
doseresponse relationships between thyroid outcomes and percentage of HLA-DR+ CD4+ and CD8+ cells (activated
radiation exposure [D16, K48, R12]. CD4+ and CD8+ T-cells, respectively) and the incidence of
ICAM-1+ T-cells was higher in lung cancer patients who had
undergone thoracic irradiation than in controls (lung cancer
3. Remarks concerning the Hanford nuclear site non-irradiated patients). Naive T-cells seem to be more
selectively damaged than memory T-cells by thoracic irradi-
425. As seen in the preceding paragraphs, 131I was the ation. The reduction of NK cells may be disadvantageous for
radioisotope that accounted for most of the dose received antitumour immunity. On the other hand, thoracic irradiation
by residents near the Hanford nuclear facility. Fifty years enhanced both peripheral and local T-cell activation, which
after exposure, the Hanford Thyroid Disease Study did not may promote antitumour effects. Nakayamas results are in
find evidence of a relationship between radiation dose and good agreement with the findings of Ishida et al. in patients
thyroid pathologies, including autoimmune thyroiditis. The who underwent thymectomy and post-operative radiation
results of this study support the hypothesis that exposure therapy, which also indicated that irradiation was associated
during infancy and childhood to 131I at these dose levels and with a higher percentage of activated T-cell subsets [I10].
in these exposure circumstances does not increase the risk of
these forms of thyroid disease. 428. Van Mook et al. studied 24 B-cell chronic lympho-
cytic leukaemia patients after splenic irradiation. Radiation
treatment consisted of a weekly dose of 1Gy up to a total
E. Patients undergoing radiotherapy dose of 10Gy to the spleen. Six weeks after splenic irradia-
tion, total leucocytes decreased significantly, with a decrease
1. General considerations in the fraction of lymphocytes and an increase in the neutro-
phil and platelet counts. The number of CD4+ and CD8+
426. Ionizing radiation is an important and often indispen- cells decreased significantly without significantly changing
sable strategy for cancer treatment. More than 50% of people the CD4+/CD8+ ratio. No significant changes in immuno-
with cancer undergo radiotherapy at some time during their globulin levels were observed [V11].
illness [F9]. Although more alternatives for fractionation are
now available, conventional fractionation schedules for local 429. A long-term deficit in total CD4+ T-cell counts after
external radiotherapy (910Gy/week delivered at dose rates radiation treatment for Hodgkins disease (HD) was reported
of approximately 50Gy/h over 56 weeks) continue to be the many years ago [P14]. In patients who received medias-
main modality. The potential for increased tumour control tinal irradiation for HD, Watanabe et al. found a marked
with protocols combining low-dose-rate with high-dose- depletion in both CD4+ and CD8+ naive T-cell counts that
rate irradiation is now under discussion [G11]. The rapid persisted for up to 30 years after completion of treatment.
In contrast, CD4+ and CD8+ memory T-cell subsets and following mediastinal irradiation, probably owing to thymus
total CD8+ T-cells recovered to normal or above normal impairment. Extrathymic (peripheral) expansion of memory
levels by five years post-treatment, with different kinetics T-cells results in a lower naive/memory cell ratio.
(early expansion of CD8+ memory T-cells versus the grad-
ual recovery of the others). Thus the long-term deficit in 432. Although reduction in the absolute number of all lym-
total CD4 T-cell counts in irradiated HD patients was due to phocyte subsets is observed after therapeutic WBI, the effects
specific depletion of the naive T-cell subset. Similarly, total differ according to the fractionation schedule. While an early
CD8+ T-cell counts returned to normal values by 5 years increase of the CD4+/CD8+ ratio is observed after a total
post-treatment, particularly because CD8+ memory T-cells whole-body dose of 1.6Gy protracted over four weeks (low-
expanded to higher than normal levels. As the thymus is dose fractions of 0.2Gy), indicating a higher radiosensitivity
the main source of naive T-cells, these findings suggest that of CD8+ T-cells, this effect was not observed after a total
mediastinal irradiation results in a long-term depletion of whole-body dose of 12Gy given over three days (high-dose
the CD4+ naive cell pool, probably owing to thymus impair- fractions of 2Gy).
ment. This dysregulation of T-cell subset homeostasis may
explain the altered T-cell function observed in treated HD
patients, including the poor response to immunization after F. Summary
treatment. An extrathymic (peripheral) expansion of mature
T-cells may partially compensate for the loss of thymus- 433. This section reviewed the effects observed on the
derived T-cells, but this expansion is primarily restricted to immune system of human populations exposed to ionizing
the memory population, thus resulting in a selective expan- radiation in very different conditions. Diverse immunological
sion of memory T-cells, while naive T-cell numbers remain parameters were evaluated in these populations, at different
low [W10]. times after exposure. There are similarities and differences
among the results reported by different authors. The analysis
430. Safwat et al. [S35] studied immunological parameters of similarities might aid identification of the predominant
in 35 non-Hodgkins lymphoma patients undergoing WBI effects of ionizing radiation on the human immune system.
consisting of two cycles of four daily fractions of 0.2 Gy However, findings should be interpreted taking account of
separated by 2 weeks of rest (total dose of 1.6 Gy over the specific characteristics of each population.
fourweeks). WBI was associated with a significant decrease
in the percentage of lymphocytes and a significant increase 434. The detonation of the atomic bombs in Hiroshima
in the percentage of CD4+ T-cells, with a consequent signifi and Nagasaki in 1945 resulted in a short burst of external
cant increase in the CD4+/CD8+ ratio. In terms of absolute neutron and gamma irradiation. Radiation-induced cell
values, WBI leads to a significant reduction in the abso- death accounts for the short-term effects observed in the
lute number of all the lymphocyte subsets. The significant immune system, mainly associated with the development
increase in the percentage of CD4+ cells in the peripheral of acute radiation syndrome. An almost complete recovery
blood was interpreted as indicating a higher radiosensitivity of the haematopoietic system of atomic bombing survivors
of the CD8+ T-cell subset. This contrasts with previous data took place within the first year after the exposure. Little evi-
published by Clave et al. [C11] for patients given WBI (total dence of dose-dependent effects on the immune system of
dose 12 Gy) before bone marrow transplantation, which the survivors was found soon after the bombings. Studies of
revealed that all major T-lymphocyte subsets appeared the long-term effects of ionizing radiation on the immune
equally radiosensitive, while the NK cells were relatively system began about 20 years after the atomic bombings.
radioresistant. In that study, however, blood samples were
collected 6h after a single dose of 2Gy, while in Safwats 435. The Chernobyl accident released large amounts of
study the samples were collected 24h after a total dose of radionuclides into the environment over a period of around
1.6Gy delivered over 4 weeks. 10 days. External irradiation was predominant among emer-
gency and recovery operations workers. Doses to residents
of contaminated areas resulted from external irradiation from
3. Remarks concerning data on patients radionuclides deposited on the ground and from internal irra-
undergoing radiotherapy diation mainly due to ingestion of short-lived (e.g. 131I) and
long-lived (e.g. 137Cs) radionuclides present in foodstuffs.
431. As presented in the preceding paragraphs, the effects Large quantities of radioiodine were internalized during the
on the immune system observed in cancer patients under- early period. Ingested and inhaled radioiodine was prefer-
going local radiotherapy include decreases in the absolute entially incorporated into the thyroid, resulting in higher
number of total leucocytes, total lymphocytes, CD8+ and/ levels of exposure to this gland compared with the rest of the
or CD4+ T-cells, and NK cells. Naive T-cells are more body. As seen in the atomic bombing survivors, short-term
selectively damaged than memory T-cells. While CD4+ and effects on the immune system were mainly associated with
CD8+ memory T-cell subsets and total CD8+ T-cells return the symptoms of acute radiation syndrome.
to normal levels within 5 years after irradiation, CD4+
naive T-cell depletion may be long-lasting (recovery sev- 436. The residents of Techa riverside villages were
eral decades after radiotherapy). This is particularly evident exposed predominantly during the early 1950s to external
gamma irradiation from fission products and internal incor- Increased humoral immunity: higher levels of
poration of short-lived (mainly 89Sr) and long-lived (mainly total Ig, IgA and IgM;
90
Sr and 137Cs) radionuclides via drinking water and food-
Shift towards an inflammatory profile: inflamma-
stuffs. In the early period, chronic radiation sickness (CRS)
tory cytokines, activated complement.
was diagnosed, including leucopenia, neutropenia, thrombo
cytopenia, impaired innate response and autoimmunity. The
440. Atomic bombing survivors presented with a reduction
effects were more severe in children exposed in utero or at
of naive CD8+ and CD4+ T-cell pool, and clonal expansion
12 years old. Normalization of haematological parameters
of memory CD8+ T-cells associated with TCR repertoire
in CRS patients was observed 30 years after the beginning
deviation. This kind of perturbation of T-cell homeostasis
of the exposure. Long-lived radionuclides contributing to
was not evident in Chernobyl workers and residents. While
chronic irradiation may explain why immunity disorders per-
total CD4+ T-cells were diminished in both populations,
sisted for such a long period, even after cessation of external
total CD8+ T-cells were decreased only in the Chernobyl
exposure and intakes. Long-term effects included decreased
population.
cellular immunity and reduced counts of NK cells.
441. Findings concerning NK cells also differ: while sig-
437. Major radioactive releases into the air, water and soil
nificant changes were found in neither their number nor
occurred at the Hanford nuclear site between 1944 and 1957.
their cytotoxic activity among atomic bombing survivors,
Thyroid diseases were selected for the study of health effects
a decrease in both parameters was found in the Chernobyl
because the release of 131I caused the highest exposures in the
population. Many workers who took part in recovery opera-
population. There is no evidence of a relationship between
tions after the Chernobyl accident were contaminated with
radiation dose and the incidence of total neoplasia, thyroid
heavy metals, which may account, at least in part, for the
cancer, non-cancer thyroid diseases, hypothyroidism and
observed changes in their immune status. An increase in the
autoimmune thyroiditis.
NKT lymphocyte subset was observed in Belarussian recov-
ery operations workers, an observation that was not reported
438. Most cancer patients undergoing radiotherapy receive
in atomic bombing survivors.
a very localized high-dose irradiation protracted over several
weeks. Most of the published data concern mainly short-
442. The development of autoimmunity is a relevant
term effects on the immune system: total leucocyte decrease,
finding among Chernobyl workers and residents. There
total lymphocyte decrease, selective damage to naive T-cells
were regions with iodine deficiency in most affected terri
compared with memory T-cells, enhancement of local and
tories of Belarus, the Russian Federation and Ukraine.
peripheral T-cell activation and decrease of NK cells. Long-
Ionizing radiation might have induced thyroid gland
term effects described in Hodgkins disease patients show
changes affecting the expression of endemic goitre. These
long-lasting (30 years) depletion of naive T-cells with a more
factors should be considered in interpreting the increase
rapid (5 years) recovery of memory T-cells. Studies concern-
in thyroid autoantibody levels and the development of
ing short-term effects of ionizing radiation on the immune
autoimmune thyroid diseases, which were not observed
system of patients receiving WBI indicate that the frac-
in the atomic bombing survivors or in residents near the
tionation regime influences the resulting effects. Although
Hanford site.
a decrease in total lymphocytes is a common feature, the
behaviour of lymphocyte subsets differs according to the
443. Studies of the long-term effects of ionizing radia-
WBI schedule.
tion on the immune system of atomic bombing survivors
began about 20 years after the bombings and continue to
439. The following findings may be considered as similar
be carried out. Because the Chernobyl accident occurred
effects on the immune system observed in human popula-
in 1986, data concerning long-term effects of ionizing
tions exposed to ionizing radiation:
radiation on the immune system are today limited to the
Impairment of T-cell immunity: decreased total first 20 years after the event. These should be considered
T-cells and CD4+ T-cells, lower T-cell responsive- for cross-comparison of the long-term effects observed in
ness to mitogens and alloantigens; the two populations.
V. Final summary
444. The immune system is certainly one of the most com- radiation-induced apoptosis. In addition to these cytotoxic
plex systems of the body. It is composed of a large variety effects, ionizing radiation may induce danger signals,
of cells spread widely throughout the body and of differ- which may in turn influence cell responses in the immune
ent organs where stem cells can differentiate into one of the system. Such evidence has led to the emerging notion that
major lineages. Immune cells communicate via cytokines, ionizing radiation has much more to offer than its quali-
which are soluble molecules that stimulate immune cell pro- ties as a powerful cytotoxic agent, and because of this, ion-
liferation and/or differentiation. Consequently the immune izing radiation is probably better considered an immuno
cells can differentiate towards specific cell types. Clusters modulatory agent rather than an immunosuppressive one.
of differentiation (CD) are cell surface glycoproteins asso-
ciated with specific functions; their expression may change 449. Although many questions remain open, the role of
depending on cell environment, e.g. the effect of ionizing the immune system with regard to cancer development is
radiation. better understood. In the classical immune surveillance
theory, tumours may develop when cancer cells escape from
445. One of the main functions of the immune system is immune surveillance either by reducing the expression of
the recognition of foreign antigens and the development of tumour antigens or by modifying the immune response to
subsequent actions of protection, for example against infec- them. Although a strong antitumour activity can be effi-
tion and cancer. Autoimmune disease may result from the ciently developed as a result of the activation of both innate
alteration of self tolerance mechanisms. and acquired immune responses, some immunological pro-
motion of tumours may result from low-grade persistent
446. For protecting the body, the immune system can use inflammation, chronic activation of innate immune cells or
two different but interrelated forms of immunity, i.e. innate the blocking of cell-mediated cytotoxicity by antibodies.
and acquired. While innate immunity provides a rapid defence
because it is always ready for use, acquired immunity devel- 450. The effects of ionizing radiation on the immune system
ops only after a pathogen has entered the body. Acquired at low doses (<200mGy) and low dose rates (<100mGy/h)
immunity is very antigen-specific and keeps the memory remain controversial. In animals, although depletion of
of a previous exposure, yielding a stronger response at the different categories of immune cells is observed, as well
time of a subsequent exposure to the same antigen. Acquired as changes in lymphocyte subsets, there is some evidence
immunity can respond to the diversity of foreign antigens, that low-dose WBI can be immunostimulatory. Data con-
those antigens being processed by APCs. The major histo- cerning suppressive effects of low doses on tumour growth
compatibility complex, in humans called human leucocyte have been reported. Such data have been obtained after low-
antigen (HLA), plays a fundamental role in the processing of LET radiation exposure, they are dependent on a number of
antigens by APCs and their presentation for recognition by factors and they are very variable. In humans, although a
T-cells via specific receptors. HLA-G is a family of particu- decrease of CD4+ T-lymphocytes, a decrease of HLA-DR+
lar molecules involved in immunotolerance; cells expressing lymphocytes and decrease of the CD4+/CD8+ ratio due to
HLA-G can escape from immune surveillance. an increase in CD8+ are frequently reported, these numeri-
cal findings could not be directly related to a decrease of
447. The effects of ionizing radiation on each component immune function. Some studies regarding people living in
of the immune system (e.g. organs of the immune system, areas with high levels of natural radiation suggest the exist-
cell populations, expression of CDs) have been documented. ence of an adaptive response induced by chronic radiation
Although significant changes occur, the results of the pub- exposure.
lications on these changes are difficult to compare, because
the circumstances and the protocols of exposure to ioniz- 451. In atomic bombing survivors and the residents of
ing radiation (dose, dose rate, quality of radiation, cell type) Techa riverside villages, the haematolymphoid system was
differ considerably. damaged in a dose-dependent manner, although the groups
underwent different types of radiation exposure. Several
448. The data reviewed in this annex indicate that exposure months or even years later, their systems regenerated, and
to ionizing radiation often leads to immunosuppression, haematolymphoid function recovered almost completely.
particularly following high-dose irradiation. Immuno However, even after several decades, with different effects in
suppression is most often ascribed to lymphocytes being the two populations, significant effects have been observed
highly radiosensitive, owing to their proclivity to undergo in the haematolymphoid systems.
167
452. In atomic bombing survivors, long-lasting effects are of these disorders from an immunological viewpoint could
still observed more than a half-century after their radiation therefore provide further insight into the mechanisms
exposure. These effects include an increase in the frequency involved in certain radiation-associated diseases. Radiation-
of somatic mutations and chromosome aberrations in lym- induced perturbation of T-cell homeostasis may have impor-
phocytes, as well as significant changes in lymphoid cell tant implications for human health, not only by reducing the
composition and function. TCR-defective cells could result ability of the immune system to fight against new pathogens
in the impairment of the immune function. Although low fre- but also by compromising the control of recurrent and latent
quencies of somatic mutations or chromosome aberrations infections. Increasing evidence indicates that persistent
would not influence the regeneration or homeostasis of the exposure to infections leads to more rapid senescence of the
immune system, the extensive proliferation of a single cell immune system. An association between non-cancer dis-
bearing a radiation-induced mutation may result in clonal eases and radiation dose has recently emerged among atomic
expansion, particularly in haematopoietic stem cells, com- bombing survivors. This association has led to the hypothe-
mitted lymphoid precursor cells and memory T-lymphocytes. sis that radiation-induced effects on the immune system may
With regard to changes of lymphoid cell composition and account at least in part for this phenomenon, although the
function, the main kinds of damage observed among atomic mechanisms involved remain incompletely understood.
bombing survivors include: impairment of T-cell immunity,
especially owing to a decreased proportion of CD4+ helper, 456. Epidemiological findings suggest that the radiation-
CD4+ naive and CD8+ cytotoxic T-cells; a dose-dependent induced impairment of immunocompetence may increase
increase in the proportion of B-cells and of immunoglobu- the risk of diseases that normally occur in elderly people.
lin production; and impairment of viral immunity and other The data reviewed in this annex reinforce the hypothesis
T-cell functions, such as PHA-dependent proliferation, that ionizing radiation may accelerate immunosenescence
ability to produce IL-2 and alloantigen responses. by perturbing T-cell homeostasis in the same direction that
ageing does. Immunological homeostasis has critical impli-
453. In Techa riverside village populations chroni- cations for human health, for example with respect to the
cally exposed to radiation, long-term immunity changes relationship between the immune system and disease sus-
involved decreased expression of differentiating antigens of ceptibility, and the possible interaction between hereditary
T-lymphocytes, reduced counts of cells involved in natural and environmental factors such as ionizing radiation.
cytotoxicity and signs of immunological imbalance. As in
the atomic bombing survivors, a preferential CD4+ cell defi- 457. A statistically significant doseresponse relationship
ciency was observed many years later in persons affected by has been found for several inflammatory biomarkers in irra-
the Chernobyl accident. Proliferative response to mitogens diated subjects. The persistent inflammatory status induced
was also altered. The dynamics of post-irradiation recovery by ionizing radiation may increase the risks of both cancer
of CD4+ and CD8+ were different, suggesting that radiation and non-cancer diseases. The negative correlation between
may induce damage to the thymus, accelerating the natural plasma levels of inflammatory biomarkers and the percent-
ageing of the immune system by a progressive decline in age of CD4+ helper T-cells in peripheral blood indicates an
thymic function. Both short-term and long-term effects were association between radiation-induced impairment of cell-
detectable in the B- and T-cell function profiles, as well as in mediated immunity and a preclinical inflammatory status that
the synthesis of immunoglobulins, depending on the popula- could further promote the development of various diseases.
tion studied. Some of these changes were dose-dependent
and characterized by phases. The immune system is involved 458. The proportion of CD4+ cells was significantly
in the pathogenesis of the thyroid diseases observed in vic- decreased among atomic bombing survivors with increased
tims of the Chernobyl accident, probably owing to antigenic dose and history of myocardial infarction. It has been sug-
mechanisms leading to autoimmune damage. gested that a diminished immune response against certain
infections implicated in the development of cardiovascular
454. Animal data involving low-dose irradiation rein- diseases could account for this finding. Moreover, inflamma-
forced some of these results, for example the gradual recon- tory biomarkers were significantly elevated in these patients,
stitution of peripheral blood and bone marrow patterns with indicating that inflammatory responses may be playing a
partial deficiency of haematopoietic and lymphopoietic pre- role in the development of cardiovascular diseases, such as
cursors, suggesting that ineffective haematopoiesis could myocardial infarction, in irradiated people.
cause restriction of myeloid and lymphoid cell reserves and
consequent disturbances of cellular and humoral immunity. 459. In order to explain the possible links between
Enhancement of immunity may be observed under certain radiation-induced perturbation of immunological homeo
circumstances, in particular following low-dose irradiation, stasis and human diseases, the Th1/Th2 paradigm has been
and modulation of oxidative status seems to be involved in invoked. Experimental data, further reinforced by human
this effect. data, seem to sustain the hypothesis that ionizing radia-
tion reduces cellular responses controlled by Th1 cells and
455. Recent developments in immunology have contrib- increases humoral responses controlled by Th2 cells by trig-
uted to our understanding of how human diseases may be gering a shift from Th1 towards Th2 (Th1/Th2 imbalance).
related to abnormalities in the immune system. The study Recent findings demonstrated that radiation-dose-dependent
increases observed in irradiated individuals involved not the context of danger signals. Whichever theory is correct,
only Th2-related cytokines but also Th1-related cytokines. ionizing radiation has emerged as an agent capable of dis-
This evidence leads to the postulate that ionizing radiation turbing the ability of the immune system to deal with this
might better be considered an agent that modulates the pro- sort of recognition. As a result of radiation-induced damage,
duction of cytokines towards a pro-inflammatory response the immune system may tolerate what should be destroyed
rather than towards a Th2 response. and, conversely, it may destroy what should be tolerated.
Examples of these two opposing consequences are the
460. Programmed cell death (apoptosis) is essential for diminished ability to mount an immune response against
the development and maintenance of cellular homeostasis of some infections and the development of autoimmune reac-
the immune system. The functional balance of proapoptotic tions as a consequence of radiation exposure, both of which
versus anti-apoptotic influences determines whether a lym- have been demonstrated by experimental and human data.
phocyte will live or die. Multiple molecules, often working
in concert, control serial stages of lymphocyte development 463. Individual genetic susceptibility to ionizing radia-
and homeostasis. Radiation-induced apoptosis is one of the tion has been clearly demonstrated in patients. Some of the
mechanisms by which ionizing radiation alters the homeo molecular and cellular mechanisms that determine sensitivity
stasis of the immune system. to ionizing radiation have been elucidated, most of them rep-
resenting a defect in the response to DNA damage. Research
461. Evaluations of the human health risks associated with on this subject will be relevant, since most of the human
radiation exposure have been based primarily on the assump- genetic disorders involving such defects are also associated
tion that the effects of radiation occur in irradiated cells. with alterations of immune system functioning.
Non-targeted cellular responses to ionizing radiation, such
as bystander effects and genomic instability as well as adap- 464. Finally, the question of how radiation-inducedeffects
tive responses, have also been demonstrated in the immune on the immune system may impact on human health
system, although their implications for human health are remains unanswered. There are many issues that need to be
still poorly understood. These effects, which predominate at more thoroughly investigated before firm conclusions can
the low doses of relevance to radiation protection, need to be reached. Possible future directions for research concern-
be fully characterized; they pose new challenges to evaluating the effects of ionizing radiation on the immune system
ing the risks associated with radiation exposure. In contrast, that should provide new insights about the underlying
local radiotherapy may facilitate the expansion of dendritic mechanisms may include:
cells and the generation of antitumour immune responses
Effects of low-dose and low-dose-rate irradiation
outside the radiation field (abscopal effect).
versus intermediate- and high-dose irradiation;
462. The idea that the immune system functions by dis- Combined effects of ionizing radiation and other
criminating self from non-self has a long history in agents;
immunology. The self/non-self theory proposes that Differential effects of external and/or internal
lymphocytes with reactivity against host constituents are irradiation;
destroyed during development, and only those tolerant lym-
phocytes that are not self reactive are left to engage for- Immunomodulation and cancer;
eign antigens. Although the notion that the immune system Perturbation of T-cell homeostasis;
has evolved to recognize (dangerous) pathogens is not new,
recent discussions have emerged concerning the notion that Immune function and disease development;
antigenicity in the immune system may be seen as a ques- Immunogenetic background and disease suscep-
tion of degree, where self evokes one kind of response tibility;
(tolerance) and foreign evokes another kind of response
(destruction) based not on intrinsic foreignness but rather Immunological ageing and inflammatory response;
on the immune systems recognition of foreign antigens in Effects on the skin immune system.
VII. CONCLUding remarks
465. This annex reviews data related to radiation-induced Lymphocytes are very radiosensitive, and their
alterations of immune response, considers the possible mech- reduction is currently used as an early indica-
anisms involved and reviews epidemiological studies of the tor of the level of an accidental acute exposure.
effects of ionizing radiation on the human immune system. Radiation-induced changes in immune parameters
seem to be more dependent on total dose than on
466. The effects of ionizing radiation on the immune system dose rate. Persisting effects on the immune system
can be assessed by estimating changes in cell numbers or have been observed after exposure to ionizing
by using a variety of functional assays. The impact of such radiation.
alterations in immune response depends on factors such as At low doses and dose rates, the effects of ionizing
the dose of radiation, its temporal relationship with immune radiation on the immune system may be suppres-
system challenge and individual genetic constitution. sive or stimulatory. The long-term impact of low
High doses of radiation produce immunosup- radiation doses on the immune function in relation
pression mainly through the destruction of cells. to human health needs to be further evaluated.
171
Abbreviations
AIDS acquired immunodeficiency syndrome

AIRE autoimmune regulator
AP alkaline phosphatase
APC antigen-presenting cell
ARS acute radiation syndrome
AT ataxia telangiectasia
ATLD ataxia-telangiectasia-like disorder
ATM ataxia-telangiectasia-mutated gene
ATP adenosine triphosphate
BCR B-cell receptor
C constant gene segment
cAMP cyclic adenosine monophosphate
CD cluster of differentiation
CFU colony-forming unit
CFU-F fibroblastoid colony-forming units
CFU-GM granulocytemacrophage colony-forming units
CFU-S stem cell colony-forming units
cGMP cyclic guanosine monophosphate
CH heavy chain constant domain
CL light chain constant domain
Con A concanavalin A
COX-2 cyclooxygenase-2
CRP C-reactive protein
CRS chronic radiation sickness
CS Cockayne syndrome
CTLA-4 cytotoxic T-lymphocyte-associated antigen-4
D diversity
DC dyskeratosis congenita
DNA deoxyribonucleic acid
DNA-PK DNA-dependent protein kinase
DNF dinitrofluorobenzene
DSB double-strand break
DTH delayed type hypersensitivity
ESR erythrocyte sedimentation rate
ETRC Extended Techa River Cohort
FA Fanconi anaemia
Fas/CD95 Fas death receptor
FasL/CD95L ligand for Fas death receptor
GM-CSF granulocytemacrophage colony-stimulating factor
GSH glutathione
Gy gray
HBsAg hepatitis B surface antigen
HBV hepatitis B virus
HD Hodgkins disease
HER2 human epidermal growth factor receptor 2
HETE hydroxyeicosatetraenoic acid
HGPS HutchinsonGilford progeria syndrome
HIV human immunodeficiency virus
HLA human leucocyte antigen
HLNRA high-level natural radiation area
HPRT hypoxanthine-guanine phosphoribosyltransferase
HR homologous recombination
HVC hepatitis C virus
ICE interleukin-converting enzyme
IFN interferon
IFN- interferon gamma
Ig immunoglobulin
IL interleukin
ILT immunoglobulin-like transcript
J joining
JNK Jun N-terminal kinase
KIR killer cell immunoglobulin-like receptor
KLH keyhole limpet haemocyanin
LC Langerhans cell
LD low dose
LDR low dose rate
LET linear energy transfer
LPB lipopolysaccharide-binding protein
LPS lipopolysaccharide
MALT mucosa-associated lymphoid tissue
MAP kinase mitogen-activated protein kinase
MBP mannan-binding protein
MCP-1 monocyte chemoattractant protein 1
MHC major histocompatibility complex
MICA class I MHC chain-related A molecule
MNCA modified neutral comet assay
MP myeloperoxidase
mRNA messenger ribonucleic acid
NBS Nijmegen breakage syndrome
NCR natural cytotoxicity receptor
NER nucleotide excision repair
NHEJ non-homologous end-joining
NK natural killer (cell)
NKG2 lectin-like receptor
NKT lymphocyte with certain characteristics of both T- and NK cells
NPP nuclear power plant
p38 MAP p38 mitogen-activated protein
PAMP pathogen-associated molecular pattern
PCNA proliferating cell nuclear antigen

PGE2 prostaglandin E2
PHA phytohaemagglutinin
PKA protein kinase A
PKC protein kinase C
PLA2 phospholipase 2
PLC phospholipase C
PRRs pattern recognition receptors
RBE relative biological effectiveness
ROS reactive oxygen species
RRD recurrent respiratory disease
RT-PCR reverse transcription polymerase chain reaction
SCID severe combined immune deficiency
SIS skin immune system
SLE systemic lupus erythematosus
SOCS supressor of cytokine signalling gene
STAT proteins signal transducer and activator of transcription proteins
TCR T-cell receptor
TCR transcription-coupled repair
TCR/CD3 T-cell receptor/CD3 complex
TGF- transforming growth factor
Th lymphocyte T-helper
Th1 lymphocyte T-helper subset or subclass 1
Th2 lymphocyte T-helper subset or subclass 2
TLR Toll-like receptor
TLS translesion synthesis
TNF tumour necrosis factor
TNFR tumour necrosis factor receptor
TRAIL tumour-necrosis-factor-related apoptosis-inducing ligand
TRDS Techa River Dosimetry System
Treg T-regulatory cells
TROC Techa River Offspring Cohort
TSH thyroid-stimulating hormone
TTD trichothiodystrophy
UDS unscheduled DNA synthesis
UV ultraviolet
UV-DDB UV-damaged-DNA-binding protein
V variable
VH heavy chain variable domain
VL light chain variable domain
WBI whole-body irradiation
WLM working level month
WS Werners syndrome
XP xeroderma pigmentosum
XP-V xeroderma pigmentosum variant
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ANNEX E
Sources-to-effects assessment for radon in homes and workplaces
Contents
Page
INTRODUCTION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201
I. SOURCES AND LEVELS OF RADON EXPOSURES. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203

A. Outdoors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
B. Indoors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
C. Workplaces. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
D. Measurements of radon and radon decay products. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
II. DOSIMETRY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215

A. Dosimetric models. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
B. Dosimetry of radon and thoron . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
C. Dose conversion factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
D. Uncertainties in dose conversion factors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
E. Exposures in homes and in workplaces other than uranium mines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219
III. EXPERIMENTAL STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221

A. Animal experiments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
B. Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
IV. EPIDEMIOLOGICAL STUDIES OF MINERS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229

A. United States: Colorado Plateau miners . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
2. Radon and radon decay products. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
3. Exposure estimation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232
4. Other hard rock mining exposures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
5. Epidemiological analyses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
6. Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
B. Canada: Ontario uranium miners. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
5. Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242
C. Czechoslovak miners. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242
5. Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247
197
Page
D. Swedish iron ore miners. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247
4. Epidemiological studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
5. Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
E. Canada: Beaverlodge, Saskatchewan, miners. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
5. Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
F. Germany: Wismut miners. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
4. Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265
G. Canada: Port Radium miner study. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266
5. Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268
H. French uranium miners . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
5. Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271
I. Canada: Newfoundland fluorspar miners. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272
5. Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
J. Chinese miners. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
K. Australia: Radium Hill uranium miners. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
L. Overall evaluation of miner studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
V. EPIDEMIOLOGICAL STUDIES OF RESIDENTIAL EXPOSURES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281

A. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281
B. Casecontrol studies of residential radon. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281
C. Ecological studies of residential radon. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285
D. Overall evaluation of residential radon studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287
VI. EFFECTS OF RADON ON organs and tissues other than THE lung. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295
A. Dosimetric considerations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295
B. Epidemiology of cancers other than lung. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297
C. Effects other than cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298
198
Page
VII. Implications for risk assessment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301
A. General studies of exposure uncertainty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301
B. Biologically based models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303
C. Risk projection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305
VIII. Overall Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
APPENDIX . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313
199
INTRODUCTION
1. For many years, the Committee presented its evalua- UNSCEAR 2000 Report [U2]. The Committee is presently
tions of information and data on the Sources and Effects updating its assessments of these sources.
of ionizing radiation separately. These were divided into
two volumes in the UNSCEAR 2000 Report [U2]. During 5. Historically, a wide variety of quantities and units were
its 50th session, in April 2001, the Committee discussed the used to assess radon exposure. AppendixA provides a short
feasibility of preparing documents in an integrated Sources- summary of the historical units used in this report and the
to-Effects approach. This document provides a test case relevant conversion factors. To maintain the integrity of the
for future UNSCEAR Sources-to-Effects assessments. historical data, the original units used in the papers cited in
this annex are preserved. Most historical, and indeed current,
2. Radon is an inert noble gas. Its most common isotope, measurements of radon in mines are in units of working
and the one that is commonly known as radon, is 222Rn, which level (WL) or working level month (WLM). The former is a
arises in the radioactive decay chain of uranium-238. Uranium measure of the potential alpha energy concentration in the air
occurs naturally in varying levels in all rocks and soils. Some and the latter is a measure of exposure for an assumed work-
fraction of the radon produced in rocks and soils escapes to ing month of 170 hours. The unit of WLM is the traditional
the air; therefore radon is present in the atmosphere. Thus, unit used to report exposure to RDPs in studies of miners.
simply by breathing, people everywhere are exposed to radi- The modern quantity for expressing concentration of RDPs
ation from radon itself and also from short-lived radon decay is the equilibrium-equivalent concentration (EEC), which
products (RDPs).1 Moreover, radon is soluble in water, and represents the concentration of 222Rn in equilibrium with
groundwater that passes through uranium-bearing soils and its decay products that would have the same potential alpha
rocks contains radon. When radon-rich groundwater is used energy. To convert from an exposure in WLM, it is necessary
as drinking water, people are exposed both through water to multiply by 6.4 105 (see appendix A) to obtain Bqhm3
consumption and by radon being released from the water to (EEC). Where appropriate, the RDP measurement expressed
the air and being inhaled. as EEC is provided in brackets or is otherwise discussed.
3. Thoron (220Rn) is an isotope of radon, and therefore 6. For many years, radon was recognized as constituting
also an inert noble gas, which arises from the decay chain a hazard to underground miners. However, while it was also
of thorium-232 (232Th). Thorium is a common element in the recognized that domestic exposure to radon might carry a
earths crust and therefore, like radon, thoron is found in air risk, there was no direct evidence of this until recently. The
at varying concentrations. Since radon and thoron are mem- risk from residential exposure to radon and its decay products
bers of different decay chains, the ratio between radon and is of great interest in many countries; thus methods to evalu-
thoron (or between the decay products of radon and thoron) ate exposure to radon and thoron and their decay products
will depend in part on the ratio of uranium to thorium in as well as the subsequent risks from exposure are of great
local soils, rocks or building materials. As discussed in the interest.
UNSCEAR 2000 Report [U2], the radioactive half-lives of
radon and thoron and their respective decay products are 7. In the past, exposures to thoron and its decay products
also very important in determining the exposures of people were often ignored. As will become evident from the discus-
in workplaces and homes. Since thoron has a much shorter sion in section I, it has become increasingly clear that the
half-life (t = 55 s) than radon (t = 3.82 days), the distance exposure to thoron and its decay products cannot be ignored
it can travel before undergoing radioactive decay is very in some environments (both workplace and residential) as it
much shorter than the distance radon can travel in the same contributes to the risks otherwise assigned solely to exposure
medium, and therefore its expression in the environment is to radon and its decay products (e.g. [S41]). In some epide-
quite different from that of radon. miological studies, no distinction is made between exposure
to radon and its decay products and exposure to thoron and
4. Sources of radon and thoron and of potential exposures its decay products. Measurement techniques for discriminat-
to workers and the public are briefly discussed in sectionI. ing between them do, however, exist (e.g. [C21, T12, T14,
A more comprehensive discussion of sources of exposures T15, T16, T17, Z3, Z4]).
to radon and thoron in the workplace is provided in the
8. The use of recent measurements to estimate exposures
1
The term radon is used generically in this report to indicate both radon and its received many years ago, for example in the uranium miner
decay products, the latter in fact contributing most of the dose to lung tissue. studies and in the studies of residential radon exposures,
201
carries particular difficulties. In the case of mining, ore radon were made using casecontrol studies. The results
grade, mining methods, ventilation practices and other of these studies demonstrate an excess risk at the levels of
factors have changed over time. Residential radon studies radon seen in homes and suggest a pattern of increasing risk
experience similar problems in estimating past exposures, with increasing exposure that is generally consistent with the
because of, for example, changes in heating and ventilation experience of epidemiological studies of miners. SectionIV
practices over time. It is thus important to recognize factors discusses the epidemiological studies of miners exposed to
that have a substantial impact on exposure estimates and to radon and sectionV discusses the epidemiological studies of
assess the potential magnitude of these impacts. For exam- residential exposure to radon.
ple, the entry of radon into structures is an important con-
sideration, is well studied and is described in many reports, 13. While an increased risk of lung cancer associated with
including references [U2, U5, U6]. exposure to radon and its decay products is well established
from epidemiological studies of underground miners and
9. To understand how radon exposure estimates can be more recently from residential radon studies, the potential
transferred from one miner population to another, or from risks to tissues and organs other than the lung are also of
conditions in mines to conditions in homes, it is important interest and are the subject of sectionVI.
to understand the differences in dosimetry of exposures in
mines compared with homes. The 1991 National Research 14. There is great interest in predicting future risks to
Council companion report [N10] to the report of the BEIRIV people who are exposed to radon and its decay products
Committee [C19] provides a comprehensive discussion of either in the workplace or in the home. It is necessary to
these differences, as do BEIR VI [C20] and the UNSCEAR understand the limitations of risk projections and how such
2000 Report [U2]. SectionII of this annex provides a concise projections may be affected by consideration of exposures
overview of current issues in radon and thoron dosimetry. to other agents (cigarette smoke being the most important)
in the workplace or in the home. The characteristics and
10. An understanding of the mechanisms for the carcino- limitations of existing models, including biologically based
genicity of radon and its decay products and of how radon models, and a recommended approach to risk projection are
interacts with other agents is important. Much information is the subjects of sectionVII.
available on these topics (e.g. [C20, N11, U2]). Information
from animal experiments and experiments at the cellular and 15. The reliability of estimates of radiation exposures is
subcellular levels relevant to understanding the mechanisms one important factor in assessing the risk of cancer following
of radon carcinogenicity is discussed briefly in sectionIII. radiation exposure. The sources of uncertainty in epidemio-
logical studies and how these uncertainties affect the dose
11. Until recently, the main basis for estimating risks from response analysis [N5] was discussed in the UNSCEAR
residential exposure to radon and its decay products was 2000 Report [U2]. Uncertainties arise in estimating expo-
provided by epidemiological studies of underground miners sures of miners at work, historically reported in WLM, and
that extrapolated the results down to the levels of exposure of people at home, reported in Bqhm3.
seen in homes. Studies of historical miners require retro-
spective estimation of exposure conditions many years in the 16. The sources and characteristics of uncertainty in the
past. Often there are few or even no actual measured expo- exposure of miners are of considerable interest and consti-
sure data from the early years of mining; the results from tute a major focus of this report. The report of the BEIR VI
such studies are less certain because of this and other fac- Committee [C20] discusses this subject at length, as does the
tors. Extrapolation from risks estimated in miner studies to most recent radon report of the National Council on Radia-
residential exposure conditions involves additional assumption Protection and Units (NCRP) [N11], which provides the
tions. For example, such extrapolations must consider the most comprehensive examination to date of the underground
impact of the relatively short exposures at high exposure miner data. There are large difficulties in developing reli-
rates seen in mines compared with the longer exposures at able estimates of underground radon exposure for epidemio-
lower exposure rates in homes. The different dosimetry of logical studies of miners, especially for the pre-1960 miners
exposures in mines and in homes, as well as other factors, [C20, L10]. Studies of miners employed more recently have
must be considered in selecting the most appropriate expo- relatively reliable exposure information (e.g. [H35, S12,
sure (or dose) response model for extrapolation down to S14]). Uncertainties in assessment of exposure are similarly
residential levels. important considerations in residential radon studies (e.g.
[D15, D17, L8]).
12. Consequently, direct estimates of residential risk from
the exposure of the general population are of great interest, 17. Finally, sectionVIII provides an overall summary of
and numerous studies of risk from residential exposure to the main observations from this annex.
I. SOURCES AND LEVELS OF RADON EXPOSURES
18. The majority of the dose to the lung arises from expo- thoron in Japan. At night and in the early morning hours,
sure to the short-lived decay products of radon and thoron. atmospheric (temperature) inversion conditions are often
Concentrations of the potential alpha energy of these short- found; these tend to trap the radon closer to the ground. This
lived decay products are estimated by considering the state means that outdoor radon concentrations can vary diurnally
of equilibrium between the parent nuclides and their respec- by a factor of as much as 10. Seasonal variations, related
tive decay products. In practice, an equilibrium factor Feq is to the effects of precipitation or to changes in prevailing
used to characterize the state of equilibrium. The equilib- winds, also exist [U2]. An evaluation of exposure to outdoor
rium factor Feq is defined as the ratio of the actual potential concentrations of radon in Iowa and Minnesota [S40] in the
alpha energy concentration (PAEC) to the PAEC that would United States concluded that outdoor exposure to radon in
prevail if all the decay products in each series were in equi- some areas can be a substantial fraction of an individuals
librium with the parent radon or thoron, as the case may exposure to radiation and moreover is highly variable across
be. However, as discussed in reference [U2], it is simpler the population. Outdoor levels of radon provide a baseline
to evaluate this factor in terms of an equilibrium-equivalent for indoor levels of radon. In tropical climates, indoor and
radon or thoron concentration. outdoor concentrations are essentially the same because of
rapid exchange between indoor and outdoor air [C43].
19. The Committee customarily reports concentrations
of radon or thoron (and also the lung dose) in terms of 22. The UNSCEAR 2000 Report [U2] suggests that typi-
equilibrium-equivalent concentration (EEC). This is defined cal outdoor levels of radon and thoron gas are each of the
as the equivalent concentration of the decay products in order of 10Bq/m3. There is, however, a wide range of long-
equilibrium with the parent gas that yields the same potential term average concentrations of radon, from approximately
alpha energy per unit volume as the existing mixture. 1 Bq/m3 to more than 100 Bq/m3, with lower levels typi-
cal of isolated small islands or coastal regions and higher
EEC(222Rn) = 0.105 (218Po) + 0.516 (214Pb) + 0.379 (214Bi)
levels typical of sites with high radon exhalation over large
EEC(220Rn) = 0.91 (212Pb) + 0.087 (212Bi)
surrounding areas. Although data are relatively sparse for
where 218Po, 214Pb, etc., and EECs are in Bq/m3. Older pub- thoron, considerable variability from place to place would be
lications often report activity in curies (Ci). The Appendix expected because of thorons short half-life, which amplifies
presents relevant conversion factors. the effect of local variations in exhalation rate. Thoron decay
products were measured continuously outdoors in suburban
20. Radon and thoron are ubiquitous in the air at ground New Jersey, United States, for a 2-year period [H20]. The
level and are significant contributors to the average dose from average outdoor concentration of 212Pb was 0.09Bq/m3 and
natural background sources of radiation [U2]. In homes, in the variability over seasons was a factor of2. Bismuth-212
underground mines and in other situations where radon (and was not detectable. The average outdoor concentration of
thoron) may be present and where ventilation may be lim- thoron gas was 15Bq/m3, yielding a value of 0.005 for the
ited, the levels of these radionuclides and their decay prod- equilibrium factor outdoors [C21].
ucts can accumulate to high levels. Soils and rocks are often
the main sources of radon. In unsaturated soils or rocks,
radon moves with air through pores and fractures. In satu- B. Indoors
rated zones, radon moves with groundwater to underground
openings, such as mines and caves, and to buildings [N9]. 23. In buildings with high radon levels, the main mechanism
for entry of radon is pressure-driven flow of soil gas through
cracks in the floor. This arises because the air inside buildings
A. Outdoors is normally at a slightly lower pressure than the air outdoors.
This underpressure is the consequence of the air inside the
21. Concentrations of radon in the outdoor environment are building being warmer than that outside. In temperate zones
affected not only by the magnitude of the release rate from especially, this causes a convective flow (chimney effect),
the ground to the atmosphere but also by atmospheric mix- which, together with the effect of the wind blowing over chim-
ing phenomena. Solar heating during the daytime induces neys and other openings (Venturi effect), draws soil gas and
turbulence, so radon is more readily transported upwards and hence radon into the building. However, in addition to pressure
away from the ground. Doi and Kobayashi [D18] provide differences, other factors, including relative humidity and soil
information on the vertical distribution of outdoor radon and moisture, can also influence radon levels in buildings [S66].
203
24. While most building materials produce some radon, product levels in high-radon regions showed a mean thoron
certain materials can act as significant sources of indoor decay product level of about 0.6Bq/m3, though the national
radon. Such materials have a combination of elevated levels average was estimated to be 0.3Bq/m3 [W14]. Subsequently,
of 226Ra (the radioactive parent of radon) and a porosity that more than 400,000 measurements were made throughout the
allows the radon gas to escape. Examples are lightweight United Kingdom aimed at identifying dwellings with elevated
concrete with alum shale, phosphogypsum and Italian tuff. radon levels; this information is available for England and
Wales [G10], Scotland [G11] and Northern Ireland [G12].
25. Groundwater, particularly in granitic areas, can have
high levels of radon. Workplaces such as laundries and res- 29. A nationwide indoor radon survey carried out since
taurant kitchens can have high radon levels from the use of 1982 in France has updated estimates of the population
such water. Because municipal water supplies are often from exposure [B38]. Indoor radon measurements were per-
rain catchment surface reservoirs, radon levels in public formed using passive dosimeters left in place for 2 months
water supplies are normally not high, and any problems are in the main room. A questionnaire was completed regard-
normally limited to wells in geological formations containing housing characteristics. In total, the survey included
ing naturally elevated levels of uranium. In the United States, 12,261 radon measurements distributed over the whole
groundwater supplies were reported to contain radon at levels country. Corrections for seasonal variations [B36] and
of as high as 106Bq/m3 or more [N9]. In Germany, treatment housing characteristics were applied. The crude average of
and distribution workplaces for groundwater supplies also indoor radon concentrations was 89 Bq/m3, and the aver-
were found to contain elevated radon concentrations in air, age corrected for season and housing characteristics was
with up to several hundred thousand becquerels per cubic 83 Bq/m3 (the range over French districts was 19 to
metre [U2]. 297Bq/m3). Weighting by district population density yielded
a national average of about 63Bq/m3.
26. There is a considerable amount of data available on
radon concentrations in indoor air, and new information is 30. Bochicchio et al. [B40] report a national radon survey
becoming increasingly available on thoron concentrations of some 5,631 dwellings distributed in 232 towns across
indoors. Substantial compilations of radon measurements Italy. The authors report a national population-weighted
appeared in the UNSCEAR 2000, 1993 and 1988 Reports average of 70Bq/m3 and a geometric mean and geometric
[U2, U5, U6]. On the basis of current data, the UNSCEAR standard deviation of 52 Bq/m3 and 2.1, respectively. The
2000 Report [U2] deduced values of 40 and 30Bq/m3 for the authors also report seasonal differences. On a national scale,
arithmetic and geometric means of indoor radon gas con- over the 21 regions studied, the authors report a winter radon
centrations worldwide, with a geometric standard deviation to summer radon ratio with a geometric mean and standard
of 2.3. On the basis of the information collected for the deviation of 1.23 and 1.71, respectively.
present report, these values are still appropriate.
31. European Union (EU) efforts to develop a radon map
27. Published literature provides additional insight into the of European countries are under way as part of an EU project
sources and levels of radon and thoron. Examples include to develop a European atlas of natural radioactivity [D20].
publications on the assessment of radon in drinking water
[N9, T22] and numerous papers on residential radon levels 32. A major survey of radon concentrations in United States
in Iowa, United States [F3, S40], Italy [B15, F4, P6], Poland homes measured radon levels in homes in 125 counties in
[Z9], the former Yugoslavia [Z2], China [W13, W16], the 50 states with the results shown in figureI (after reference
Isle of Man [G6] and the Republic of Korea [C33], among [M1]). Approximately 6.1% of the homes surveyed exceeded
others. The influence of groundwater on radon concentra- the United States Environmental Protection Agency (EPA)
tions in drinking water and subsequently on residential radon action level of 148 Bq/m3 (4 pCi/L). This study indicated
levels in air from the use of potable water indoors was also that the distribution of radon concentrations in homes could
investigated in radon-prone areas of Japan [K27, I6, N17]. be reasonably described by a log-normal distribution. The
overall geometric mean (median) of the radon concentration
28. A great deal of information is available from radon data was 25Bq/m3 with a geometric standard deviation of
measurements in homes in the United Kingdom. A national about 3.1.
survey carried out in the early 1980s provided results of
gamma ray dose rate and radon concentration measure- 33. Information on radon levels in Latin American coun-
ments in more than 2,000 dwellings selected systematically tries is also becoming available (e.g. [C41, M41, S65]).
according to postal codes [W14]. The mean radon level According to reference [C41], most indoor radon levels in
from the survey, after adjustment for dwelling types, was Latin America are below 100Bq/m3. However, levels can
20.5Bq/m3. The same study also reported data from studies be quite variable in different regions within a country, as
carried out in regions of the United Kingdom with elevated evidenced by data for 17 states in Mexico, which report
uranium mineralization. The regional surveys showed aver- mean radon levels across the 17 states surveyed ranging
age radon levels of up to 300Bq/m3 for areas of south-west from less than 40 Bq/m3 to near 200 Bq/m3. The overall
England, which are about 15 times the national average. mean value reported across the 17 states surveyed was
In addition, simultaneous measurements of thoron decay 111.6Bq/m3.
ANNEX E: SOURCES-TO-EFFECTS ASSESSMENT FOR RADON IN HOMES AND WORKPLACES 205
Figure I. Distribution of indoor radon levels in homes in the 36. In the 1980s and 1990s, two nationwide surveys [R12,
United States (after reference [M1]). W21] of indoor radon decay products were performed
in China using various grab sampling measurements
1 000 (e.g. scintillation cell method and two filter methods) or
short-term measurements (24 days of activated charcoal
adsorption). The arithmetic mean (AM) of the indoor radon
concentration was 24Bq/m3 and the geometric mean (GM)
EPA* (148 Bq/m, 4 pCi/L)
was 21 Bq/m3 [U2]. Since 1996, Chinas housing situa-
100 tion has greatly changed. A new survey of indoor radon
Mean (46 Bq/m, 1.25 pCi/L) in 26cities and regions during 2001 and 2005 used alpha
track detection (exposure period of 36 months) [S67]. The
RADON CONCENTRATION (Bq/m)
Median (25 Bq/m) AM of indoor radon concentration was 43.8 37.7 Bq/m3
and the GM was 34.4 1.95 Bq/m3, with the median of the
concentration at 32.9Bq/m3. These results are significantly
10 higher than those of previous surveys. The radon concen-
tration in some high-rise buildings exceeds the national
action level of 400Bq/m3.
LEGEND:
All housing units
37. Traditional soil-brick and mud-wall structure houses
Single-family housing units are still popular in the countryside of China. At least 100mil-
1
Multifamily housing units lion people are currently living in such houses. Surveys of
NOTE:
thoron and its decay products in Chinese traditional soil
* EPAs recommended remedial
structure houses have been conducted. Fan et al. observed
action level for indoor radon a thoron EEC of 4.0Bq/m3 (n = 56) in 1991 in Shaanxi soil
houses [F20]. More recently a survey using improved alpha
0.1 track monitors was completed in Guangdong, Gansu, Yun-
1 2 5 10 20 30 40 50 60 70 80 90 95 98 99 nan, Xinjiang, and Guizhou provinces: thoron and its decay
product concentrations (AM) were 318Bq/m3 and 3.8Bq/m3
CUMULATIVE PROBABILITY (%) (n = 148, maximum value 15.8Bq/m3), respectively [S68].
Applying a dose conversion factor of 40nSv/(Bqhm3), the
average annual effective dose from inhalation of 220Rn was
34. A study of indoor and outdoor radon levels in Brazil estimated to be in the range 1.14.4mSv. The dose contribu-
reported that a variability in radon levels of about 50% in a tion from thoron is obviously significant in this situation.
single day could be measured on an hourly basis, with the
highest values in the morning and the lowest values in the 38. Surveys of radon and thoron decay products were
afternoon. The authors also reported a seasonal variability of carried out in Fujian province in China, where the natural
two orders of magnitude in outdoor levels, with the highest levels of 238U and 232Th in soil are elevated (about 53.4Bqkg
levels in the dry winter season and the lowest levels in the and 116.8 Bq/kg, respectively) [Z5]. Radon and thoron
wet summer months [M41]. The mean indoor radon concen- decay products were measured in homes and various other
tration within the urban area of Rio de Janeiro is 40Bq/m3, locations, including outdoors, in mineral processing plants,
while the indoor radon concentrations within urban and rural underground and in railway tunnels. The average radon and
areas in Poos de Caldas are 61 and 204Bq/m3, respectively thoron decay product concentrations (expressed as EEC)
[M41]. measured in 204 dwellings were 12.9Bq/m3 and 0.87Bq/m3,
respectively. The mean outdoor level of radon decay product
35. Several Japanese studies, including two nationwide concentrations (expressed as EEC) derived from measure-
indoor radon surveys, showed significant differences [F14, ments made at 180 locations was 9.69Bq/m3. The authors
F15, S64]. The first survey of more than 7,000 dwellings, also assessed potential exposure of people living in Fujian
using passive radon detection, reported a mean radon con- province, and concluded that thoron (and decay products)
centration of 20.8Bq/m3 [F14]. To investigate potential con- contributed about 20% of the estimated effective dose of
founding by thoron, a survey of 900 dwellings used a detector 1.28mSv/a from radon and thoron combined.
that could discriminate between radon and thoron. The mean
radon concentration from the second survey was 15.5Bq/m3 39. Measurements of outdoor (1,100 samples) and indoor
[T12]. The authors noted a gradient in thoron concentration (1,050 samples) levels of radon and thoron decay products
in the homes, the concentration decreasing by nearly a factor were made at a university campus in northeastern Japan over
of 2 with increasing distance, up to about 1.5m, from walls a period of 4 years [K20]. The authors analysed the data
made of soil. Radon concentrations are reported as generally using a variety of statistical methods. A seasonal variation
homogeneous in rooms, except for places near the inlet and was observed, with higher radon concentrations for autumn
outlet of indoor airflow [Z8]. This result should be consid- and winter, both outdoors and indoors. A seasonal variation
ered when choosing locations for detection. of thoron levels was not as clear.
40. Shang et al. [S67] report the results of a countrywide determined. In most cases, the individual activities are not
survey of 3,098 homes in China carried out with alpha track directly measured. Thus the exposure rate must be indirectly
detectors between 2001 and 2005 by the Chinese National determined using assumptions on concentration ratios, i.e.
Institute for Radiological Protection. Measurement sites were equilibrium factors, which lead to the determination of the
statistically distributed in the municipalities (Beijing, Shang- EEC. The environmental factors that influence concentration
hai and Tinjing) and 15 provinces, using a sampling rate of ratios in each of the radioactive series are of great significance
0.09 in 10,000 houses across the country. The authors report for assessments of both exposure and dose [M33, U2].
an arithmetic annual average radon concentration of 43.8 +
37.7 Bq/m3 and a geometric mean of 34.4 + 2.0Bq/m3, and 44. Many measurements of RDPs have been reported.
note that about 6.4% of the measured houses had levels of These suggest that a rounded value for the equilibrium factor
above 100Bq/m3, although only 0.7% were above 200Bq/m3. of 0.6 may be appropriate for the outdoor environment [U2].
The authors also report that in dwellings made of soil or mud, Ramachandran and Subba Ramu [R6] reported variations
exposure from thoron may be significant, and that a study of in indoor equilibrium factors. The UNSCEAR 2000 Report
thoron has been designed. also noted that there is a wide range of values from indi-
vidual measurements. This is understandable given the many
41. Additional data on indoor levels of thoron in Europe environmental factors, including exhalation rates and atmos-
and Asia are also reported in reference [S41], which notes pheric stability conditions, that influence the various activity
that the doses from thoron and its short-lived decay prod- ratios. The range of the equilibrium factor for outdoor radon
ucts can be comparable to, or even larger than, the dose is from 0.2 to 1.0, indicating a high degree of uncertainty in
from radon and its short-lived decay products. Others also the application of a typical value to derive EECs [U2].
reported data on thoron and thoron decay products for some
areas of East Asia (e.g. [T21, Z5]). 45. Measurements of both thoron and radon gas using
passive alpha track detectors have been reported (e.g. [B16,
42. It was not practical to calculate lung dose directly D11, G13, I8, I9, L37]). Measurements were obtained over a
from thoron gas measurements because the equilibrium 2-year period for both thoron gas and its 212Pb decay product
factor (Feq) between the gas and decay products was not in four locations three indoors and one suburban outdoor
well established. Past dose estimates for thoron were made location [C22, H20, H21]. Tokonami et al. [T48] provide
mainly from filtered air measurements of the thoron decay information on the contribution from thoron for several
product 212Pb. However, much work on methods of meas- radon detectors. The authors also provide a comparison of
uring radon and thoron and their decay products was car- small indoor surveys in the Gunna prefecture in Japan and
ried out in Japan (e.g. [T12, T13, T14, T15, T16, T17, T18, in Kovagoszlos, Hungary. The average radon/thoron ratio
T19, T20, T34, T41, Z3]). A Japanese study [I15] observed from the Japanese survey was 1.3, compared with a mean
that it was important to consider the influence of thoron on of 4.5 in the Hungarian survey. The authors concluded that
the measurement of RDPs. A great deal of work was also measurements without discrimination of radon isotopes
carried out in Japan concerning the measurement of radon have the potential to affect risk estimates. Sugino, Tokonami
and thoron and their decay products, including passive and and Zhuo [S70] report radon and thoron concentrations in
continuous systems, and the measurement of various factors offices and dwellings of the Gunna prefecture. The average
(e.g. Feq and the fraction fp of decay products attached to par- radon concentrations in offices were about 29Bq/m3, higher
ticulates) which are important in assessing lung dose [K28, than the 17Bq/m3 reported for dwellings. As for reference
T42, T43, T44, T45, T46, T47, T48). Shang et al. also inves- [T48], the mean ratio of thoron and radon was estimated as
tigated the effect of thoron on the measurement of RDPs in approximately 1.3.
Chinese cave dwellings [S69]. Since thoron will be present
in many homes, if a detector is used that responds to thoron 46. The UNSCEAR 2000 Report [U2] assumed average
and radon without distinguishing between them, the contri- equilibrium factors obtained from 212Pb/220Rn ratios of 0.003
bution from thoron will be attributed to radon. For example, outdoors and 0.02 indoors to derive estimates of a dose
in testing the sensitivity of one thoron monitor, the average conversion factor for thoron EEC and recommended a value
thoron level in 20homes in southern India was 168Bq/m3 of 40nSv/(Bqhm3) for dose estimation.
[Z3]. More detailed information on the average thoron levels
in these homes is provided in reference [T33]. 47. Determinations of the equilibrium factor for radon
indoors generally confirm the typical value of 0.4 previously
43. Evaluation of exposure to radon and thoron and their assessed by the Committee [U5, U6]. While indoor measure-
decay products thus must take account of the actual activity ments show a range from 0.1 to 0.9, most are within 30% of
concentrations of the various alpha-emitting radionuclides the typical value of 0.4 [H22, R6]. A study [H22] in seven
from the two series in the air that is inhaled. As noted previ- North American houses showed that the equilibrium factor
ously, the total alpha particle energy yet to be released by varies significantly with time, typically by a few tens of per
the decay of inhaled radon or thoron is reported in terms of cent. Measurements were carried out over a 4-year period to
potential alpha energy concentration (PAEC), with units of gain an understanding of the characteristics of radon and its
either J/m3 or WL (working level). This quantity can be cal- decay products in air-conditioned office buildings in Tokyo,
culated once the activities of the individual radionuclides are Japan. The equilibrium factor was evaluated during working
hours and over the whole day in this survey; there was little 51. Table 1 provides a summary of concentrations of
difference between the two conditions. These values were radon in indoor air determined from surveys. Many of the
within 30% of the assumed typical value of 0.4 [T34]. data in table1 are from annex B of the UNSCEAR 2000
Although the measurement of radon gas concentration may Report [U2]. Data carried forward from reference [U2] are
be a surrogate for direct measurement of the decay product indicated as such. Original sources of data in [U2] are from
concentration in the determination of exposure, EECs or UNSCEAR surveys of Natural Radiation Exposure and
PAECs estimated using this assumed typical value may be in literature as cited in [U2]. Since the publication of [U2],
error, frequently by several tens of per cent, though rarely by the Committee has carried out three surveys of the natural
as much as a factor of2. radiation environment, in 2001, 2004 and 2006. Summary
results from these surveys are provided in table1. Not sur-
48. More caution should be exercised in assuming the prisingly, many of the indoor radon data were collected for
average values of the equilibrium factor for dose assess- areas or regions where indoor radon levels were thought
ment from inhalation of thoron decay products. An objection to be elevated. Thus, where the survey results provided to
to the use of thoron gas measurements for dosimetric pur- the Committee make such a judgement possible, a note is
poses is that thoron may not be well mixed in the indoor air given in the last column of table1 indicating whether the
because of its short half-life. As indicated previously, some data provided in the table may be considered as some form
data indicate that indoor thoron concentrations vary with the of national average or whether they are more indicative of
distance from walls and floors [Z8]. In many samples, the a regional or local area of elevated levels. In some instances
thoron concentrations in the centre of the room or more than the national authorities provided this judgement, while in
1m from the surface of building material containing 224Ra others the judgements were made by the Committee. In all
were as low as in outdoor air, while the thoron concentra- instances, precedence was given to data provided to the
tion near the surface of the building material was more than Committee, as opposed to literature values. The data in
10times that in the centre of the room. Only where a room table1 show considerable variability both within countries
fan is used would thoron be well mixed and a large varia- and from country to country, with, for example, reported
tion of the thoron concentration in the room not be found nominal geometric mean indoor levels ranging from
[M40]. <10Bq/m3 in Egypt and Cuba, to more than 100Bq/m3 in a
number of European countries, and to above 600Bq/m3 in
49. Equilibrium factors for estimating 220Rn EEC parts of the Islamic Republic of Iran.
are given above as single values. Because of the large
spatial variations in thoron concentrations in a room, 52. The UNSCEAR 2000 Report [U2] gives worldwide
these single values should be regarded as being subject arithmetic mean values of 46 Bq/m3 (unweighted) and
to large uncertainties. Thus the use of an equilibrium 39Bq/m3 (population-weighted). Worldwide geometric mean
factor for thoron should be limited to situations where values of 37Bq/m3 (unweighted) and 30Bq/m3 (population-
large spatial variation is not found. On the basis of the weighted) with corresponding geometric standard duration
results of simultaneous measurements of thoron concen- of 2.2 (unweighted) and 2.3 (population weighted) are also
tration and thoron EEC by long-term passive methods, presented in [U2]. Given the wide variety and disparity of
Yonehara et al. were unable to find a good correlation data currently available, no attempt was made to update the
between thoron concentration and the EEC [Y9]. How- nominal values from [U2], and the values provided in [U2]
ever, Yamada et al. were able to find good agreement in a are retained for the purposes of this report.
study of 265 cave dwellings [Y10].
53. The UNSCEAR 2000 Report [U2] gives an annual
50. Although only a limited number of measurements per caput dose estimated at 1.15 mSv from exposure to
of thoron in indoor air are available, several investigations natural sources of radon. This value is still appropriate.
reported both radon and thoron EECs. While acknowledging The UNSCEAR 2000 Report also gives an annual dose of
the uncertainty noted earlier, this allows some generaliza- 0.1 mSv from natural sources of thoron [U2]. While this
tions to be made from the derived ratios of the radon and value is still reasonable, data collected for the present study
thoron EECs. On the basis of the physical characteristics of indicate that the levels of thoron (and hence doses from
radon and thoron, model entry rates to buildings and a venti- exposure to thoron and its decay products) are highly vari-
lation rate of 0.7 h1, the International Commission on Radio- able and that thoron may provide a larger contribution to
logical Protection (ICRP) estimated expected concentrations natural background dose than previously thought. Doses
in buildings [I5], which in terms of EEC are 250Bq/m3 for from radon and thoron represent approximately half of
radon and 0.042 Bq/m3 (mean = 0.5Bq/m3) for thoron. This the estimated dose from exposure to all natural sources of
corresponds to a thoron/radon EEC ratio of 0.03 [U2]. ionizing radiation.
Table 1 Concentrations of radon in indoor air
Region/country Population Indoor radon (222Rn) (Bq/m3) Notes

(10 6)
Arithmetic Geometric Maximum Geometric
mean mean value standard deviation
Africa
Algeria [U2] 28.78 30 140
Egypt [U2] 63.27 9 24
Ghana [U2] 17.83 340
North America
Canada [U2] 29.68 34 14 1720 3.6
Canada [L47] 32.27 28.35 11.2 1720 3.9
Mexico 107.03 140 90 1193 [M39]
United States [U2] 269.4 46 25 3.1 National survey [M1, U18]
South America
Argentina 38.75 35 25 211 2 Countrywide averagee
Brazil 186.40 81.95 310.0 [C41]
Chile [U2] 14.42 25 86
Cuba 11.20 7.7 5.2 15.3 3.3 Countrywide averagef
Ecuador 200 [Z11]
Paraguay [U2] 4.96 28 51
Peru 27.97 32.29 50.20 [C41]
Venezuela 26.75 52.50 346 [C41]
East Asia
China 1315.84 43.8 34.4 596 National average based on

sampling 3098 dwellings [S67]
China [U2] 1 232 24 20 380 2.2
Hong Kong SAR 6.19 41 140

[U2]
Taiwan 22.89 10.0 8.5 63.5 0.6 Countrywide averagef
India [U2] 944.6 57 42 210 2.2
Indonesia 213.67 35.1 35.1 165 1.2 Countrywide averagee
Japan [U2] 125.4 16 13 310 1.8
Kazakhstan 14.83 5000 Countrywide averagee
Republic of Korea 48.85 53.4 43.3 1350 1.8 Countrywide averagee
Malaysia [U2] 20.58 14 20
Pakistan [U2] 140.0 30 83
Philippines 75.90 23 22 62 1.13 Countrywide averagee
Philippines 76.57 23 23 62 6 Countrywide averageg
Russian Federation 5060 [Z11]
Thailand [U2] 58.7 23 16 480 1.2


(10 6)
West Asia
Armenia [U2] 3.64 104 216 1.3
Islamic Republic 63.76 82 3070 Countrywide average

of Iran
Islamic Republic 795 2745 31000 High-background areas

of Iran
Islamic Republic 600 1000 High-background areas

of Iran
Kuwait 1.69 [U2] 14 [U2] 10.6 119.2 0.74 Countrywide average
Palestine (Gaza) [Y7] 0.95 34 105
Saudi Arabia [A25] 16 36
Syrian Arab Republic 14.57 44 520

[U2]
North Europe
Denmark 5.2 59a 39a 1200 2.2 Countrywide average
Estonia [U2] 1.47 120 92 1390
Finland 5.2 120 84 20000d 2.1 Countrywide average
Iceland 0.3 10 26 Countrywide averageg
Lithuania 3.73 49 38 1900 Countrywide average
Lithuania 3.49 55 36.5 636 Countrywide average
Norway [U2] 4.35 73 40 50000
Sweden 8.88 108 56 84000 Countrywide average
West Europe
Austria [U2] 8.11 15 190
Belgium 10.22 48 38 12000 2 Countrywide average
France [U2] 58.33 62 41 4690 2.7
89.3 53.5 4964 Population-weighted mean of

63Bq/m3 based on 12,261
measurements in dwellings
Germany [U2] 81.92 50 40 >10000 1.9 Countrywide average
Ireland 3.84 89 57 7000 2.4 Countrywide average
Liechtenstein 0.03 80 1098 e
Luxembourg 0.22 110 70 2500 2.0 Countrywide average
Netherlands [U2] 15.58 23 18 380 1.6
Switzerland 6.71 75 41 10000 Countrywide average
Switzerland 142b 81b 15000b 2.6b Countrywide average

73c 59c 15000c 1.8c
United Kingdom [U2] 58.14 20 14 17000 3.2 [C26]
England [G10] 90 50 Average (20Bq/m3) population-

weighted average
Wales [G10] 84 48

(10 6)
East Europe
Belarus 31.8 221 Countrywide average
Bulgaria 8.10 22 250 2.1 Countrywide average
Czech Republic 118 94.4 70000 1.84 Countrywide average
442 20000 High-background area
Hungary [U2] 10.05 107 82 1990 2.7
Poland 38.12 49.1 1300 Countrywide averagee
Poland 38.17 49 31 3260 2.3 Countrywide averageg
Romania 22.55 25.0 564 Countrywide averagee
Slovakia [U2] 5.35 87 3750
South Europe
Albania [U2] 3.40 120 105 270 2.0
Croatia [U2] 4.50 35 32 92
Cyprus [U2] 0.76 7 7 78 2.6
Greece [U2] 10.49 73 52 490
Greece 55 44 1700 2.4 Countrywide averageg
Italy [U2] 57.23 75 57 1040 2.0
Italy 57.3 70 52 1036 2.1 Countrywide averageg
Montenegro 0.60 184 110 1128 2.74 Countrywide averagee

(Yugoslavia)
Portugal [U2] 9.81 62 45 2700 2.2
Slovenia [U2] 1.92 87 60 1330 2.2
Spain 36.72 90.38 45.69 15400 Countrywide averagee
Spain 0.001 748.5 242.64 15400 High-background arease
Spain 40.84 90.4 45.7 15400 2.9 Countrywide averageg
Spain 0.02 610.0 1400.0 High-background areasg
Oceania
Australia [U2] 18.06 11 8 420 2.1
New Zealand 3.81 21.5 19.5 80 Countrywide averagee
a Population-weighted average. e Data from UNSCEAR Global Survey on Exposures to Natural Radiation Sources
b Upper value, unweighted data. (2001-2006), submitted in 2001.
c Lower value, data weighted for floor dependence, population distribution, error f Ibid., submitted in 2004.
of exposition and mobility. g Ibid., submitted in 2006.
d Annual mean.
C. Workplaces workers involved in the nuclear fuel cycle, radon exposure

from mining and milling is a relatively important contributor
54. The spectrum of workplaces other than mines where to the per caput dose.
radon can present a hazard is large. While it includes below-
ground workplaces such as subways, tunnels, underground 58. The total number of workers exposed to human-made
parking, stores, caves, spas and closed-out mines open to sources and enhanced natural sources was given in the
visitors, the majority of such workplaces, such as factories, UNSCEAR 2000 Report [U2] as 11.1 million. Approximately
shops, schools and offices, will be above ground. 4.6 million workers were exposed to human-made sources
at an annual average (effective) dose of about 0.6 mSv.
55. Other workplaces where large quantities of materi- Some 6.5 million workers were exposed to enhanced natural
als with elevated radium concentrations are stored or pro sources at an annual average dose of about 1.8mSv, of which
cessed, for example phosphate fertilizer production [R11] or approximately half was from radon. The estimate for radon
monazite sand mining, can similarly exhibit elevated radon in above-ground workplaces (for example in the phosphate
and thoron levels [A30, C42]. One study [S71] reporting on industry) is still considered to be crude.
radon and thoron concentrations in the monazite production
area of a rare earth facility in Kerala, India, found radon 59. In the case of occupational exposure, there are
levels to be below the detection level of about 1.7Bq/m3 (see several situations where workers who have the highest
reference [S72] for discussion of monitoring techniques), radiation doses receive a significant contribution from
but the c orresponding thoron levels were 5.9kBq/m3. radon. These include the situations listed in table2 (from
reference [U2]). For workers involved in nuclear power
56. Underground workplaces, including mines other than production, those involved in the mining of uranium typi-
uranium mines, especially coal mines (e.g. [B17, J8, S43, cally receive the highest collective doses; a significant part
U16, V5]), can accumulate high radon levels in the same of that exposure is from radon inhalation. The group of
way as natural caves or abandoned mines. High radon levels workers in the category of above-ground workplaces (see
in underground workplaces will not be limited to only those table2) are the second largest group identified in annex B
areas where elevated levels were found in above-ground of the UNSCEAR 2000 Report [U2]. These workers were
workplaces. The experience of the Newfoundland fluorspar estimated to receive an average annual effective dose of
miners illustrates this. The levels of 226Ra in the host rock 4.8mSv. This is the largest average annual dose received by
were low, but the miners were exposed to elevated levels of any type of worker and was due entirely to radon. Accord-
radon and short-lived decay products arising from radon in ing to the UNSCEAR 2000 Report [U2], radon inhalation
the groundwater, which entered the mine and subsequently is also a significant contributor to the doses to the other
the mine atmosphere (e.g. [A14, M16, M17]). categories of workers in table2. While information to fully
update table2 is not available, a paper by Liu et al. [L46]
57. Exposure to environmental sources of radon from indicates that there are about 6 million miners in Chinese
mining and mineral processing is common, and the inha- coal mines alone, which nearly doubles the number of coal
lation of RDPs can be a significant exposure pathway. For miners reported in reference [U2].
Table 2 Situations where doses from radon are significant [U2]
Source/practice Number of monitored workers Average annual effective dose (mSv)
Nuclear fuel cycle (including uranium mining) 800000 1.8
Mining (other than coal and excluding uranium mining) 760000 2.7
Coal mininga 3910000 0.7
Mineral processing 300000 1.0
Above-ground workplaces (radon) 1250000 4.8
a See paragraph 59.
D. Measurements of radon and radon decay products exposure arising from the decay products of thoron (220Rn) is
also of increasing interest. Traditionally, the potential alpha
60. It is well established that the inhalation of the short- decay energy per litre of air (referred to in units of working
lived decay products of radon (222Rn) and their subsequent level month (WLM)) was the measure of exposure to RDPs
deposition along the walls of the various airways of the bron- used in evaluations of exposures in mines. Miner epidemio-
chial tree are the main pathways of radiation exposure of the logical studies use data based on measurements of this type.
lungs [U2]. As discussed elsewhere in this report, the lung Later, time-integrated radon measurement techniques were
developed and are the method of choice for modern studies of WL in one or more areas of a mine (combined with an
of residential radon. The discussions of each miner cohort evaluation of the hours worked in the same location).
(section IV) or residential casecontrol (sectionV) epide- According to reference [L13], the first radon gas measure-
miological study include a brief description of the methods ments in United States mines were in 1949, and the first
used for measuring radon and its decay products; in addition, RDP measurements were in 1951. In 1973, the American
a few general comments are provided below. Further infor- National Standards Institute (ANSI) published a consensus
mation is available in published reports (e.g. NCRP Report standard for radiation protection in uranium mines in the
No. 97 [N15]). United States [A22]. According to this standard, a moni-
toring system for RDPs must be capable of measuring the
61. Various techniques were used in the past to assess resi- annual accumulated exposure in WLM within an uncertainty
dential radon exposure, including: instantaneous grab samples interval of 50% at the 95% confidence level. To satisfy the
and subsequent analysis in a scintillation cell; accumulation ANSI criterion, uranium mining companies in the United
on a charcoal absorber with subsequent gamma spectroscopy; States adopted a procedure based on periodic measurements
various solid state detectors; and a variety of other techniques, of the air concentration of RDPs. All of the measurement
including continuous measurements [I12, N15]. Overall, long- methods in routine use at the time involved drawing a known
term track etch radon measurements are widespread and are volume of air through a filter. After a specified time delay,
almost universally used for residential epidemiological studies. the activity on the filter was analysed. The concentration of
In recent years, increasing attention was given to measurements short-lived RDPs, in units of working levels (WL), was cal-
that assist in the reconstruction of past exposures, including culated from the measured activity on the filter. The most
the measurement of polonium (210Po) activity on glass surfaces common method was that of Kusnetz [K23], who devised
or in volume traps (e.g. [F1, F9, L31, M33, N11, N15, P15]). a procedure for estimating WL from a single alpha count.
Bochicchio et al. [B41] describe a comprehensive quality (The Kusnetz method generally involves a 5-minute sample
assurance programme for radon measurements carried out as of air drawn through a glass fibre filter paper at a rate of
part of a residential radon casecontrol study. 12 L/min; the filter paper is counted for total alpha activ-
ity after a delay of 4090 min and the concentration in WL
62. A paper on the use of (outdoor) radon levels in meteor is determined from the total alpha count using a correction
ology provides additional information on environmental factor based on the decay time [K23].) For control purposes,
radon monitoring and experimentally available lower limits a single measurement was used to establish whether or not
of detection [Z7]. Tokonami et al. [T42] conducted an inter- a work area was safe for occupancy by miners. For routine
comparison of measurement methods for radon, RDPs and dosimetry, the concentration estimated from the grab sample
particle size using a radon/aerosol chamber. The authors was assigned to the appropriate work area. As discussed later
report good agreement (typically within +5%) across institu- in sectionIV, similar practices were followed in many ura-
tions and methods for continuous radon monitoring. How- nium mines outside the United States.
ever, the ratios of the radon concentrations measured by
various institutions to those measured by alpha track detec- 64. Twelve grab sampling methods for measuring airborne
tors ranged from about 0.71 to 1.34. The authors noted that radon decay product concentrations were analysed by Schiager
these types of detector (alpha track detectors) are often used et al. [S56] to determine whether they would satisfy the ANSI
in surveys and that quality control is always needed. standard [A22]. The evaluations considered six independent
sources of uncertainty that together, according to reference
63. Much of the miner epidemiology is based on exposures [S56], comprised the overall uncertainty of the method. The
characterized by relatively short-term (grab) measurements results of their evaluation are summarized in table3.
Table 3 Uncertainties in grab sampling (adapted from reference [S56])
Nature or source of uncertainty Total uncertainty

(Percentage of measured value)
Variations in airborne RDP concentrations 36
Inherent errors of the method 420
Precision based on counting statistics (dependent on concentration) 1.49.3 a
Human error 14
Estimation of occupancy time 4
Record-keeping and data transcription 1.5
Overall uncertainty 3741
a Range for 10 out of 12 methods analysed at 0.3WL.

65. For comparing the uncertainties involved in differ- observations per location varied from 22 to 188, and the sam-
ent grab sampling methods, Schiager et al. [S56] assumed pling periods ranged from 4 to 12 days. The combined data at
that all of the sources of uncertainty were independent, each location had a coefficient of variation ranging from 5 to
multiplicative and normally distributed. The total relative 95%, with an arithmetic mean value of 30%, consistent with
uncertainty in an individual measurement was estimated, the ANSI standard. Francis et al. [F18] evaluated the effects
by conventional propagation of error techniques, as the of autocorrelation on workers daily exposures and concluded
square root of the sum of the squares of the individual that sampling programmes that rely on measurement on con-
relative uncertainties. The result was an approximation, secutive days (a possibility in the uranium mine environment)
since the shape of the distribution of errors was not deter- can result in biased estimates of exposure if autocorrelation
mined. In spite of the limitations of the analysis, Schiager is present. They suggested a random sampling strategy be
et al. [S56] determined that the estimated uncertainties are employed where day-to-day correlation is high.
entirely adequate to indicate the nature and magnitude of
the various sources of potential errors and the adequacy 67. The possible role of exposure to thoron and its decay
of the sampling methods used for meeting the ANSI products is of increasing interest, and a number of authors
criterion. report that the contribution of thoron and its decay prod-
ucts can be a significant component of the total exposure
66. Makepeace and Stocker [M35] presented a statistical (radon plus thoron); thoron can thus be a source of error in
analysis of WL measurements in Canadian uranium mines. residential radon studies that do not distinguish the two con-
No attempt was made to establish the accuracy or precision tributions to exposure (e.g. [C21, T11, T17]). Future meas-
of the individual measurements. A total of 2,427 observa- urement studies should therefore consider the contribution
tions were obtained at 33 mine locations. The number of of both radon and thoron.
II. DOSIMETRY
68. The health risk associated with radon arises from the radioactive material. Such models incorporate data on res-
inhalation of the short-lived decay products and the conse- piratory tract deposition, including data on deposition of
quent dose to critical cells of the respiratory tract. Estimates ultrafine particles in nasal passages (e.g. [H22, I3, I13, J1,
of the absorbed dose to the critical cells of the respiratory tract J2, N8, N10]). These models, widely used for the assess-
per unit radon exposure can be derived from an analysis of ment of dose for most inhaled radionuclides, show that the
information on aerosol size distribution, unattached fraction, dose per unit intake of RDPs is dependent upon the site of
breathing rate, fractional deposition in the airways, mucous deposition within the respiratory tract. The site of deposi-
clearance rate and location of the target cells in the airways. tion in turn is strongly dependent on the particle size of
Such estimates are model-dependent and necessarily subject the airborne RDP, particularly for those particles of below
to all the uncertainties associated with the input data as well as 10 nm diameter (typically the unattached fraction of
with the assumptions built into the particular model. The dose the RDP, i.e. the fraction not attached to ambient particu-
calculation procedure and assumptions are described in the lates). A weighted dose conversion factor for a particular
UNSCEAR 2000 Report [U2]. The magnitude of the risk from exposure location can be derived from measurements of
exposure to RDPs was quantified in epidemiological studies of RDP size distribution combined with the particle-size-
the increased rate of lung cancer among uranium mine workers dependent dose conversion factors, calculated using one
and more recently in residential casecontrol studies. of these dosimetric models.
69. ICRP Publication 65 [I2] recommended the use of 72. Various techniques are used to measure size distri-
the risk factors determined from epidemiological studies butions of RDPs associated with fine (5nm) and ultrafine
of uranium miners as the preferred method for convert- (0.5nm) particles. These are extensively reviewed elsewhere
ing RDP exposure to effective dose. Since that time, as (e.g. [N8]). Many of these methods rely on fractionation
discussed in sectionVI, numerous casecontrol studies of of the sub-micrometre radioactive particles by diffusion
residential exposure to radon suggest risk factors that are processes, using sets of wire screens, or by inertial and
generally consistent with those from miner epidemiology. impaction processes, using cascade impactors. The latter
These casecontrol studies provide direct evidence of risk systems are also capable of resolving particle sizes exceed-
from residential radon, removing the dependence on dosi ing 1m. These systems have been used to measure RDP
metric adjustments from conditions in mines to conditions size distributions in homes, workplaces and uranium mines
in homes. Thus, as discussed in sectionV, the assessment of [G1, G2, R7, S44, S57, T23, T25]. A simpler technique
risks from exposure to radon in the home can now be based involving the measurement of the unattached fraction is
on the evidence from residential casecontrol studies. widely used [H23]; this method relies on the separation of
the ultrafine and accumulation modes (particles in the size
70. The ICRP has provided guidance on a dose conversion range 50500nm, which grow on inhalation, affecting the
convention for radiation protection purposes [I2]. For radon, pattern of deposition in the lungs) using a diffusion sam-
the ICRP recommends the RDP conversion convention that pler, usually a single wire screen. When used with the opti-
all exposures are combined on a dose- and risk-equivalent mized configuration, a system with a set of wire screens
basis. The use of a single value for the dose conversion factor can measure size distributions in both modes concurrently
implicitly assumes: (a) that the distribution of RDP particle [F16, F17]. Tokonami et al. [T49] describe two methods of
size for occupational exposure, in particular the fraction and measuring the particle size distribution of RDPs and report
particle size of the ultrafine mode, is not too different from data measured in a mine in Japan, as well as in a well-
the particle size distribution in uranium mines; and (b) for controlled radon chamber.
exposures of the general public, that the differences in aerosol
conditions are offset by lower breathing rates for members of
the public, particularly children. The current ICRP conversion
convention is not applicable to thoron decay products. B. Dosimetry of radon and thoron
73. A number of researchers have used the ICRP dosi

A. Dosimetric models metry model to assess the doses from radon and thoron and
their decay products (e.g. [B35, I7]). The ICRP advises
71. Dosimetric models can be used to estimate the against using the human respiratory tract model for risk
radiation doses arising from the inhalation of airborne estimation [I3].
215
74. Tokonami et al. [T36] report measurements of physi- The publication of James [J5] contains an illustration of the
cal parameters related to dose assessment in an actual room dose conversion factors according to various models.
where environmental conditions such as ventilation rate,
air-conditioning and the operation of an air cleaner were 76. The UNSCEAR 2000 Report [U2] listed, in table 26 of
varied. Using the data and the ICRP Publication 66 respi- annex B, the principal dosimetric assessments for the lung
ratory tract model, dose conversion factors were calculated dose from deposited RDPs. For convenience, this table is
under different situations and compared with each other. The reproduced here as table 4. Graphs of the dose coefficient
paper investigated the wide variation of dose conversion fac- as a function of median inhaled aerosol diameter, breathing
tors with environmental conditions and concluded that the rate and unattached fraction are reproduced from reference
most sensitive parameter is the unattached fraction of decay [U2] in figureII. The current RDP dosimetric models use the
products (fp). standard values for tissue and radiation weighting factors to
convert tissue dose to effective dose. The effective dose esti-
75. Other dosimetric models have also been described [H3, mates vary, but are within a factor of 3 higher than the esti-
N10], and current models are relatively consistent in their mates derived from the epidemiological approach used by
dose estimates, particularly in showing a strong dependence the ICRP conversion convention. Considering the uncertain-
of the radiation dose per unit intake on the size of the inhaled ties in both the epidemiological and dosimetric approaches,
radioactive particles (aerosol in the range 0.8nm to >1 m). this agreement is remarkable.
Table 4 Principal dosimetric assessments of lung dose from deposited RDPs [U2]
Year Investigator Parameter values Target region Model type Dose factora
[nGy(Bqhm3)1]
Unattached Breathing rate
fraction (m3/h)
1956 Chamberlain and 0.09 1.2 Average in 45m Cast of trachea and bronchi 11
Dyson [C1] epithelium
1959 ICRP [I4] 0.1 1.2 Mean tracheobronchial Deposition retention assumptions 6.7
region
1964 Jacobi [J1] 0.25 Basal cells (30m) FindeisenLandahl 6-region anatomical 24
model
1964 Altshuler et al. 0.085 0.9 basal Cells (22m) FindeisenLandahl 6-region anatomical 32
[A3] model
1967 Haque and 0.35 Basal Cells (30m) Weibel dichotomous airway model 71
Collinson [H3]
1972 Harley and 0.04 0.9 basal Cells (22m) Weibel dichotomous airway model 5.7
Pasternack [H5]
1980 Jacobi and Eisfeld 0.1 1.2 Mean epithelium Weibel dichotomous airway model, 8.9
[J2] correction for upper airway turbulent
diffusion [M2]
1980 James et al. [J6] 0.1 1.2 Mean epithelium YehSchum anatomical model [Y2] 14
1982 Harley and 0.07 1.1 basal Cells (22m) Same as Jacobi and Eisfeld [J2] 6.4
Pasternack [H6]
1982 Hofmann [H10] 0.2 0.9 Mean epithelium Same as Jacobi and Eisfeld [J2] 11
1991 National Research 0.16 1.2 basal Cells (3550m) YehSchum anatomical model [Y2], 21
Council [N10] correction for upper airway turbulent
diffusion
1996 Harley et al. [H4] 0.1 1.2 basal Cells (27m) Nikiforov and Schlesinger [N12] ana- 9
tomical model, airway deposition from
empirical data from human airway casts
1998 Marsh and Birchall 0.08 0.8 Bronchial cells: basal ICRP lung model [I1]
[M2] (3550m), secretory 8.5
(1040m) Bronchiolar 19
cells: secretory 14
(412m)
a Per unit 222Rn concentration (EEC). WLM converted to Bqhm3 using 0.27 103WL(Bq/m3)1 and 170h per working month.
Figure II. Absorbed dose in bronchial epithelial cells per unit exposure to radon decay products as a function of aerosol
size [U2].
70 50
For unattached fraction For breathing rate 0.6 m3/h
of 0.05 Unattached fraction fp
60
1.2 m3/h (oral) 40 0.21
50 1.2 m3/h (nasal) 0.11
DOSE COEFFICIENT
[nGy (Bq h m-3)-1]
DOSE COEFFICIENT
0.6 m3/h (nasal) 0.05
[nGy (Bq h m-3)-1]

40 30
0.3 m3/h (nasal) 0.02
30
20
20
10
10
0 0
0 200 400 600 800 1000 0 200 400 600 800 1000
MEDIAN AEROSOL DIAMETER (nm) MEDIAN AEROSOL DIAMETER (nm)
Note: Extract Figure XIV from UNSCEAR 200, Annex B

77. It is not possible to assess the radiation dose from assessments of lung dose from deposited thoron decay
inhalation of thoron decay products by epidemiological products and supports the continued use of a conversion
means, and therefore it must be estimated using dosimetric factor of 40nSv(Bqhm3)1. Marsh and Birchall [M42],
modelling. In annex A of the UNSCEAR 2000 Report in a comment on the review of thoron dosimetry issues
[U2], a conversion factor for thoron decay products of [N16], report thoron dose conversion factors based on the
40nSv(Bqhm3) was used. According to reference [U2], latest ICRP biokinetic models and provide a range of dose
this value was intended to include the dose to organs other conversion factors from 1.1mSv/WLM to 3.8mSv/WLM,
than the50lungs due to the transfer of 212Pb from the lungs. which encompasses the full range of previously estimated
Table 5 provides a summary For breathing rate 0.6 m3/h
of the principal dosimetric thoron dose conversion factors.
Unattached fraction fp
40 0.21
0.11
DOSE COEFFICIENT
Table 5 Principal dosimetric assessments

0.05 of lung dose from deposited thoron decay products
[nGy (Bq h m-3)-1]
30
0.02
Year Investigator Parameter values Target region Model type Effective dosea
20 [nSv(Bqhm3)1]
Unattached Breathing rate
fraction 212Pb (m3/h)
1956
10 Chamberlain and 0.02 0.3 Average in 45m epithelium Cast of trachea and bronchi 30
Dyson [C1]
1959 0 ICRP [I4] 0.02 1.2 Mean tracheobronchial region Deposition retention assumptions 43
0 200 400 600 800 1000
1973 Harley and 0.02 0.9 Basal cell generations 215 Weibel 43
MEDIAN AEROSOL DIAMETER (nm)
Pasternack [H31]
1980 Jacobi and Eisfeld n.a. 1.2 Basal cell generations 215 Weibel 35
[J2]
Note: Extract Figure XIV from UNSCEAR 200, Annex B Bronchial from Weibel 64
whole lung 0.06
1981 ICRP 32 [I10] n.a. 1.2 Bronchial from Based on Jacobi and Eisfeld [J2] 73
whole lung 0.06
1982 James et al. [J16] n.a. 1.2 Bronchial basal cell BirchallJames model using 34103
(1993) (James [J5]) either Weibel or YehSchum [Y2]
model
1983 NEA 1983 [N8] 0.02 1.2 Mean bronchial Jacobi and Eisfeld [J2] 36
2000 UNSCEAR [U2] n.a. 1.2 Whole body ICRP 50 [I5] 40
2001 Porstendorfer 0.0050.02 0.75 Bronchial Modified from ICRP 66 [I3] 53

[P12] weighting by basal and secretory
cell density
a Per unit 220Rn concentration (EEC). WLM converted to Bqhm3 using 3.6 103WL(Bq/m3)1 and 170h per working month.
C. Dose conversion factors included in ICRPs calculations, though cited in them. Their
inclusion yielded a mean ERR coefficient of 3.08(Jhm3)1
78. The health risks from exposure to radon and thoron (1.09% WLM1), about 80% of the 3.79 (J h m3)1
are principally due to the inhalation of the short-lived decay (1.34%WLM1) value estimated by the ICRP.
products and alpha particle irradiation of the bronchial air-
ways. Radon and thoron decay product exposure rates are 82. Alternative methods to ICRPs weighting by person-
specified by the measure of potential alpha energy concen- years can also be used to arrive at a mean risk estimate.
tration (PAEC), given in units of J/m3 or working levels One alternative considered by Lowe and Chambers [L7]
(WL), and the equilibrium-equivalent concentration (EEC), was based on the confidence interval (CI) associated with
given in Bq/m3. The potential alpha energy concentration each estimate: in this approach, the estimates with the least
is derived from a linear combination of the activities of the assigned uncertainty are given the most weight in estimat-
short-lived decay products in each radon decay series (see ing an overall mean. The method of combining values with
paragraph 122, annex B, UNSCEAR 2000 Report [U2]). different CIs was to weight each value by the inverse of its
The constants in the linear combination are the fractional variance. It was assumed that the 95% CI about each esti-
contributions of each decay product to the total potential mate approximated to a range of 2 standard deviations
alpha energy. The EEC (in Bq/m3) can be converted to the about the estimate, and that the variance was the square of
PAEC by the relationships: the standard deviation. This weighting method gave a mean
ERR of 0.73(Jhm3)1, or 0.26%WLM1.
1Bq/m3 = 5.56 109Jm3 = 2.7 104 WL (222Rn);
and 83. Stather [S62], in a discussion of the dosimetric and
1Bq/m3 = 7.6 108Jm3 = 3.64 103 WL (220Rn). epidemiological approaches, arrives at a similar conclu-
sion and suggests that the difference of about a factor of 3 is
79. For occupational exposure to inhaled 222Rn decay surprisingly good. The Committee agrees with this view
products, the ICRP 65 [I2] recommended the use of a single and simply notes that the calculated doses are in reason
factor (conversion convention) to relate the 222Rn decay able agreement with risk factors derived from epidemiology,
product exposure to the effective dose to an individual. uncertainties in both approaches considered.
This conversion convention is based on a comparison of the
risk to a uranium miner, based on epidemiological studies,
with the risk to a radiation worker from an effective dose of D. Uncertainties in dose conversion factors
1Sv, in other words, comparison of the radiation detriment
coefficient (risk per unit dose) with the miner detriment 84. Uncertainties are present in both epidemiological
(risk per PAEC exposure). For worker exposure, this factor (see sectionsIV and V) and dosimetric approaches, and the
is 1,430 mSv (J h m3)1 (rounded to 1,400), 5.06 mSv/ dosimetry of inhaled RDPs is quite complex and depends on
WLM (rounded to 5mSv/WLM), or 7.95nSv(Bqhm3)1 many factors (biological, physical and behavioural). Many
(rounded to 8nSv(Bqhm3)1) EEC (tables 7 and 8, ICRP authors have reported estimates of doses, including refer-
Publication 65 [I2]). ences [A3, C1, H4, H5, H6, H10, J1, J2, J5, J6, N1, Y2, Y3,
Y4, Y5], and both sensitivity (e.g. [M2]) and uncertainty
80. In recommending that a similar approach be used for analyses (e.g. [M32]) have been conducted. It may be that
members of the public, ICRP Publication 65 [I2] assumed a single dose conversion factor cannot adequately cover the
that the lung cancer risk per unit exposure in a home was the variety of natural and occupational exposure situations.
same as that in an underground uranium mine, in order to
derive a conversion factor for members of the public. Since 85. Marsh et al. [M32] described a detailed parameter
the detriment coefficient for the public is greater than for uncertainty analysis for the weighted equivalent lung dose
workers (7.3%Sv1 against 5.6%Sv1), the derived conver- (absorbed dose averaged over the lung that is weighted for
sion convention for members of the public was calculated the relative biological effectiveness of alpha radiation) per
to be 1,100mSv(Jhm3)1, or 3.88mSv/WLM (rounded to unit exposure to RDPs in the home. The authors commented
4mSv/WLM), or 6.1 nSv(Bqhm3)1 EEC. that the ICRP (para. 356 of reference [I3]) recommended
that the risks from residential radon be based on epidemio-
81. In developing ICRP Publication 65 [I2], data from epi- logical studies of miners, from which a conversion factor
demiological studies of seven miner cohorts were used to (effective dose per unit exposure to radon) of 5mSv/WLM
derive a central estimate of the excess relative risk (ERR) for workers was estimated. In contrast, Birchall and James
of exposure to RDPs. The ICRP (table A.2 of reference [B18] calculated a conversion factor of 13.4mSv/WLM for
[I2]) estimated a mean ERR coefficient of 3.79 (Jhm3)1 miners based on the ICRPs human respiratory tract model
(1.34% WLM1), by averaging the results from the seven [I3], a factor of 23 times larger than that estimated from
selected cohorts, weighted according to person-years of risk miner epidemiological studies. In carrying out the parameter
for each cohort. Lowe and Chambers [L7] considered three uncertainty analysis, Marsh et al. [M32] assumed a dosi
additional epidemiological studies (the Port Radium ura- metric tissue weighting factor of 0.12 for the lung and an
nium miners, the Chinese tin miners and the Newfoundland alpha radiation weighting factor of 20. Their analysis con-
fluorspar miners, as discussed in sectionIV) that were not sidered various aerosol parameters, target cell parameters,
and parameters such as breathing rate and fraction of breath- from references [R8] and [H9]). Models of ERR were used,
ing through the nose, related to the characteristics of indi- and time since exposure, smoking and sex were considered.
viduals at home. Using the ICRPs weighting factors for Little found that, although there are statistically significant
exposure at home, the mean ratio of the distribution of milli differences between the two data sets in how ERR varied
sieverts per working level month was found to be about 15. with time since exposure, these differences were no longer
It was further concluded that a conversion factor of as low statistically significant when only male atomic bombing
as 4mSv/WLM was extremely unlikely from a dosimetric survivors were used as the basis for comparison with the
perspective [M32]. Colorado Plateau miners. Little concluded that the conver-
sion factor based on the atomic bombing survivors was 18
86. In a separate analysis of the physical parameters and (95% CI: 6.1, 110) mSv/WLM, using a model with exponen-
(dose) conversion factors for RDPs, Porstendorfer [P12] tial adjustments for the effects of radiation with time since
calculated a range of (dose) conversion factors of 4.2 exposure and age at exposure, and 19 (95% CI: 6.2, 160)
11.5 mSv/WLM, depending on aerosol concentration and mSv/WLM, using a model with adjustments for the effects
other factors. Homes with higher aerosol concentrations had of radiation proportional to a power function of time since
lower dose conversion factors. Porstendorfer [P12] noted exposure and attained age. The absence of smoking data for
that, while dose conversion factors calculated for homes with the Japanese atomic bombing survivors was acknowledged
high aerosol levels were comparable to those derived from to be a potentially important confounding factor. Littles
miner epidemiological studies, the discrepancy between the estimates compare with the range developed by Birchall and
dose conversion factors derived from miner epidemiology and James [B18] of 17.222.5mSv/WLM (with 95% CI extend-
dosimetry remained for homes with normal aerosol con- ing from at least two times smaller to at least two times
centrations. Dose conversion factors for exposure to thoron larger) using the ICRP lung model [I3] and with the ICRPs
decay products of 23mSv/WLM were also calculated. estimate of 5mSv/WLM [I5] based on the Japanese atomic
bombing survivor data and the uranium miner data. Overall,
87. Nikezic et al. [N13] discussed the importance of the Little concluded that the various estimates of the dose con-
absorbed fraction (of alpha particles in sensitive cells) when version factor are very close to that predicted by dosim-
estimating dose conversion factors for RDPs. The authors etry and statistically compatible with the epidemiological
noted that the most important parameter in estimating the derivation of the conversion factors [L21].
absorbed fraction was the depth of the sensitive cell layers.
In another paper [N14], the ICRPs human respiratory tract
model [I3] and microdosimetric considerations were used to E. Exposures in homes and in workplaces
investigate the dose conversion factors for RDPs. The authors other than uranium mines
concluded that having the alpha particles deposit their energy
only in the nuclei of sensitive cells reduced the dose conversion 90. Both the BEIR IV and the BEIR VI Committees [C19,
factor from 15mSv/WLM to about 11mSv/WLM. C20] used dosimetric models to examine the comparative
doses for exposures of miners and people exposed at home.
88. All of the above calculations assumed the standard As a follow-up to the BEIR IV report, the United States
alpha radiation weighting factor of 20. Brenner et al. [B19] National Academy of Science compared the dosimetry of
suggested that a quality factor of 20 may be too large, on radon in mines with that in the home [N10]. This study
the basis that RDP alpha particles deposit most of their expressed differences in exposuredose relationships in
energy in a region of relatively low biological effectiveness, terms of a K-factor, defined in reference [C19] as the
and recommended a value of about 10 for residential radon ratio of dose per unit exposure at home to the dose per unit
exposure. The suggestion of Brenner et al. [B19] seems quite exposure to a male miner. Thus, for K<1, the dose per unit
reasonable on the basis of their review of the extensive data exposure at home is less than in a mine, and for K > 1, the
available at present on the in vitro transformation of cultured dose per unit exposure at home is larger than for exposure
mouse cells. However, Brenners suggestion would also be in a mine. As reported in reference [N10], the K-factors for
likely to raise questions at the tissue level, where the cell loss children and infants, calculated for a wide range of expo-
by killing may stimulate cell renewal that eventually pro- sure scenarios, were somewhat larger than those calculated
motes the development of cancer (i.e. increasing the weight- for adults, but nevertheless did not exceed1. BEIRVI [C20]
ing factor). In ICRP Publication 92 [I11], the ICRP noted used the concept of the K-factor and included various envi-
that the current radiation weighting factor (wR) of 20 for ronmental and physiological factors. BEIR VI reviewed
internally deposited alpha emitters can serve as a guideline, measurements of RDP activity size distributions for data
and suggested that for specific situations such as exposure to collected in Germany, the United Kingdom and the United
radon and its progeny more meaningful weighting factors States (annex B of reference [C20]). These size distribu-
can be derived, whether based on specific assumptions about tions were used with the RDP dosimetric model to estimate
target cells and dosimetric models or on epidemiology. the K-factor for exposure in homes. The values obtained
were close to 1 for male and female adults and for chil-
89. Little [L21] compared lung cancer risk in the survivors dren. James et al. [J15] described the technical basis for the
of the atomic bombings in Japan (using data from reference comparative radon dosimetry applied to BEIR VI [C20],
[P13]) and the Colorado Plateau uranium miners (using data including a thorough review of the basis for the BEIR VI
[C20] Committees choice of unity for the K-factor. James exposure situations would lead to a significant underestima-
et al. concluded that a K-factor of unity is appropriate, but tion of radiation doses. Thus it is important to understand the
noted that it is not yet established that the conditions in factors that affect the estimation of dose in workplaces other
the houses considered in the BEIR VI analysis are repre- than uranium mines.
sentative of conditions in houses in other regions across
the United States (including the effects of seasonal and 92. As discussed in the UNSCEAR 2000 Report [U2], the
climatic conditions) [C20]. Committee adopted the dose conversion factors set out in
ICRP Publication 65 [I2], which had been based on epide-
91. No similar review of RDP activity size distributions miological evidence. Dosimetric evaluation of the absorbed
has been undertaken for occupational exposure. While it dose to the basal cells of the bronchial epithelium per unit
might be expected that RDP exposure in uranium mines exposure gave values in the range 525 nGy (Bq h m3)1,
would be consistent with the ICRP conversion convention, and a value of 9nGy(Bqhm3)1 was estimated for average
namely 8 nSv (Bq h m3)1, there are a significant number indoor conditions. Using a tissue weighting factor of 0.08
of workers exposed to elevated levels of environmental for the bronchial and bronchiolar regions and a radiation
radon in workplaces other than uranium mines (buildings, weighting factor of 20 for alpha particles, the effective dose
other kinds of mine, caves, etc.). A series of RDP aerosol per unit equilibrium-equivalent concentration (EEC) became
measurements carried out in Australia in a range of work- 15nSv(Bqhm3)1. The epidemiological approach provides
places [S45] showed that some workplaces have aerosol a value of 6nSv(Bqhm3)1, a factor of 2 times lower,
conditions that differ markedly from those found in operat- and the dosimetric evaluations provide dose coefficients
ing uranium mines, particularly those operating during the in the range 615 nSv (Bq h m3)1. The UNSCEAR 2000
1950s and 1960s. Adjustment factors for these workplaces, Report concluded that the value used by the Committee in
also referred to as K-factors, were derived from the Austral- earlier evaluations [U5, U6], 9 nSv (Bq h m3)1, is within
ian measurements for occupational exposures and are in the this range, and recommended that this value continue to be
range 12.6. Use of the ICRP conversion convention in these used in dose evaluations [U2].
III. EXPERIMENTAL STUDIES
93. Information from animal experiments and from cellular and major bronchi, and in other portions of rat lungs after
and molecular biology is helpful in understanding the under- exposure to radon and/or RDPs. The respiratory tracts of
lying mechanisms of cancer induction, potential interactions animals that inhaled radon plus its decay products contained
among agents and the uncertainties associated with extrapo- 125 times more radioactive material than those of animals
lating risks from exposure in mines to residential exposure. that inhaled radon alone [C44].
The UNSCEAR 2000 Report [U2] discussed the biological
effects of low doses of ionizing radiation (annexG) and the 96. Beginning in the mid-1950s, at the University of
combined effects of exposure to radiation and other agents Rochester in the United States, Morken and Scott initiated a
(annex H), and provided much information from animal pioneering series of experiments (e.g. [M13]) to evaluate the
experiments, studies of DNA, and cellular and molecular biological effects of inhaled radon and radon decay products
responses to various forms of radiation. This section pro- in mice; later experiments used rats and beagle dogs. The
vides a concise summary of experimental results, including essentially negative biological results of these studies sug-
more recent data than reported in reference [U2]. gested that alpha irradiation alone was relatively inefficient
in producing tumours in the respiratory system. NCRP
Report No. 78 [N7] provides a comprehensive summary of
A. Animal experiments many of the early animal data.
94. Animal studies have been conducted for several 97. In the late 1960s and early 1970s, other studies in France
decades to identify the nature and levels of the uranium mine (Compagnie Gnrale des Matires Nuclaires (COGEMA))
air contaminants responsible for producing the lung cancers and the United States (Pacific Northwest Laboratory (PNL,
observed among uranium miners (e.g. [C40, M29]). Many of later PNNL)) were initiated and later proved successful in
the initial studies were concerned with early effects or short- producing lung tumours from RDPs. The French investiga-
term pathological changes (e.g. [R4]). Exposures were based tors exposed rats to RDPs, either alone or in combination
primarily on radon gas concentrations, and provided little with stable cerium, uranium ore dust or cigarette smoke, to
or no information on the radon decay product concentra- produce tumours in the lung (e.g. [C4, P4]). Later, the poten-
tions that contribute the greatest radiation dose to the lung. tial co-carcinogenic effects of various environmental and
The early studies (e.g. [K10]), in which lung tumours were industrial airborne pollutants, e.g. minerals from metallic
produced, were methodologically or statistically inadequate ore mines and diesel exhausts, combined with radon and/or
to show an unequivocal association of lung tumours with radon progeny exposure were also investigated [M31]. The
exposure to radon and/or RDPs. later United States studies were designed to systematically
determine the pathogenic role of RDPs, either alone or in
95. In the 1950s, there was growing concern that the various combinations with uranium ore dust, diesel engine
increased incidence of respiratory cancer observed in Euro- exhaust and cigarette smoke. These studies involved lifespan
pean uranium miners would also be found in United States exposures of beagle dogs and Syrian golden hamsters, and
miners. This led to the initiation of systematic studies chronic exposures of rats (e.g. [C13, C14]). A joint review
in the United States to identify the agents responsible for of PNNL (United States) and the Commissariat lnergie
increased incidence of lung cancer in miners and to develop atomique (CEA)COGEMA (France) animal experimental
exposureresponse relationships in animals. Investigators data was published in 1999 [C40]. Bronchial dose models
at the University of Rochester began to focus attention on were published for the Syrian golden hamster, rats (Long
the biological and physical behaviour of RDPs as well as Evans, Wistar, SpragueDawley, Fischer) and beagle dogs
on their contribution to the radiation dose to the respiratory [D23, H39, H40].
tract [B1, M12, M13]. Shapiro [S33] exposed rats and dogs
to several levels of radon alone and in the presence of RDPs 98. A review of the animal studies through 1970 appeared
attached to room dust aerosols. He also showed that the in the final report of subgroup IB, Interagency Uranium
degree of attachment of RDPs to carrier dust particles was Mining Radiation Review Group [R4]. That report, which
a primary factor influencing the alpha radiation dose to the addressed the early acute radon toxicity studies, concluded
airway epithelium. This dose was further demonstrated to be (as had an earlier Federal Radiation Council report [F2]) that
due primarily (>95%) to the short-lived RDPs rather than to experimental work prior to the 1970s had not demonstrated
the parent radon. Cohn et al. [C8] reported the relative lev- that pulmonary carcinomas could be produced in animals in
els of radioactive material found in nasal passages, trachea a systematic way from controlled exposures to radon and its
221
decay products. Since that review, discussions of the bio- of Wistar rats, and the combined cohort of SpragueDawley
logical effects of inhaled radon and RDPs in animals have rats at the CEA and at AEA Technology Plc (AEAT), United
appeared in ICRP Publication 31 [I1] and NCRP Report Kingdom. The study was restricted to fatal tumours. Using
No. 78 [N7]. A more detailed review of animal studies was a refined technique of age adjustment [H34], the lifetime
provided in the most recent NCRP SC65 Report [N11]. absolute risk was standardized with the survival function for
competing risks in the control population. The age-adjusted
99. Gilbert et al. [G3] analysed data on the risk of lung excess risks for both strains of rats were of similar magni-
tumours in rats exposed to radon. Male, specific-pathogen- tude, despite the higher lifetime excess absolute risks per
free rats were exposed starting at about 90 days of age to unit exposure (LEAR at 1 WLM) in the European cohort
RDPs (and uranium ore dust) at levels of from 20 WLM because of the very low mortality in the control group.
to more than 105WLM, and at exposure rates of 10WL to
103 WL. (The experiments are reported by the authors to 102. Rats were exposed to tobacco smoke and radon
have resulted in an estimated dose of about 5mGy/WLM at (1,000WLM) at the CEA. When animals were exposed to
the cellular level.) The authors used a time-dependent hazard cigarette smoke prior to radon exposure, a slight decrease in
model to accumulate risk and examined several exposure lung carcinoma incidence was observed compared with rats
response functions, the simplest being a simple linear model. exposed to radon only, but when the cigarette smoke expo-
They concluded that the rat data were in reasonable agree- sure occurred after the radon exposure, there was a highly
ment with a linear exposureresponse model and estimated significant factor of 4 increase in lung carcinoma incidence.
an overall linear (risk) coefficient of 237 per 106WLM. In This resulted mainly from an increase in squamous-type
addition, their analysis showed no observed evidence of tumours. These data were used to estimate smoke-dependent
exposure-rate effect below 1,000WLM. parameters in the biologically based two-stage clonal expan-
sion model [H36]. Although smoke had no effect on tumour
100. Bijwaard et al. [B20] used equations based on a two- initiation, an effect was seen on tumour promotion. Promo-
mutation biological model for two large data sets of radon- tion by cigarette smoke was also seen in levels of adeno-
exposed rats (10,000 in total). The improvement in fitting matosis in the PNNL studies. It appears that preneoplastic
these data sets separately compared with fitting them jointly lesions induced by radon are promoted by cigarette smoke.
was statistically insignificant, indicating that a joint fit
represented the data well. The joint solution exhibited a first 103. Monchaux and Morlier [M28] reported the results
mutation rate two orders of magnitude larger than the second from a study of the effect of exposure rate on lung cancer
mutation rate, which was strongly suppressed by a mutation induction in radon-exposed SpragueDawley male rats. The
killing term acting at high exposure rates. Maximum cancer study was conducted at relatively low cumulative exposures
incidence occurred for exposure rates of 110WLM/d, which of about 100WLM, which is comparable to lifetime expo-
is in good agreement with reference [M10]. An inverse exposures in high-radon houses or to current underground mining
sure-rate effect was evident at higher exposure rates, with exposures. The risk of lung cancer in rats decreased with
incidence orders of magnitude larger than for lower exposure potential alpha energy concentration (PAEC), i.e. exposure
rates. A very pronounced effect of age at exposure was also rate, confirming the results obtained at lower exposures
observed. In all cases, ERR ranged between 0.007WLM1 [M30]. These results and those from former experiments
and 0.025WLM1. The proposed model compared reason- [M31] indicated that the risk of lung tumour induction in
ably well with a similar model derived for Colorado uranium rats was maximal for cumulative exposures ranging from 25
miners [L23], when the data for rats were scaled by the ratio to 200WLM and PAEC ranging from 50 to 150WL, i.e.
of human to rat lifetimes. exposure rates ranging from 5 to 25WLM per week. These
data suggest that there is a watershed at cumulative expo-
101. Heidenreich et al. [H8, H26] used a two-step clonal sures of about 50WLM. Below this exposure, decreasing the
model, based on Luebeck et al. [L9] and Moolgavkar et al. exposure concentration (WL) or protracting the time over
[M11], to investigate the risk of lung cancer induction in rats which the dose is delivered results in a reduction in the lung
exposed to radon. The authors concluded that only fatal lung tumour risk. Above this level, the reverse is true: decreas-
tumours among the rats could be used for generalizations ing exposure concentrations or protracting the exposure time
to models for lung cancer induction in humans. This model results in an elevated lung cancer risk [M29]. These results
for fatal tumours showed an inverse dose-rate effect at aver- were confirmed by Collier et al. [C38] in a series of lifespan
age exposure rates of above 20WL, but below 10WL the experiments in which the effects of radon and its decay prod-
lung cancer risk per unit exposure decreased with increasing ucts were investigated at different total doses, dose rates and
duration of exposure. Finally, on the basis of their analysis, unattached fraction. Collier et al. [C16, C34] also reported
the estimated ERR for rats at low exposure rates was in the on studies of the factors that affect the risk of inducing lung
range from 0.003WLM1 to 0.012WLM1, depending on the tumours in rats exposed to radon and RDPs.
exposure periods; this is of the same order of magnitude as
the ERR seen in humans. Because a statistical test had given 104. The results of rat experiments conducted in parallel
a strong indication that the results from different rat strains at the CEA and AEAT (as described in Work Package 4 of
should not be pooled together, Kaiser et al. [K25] carried out reference [T30]) have been reviewed by various individuals.
separate risk analyses for two rat cohorts: the PNNL cohort The studies were carried out specifically to investigate the
effect of exposure rates on induction of lung cancer at cumu- to RDPs. Readers interested in a more extensive discussion
lative exposures of about (100WLM) (0.36Jhm3). Except of this subject are referred to annex C, Non-targeted and
for the fact that rat exposures in the CEA experiments were delayed effects of exposure to ionizing radiation.
carried out for a working day without a carrier aerosol and
the AEA Technology experiments were for continuous expo- 109. In biodosimetry, the emphasis has traditionally been
sure with carnauba wax as a carrier aerosol, the experimen- on assessing doses per se; however, an important perspective
tal designs were similar. The joint analysis comprised more nowadays is to think of these biomarkers as possible surro-
than 4,000 exposed rats and 1,500 non-exposed control rats. gates for measuring the bodys integrated response to radia-
The authors calculated both relative and absolute risks and tion damage, rather than as simply indicators of absorbed
found, in general terms, increased risks of lung cancer both dose. The focus of this section is on the potential use of
with increasing cumulative exposure and with increasing biomarkers of effects of radiation exposure rather than on
exposure rate. These results indicated that, at low exposures biological dosimetry per se.
comparable to those in modern mines or high-radon homes
and for cumulative exposures of up to about 100WLM, the 110. In addition to interactions with DNA, ionizing radi-
risk of lung cancer in rats decreased with decreasing exposure ation also damages other cellular components. Cellular
rates, confirming earlier results [L43, M30] at lower cumula- responses to various forms of radiation include structural
tive exposures. A parallel analysis of these experimental data and functional changes to cells and cell organelles. In addi-
with data from European uranium miner cohort studies was tion to the morphological signs related to cell death, several
performed [L44, T30]. It confirmed that epidemiological reversible alterations are seen in the structure of different cell
and animal data are consistent in showing an increase of risk organelles. Radiation-induced changes in the supramolecular
with cumulative exposure protracted at low exposure rates. organization of the membranes, including the plasma mem-
brane as well as different cell organelle membranes, can play
105. Mitchel et al. [M9] reported an experimental study a significant role in the development of radiation effects.
using a nose-only breathing system with male Sprague Various morphological alterations of nuclear chromatin (e.g.
Dawley rats exposed to one of two concentrations of natural changes of fine structure, development of chromosome aber-
uranium ore dust (44% U, at 50mg/m3 or 19mg/m3) with- rations, etc.) are thought to originate from radiation-induced
out significant radon exposure. They concluded that chronic damage to the supramolecular organization of DNA and/or
inhalation of ore dust alone posed a risk of lung cancer in nuclear proteins [N3, S35]. Changes in chromosomes are
rats that was directly proportional to dose rate. considered to be useful as biological indicators or even bio-
logical dosimeters of radiation injury [A26, A27, A28, A29,
106. Although it was established that the rat constitutes a B2, C3], and can be evaluated qualitatively and/or quantita-
valuable model to study radon-induced cancers, Petitot et al. tively by various techniques, such as morphological analysis
proposed a system which is designed to allow direct exposure of of metaphase chromosomes, fluorescence in situ hybridiza-
isolated cell populations cultured in vitro to radon and its decay tion (FISH) and the scoring of micronuclei. Brenner et al.
products [P18]. One advantage of this is that cells cultured in [B32] argued that there was a need for a biomarker to dis-
vitro are irradiated directly by a natural radon emanation and a tinguish between the effects of exposure to high-linear-
mixture of RDPs in exposure conditions similar to those used energy-transfer (LET) radiation and other carcinogens. They
for inhalation exposures of rats (in vitro studies). This new suggested that exposure to high-LET radiation produced
method could help to identify biological markers of irradiated a distinctly low ratio of stable interchromosome to intra
cells in radon-induced cancers by an in vitro approach. chromosome aberrations, and recommended this ratio as a
candidate for such a biomarker.
107. Overall, animal data support the conclusion from
epidemiology that exposure to radon and its decay prod- 111. Miller et al. [M7] exposed cultures of C3H 10Tcells
ucts is carcinogenic. Moreover, animal data also confirm the either to microbeam irradiation using the Columbia Uni-
observations from epidemiology that the risk from exposure versity microbeam or to broadbeam irradiation in order to
to radon and its decay products increases with increasing investigate oncogenic transformation rates, and demon-
cumulative exposure, even for protracted exposures at low strated that cells exposed to exactly one alpha particle each
exposure rates. had a significantly lower response than cells exposed to a
Poisson mean of one alpha particle each. Millers group con-
cluded that cells intersected by multiple alpha particles (as
B. Biomarkers may occur in high-exposure miner studies) contributed most
of the response. This suggested that extrapolating from the
108. Traditionally, biomarkers have been used to determine high-exposure conditions of miners could result in an over-
exposures or doses. Jostes [J14] provides an overview of estimation of the risk of cancer induction at domestic levels
the use of biomarkers as measures of effects of exposure to of radon exposure, in which situation essentially no target
radon. It is becoming increasingly apparent that biomarkers cell is ever traversed by more than a single alpha particle.
of effect are potentially of great value in evaluating potential
health impacts. The following discussion provides an over- 112. Brenner and Hall [B10] commented on a phenomenon
view of selected studies of biomarkers involving exposure known as the inverse dose-rate effect. They noted that it is
widely observed for radiation with medium to high LET, area of the cell relative to that of the nuclear target was sug-
such as neutrons and alpha particles, and that a given dose gested to be an important consideration. It was hypothesized
delivered over a longer time (i.e. protracted) had a greater that the effect was mediated by the free radicals formed in
effect than an acute exposure at the same total dose. They the cytoplasm as the result of traversal by alpha particles. In
suggested that the dose-rate effect was significant only when support of this hypothesis, a paper subsequently described
a certain combination of dose, dose protraction and radia- the production of superoxide anions and hydrogen peroxide
tion quality was present. When uranium miners are exposed by alpha particles traversing the cytoplasm [N1].
to low WLs for a long period of time, the possibility of the
(inverse) dose-rate effect occurring exists, but such dose-rate 116. In recent years, evidence has accumulated that
effects in cases of typical domestic exposures to radon are suggests that both directly hit and bystander cells may show
unlikely, because the average cell is traversed by one or zero effects of exposure to alpha radiation (e.g. [M36]). Goodwin
alpha particles in a lifetime. Hence when risk estimates for and Lehnert [G8] found from in vitro studies that a low dose
domestic exposure are extrapolated using data from miners, of alpha radiation increased levels of SCE, an indicator of
the radon risk may be overestimated. genetic damage in the lungs of mice and humans. In addition,
the amount of ROS increased. SCE and ROS levels were also
113. Similar to the conclusion reached by Brenner and Hall increased in non-irradiated cells. The authors concluded that
[B10], Jostes [J14] noted that epidemiological studies have harmful effects of radiation are induced in bystander cells to
shown that radon is a risk factor for both smoking and non- the same extent as in irradiated cells. There was evidence that
smoking miners, and that it is reasonable to suppose, on the the ROS response triggered the up-regulation of cytokines
basis of molecular and cellular considerations, that exposure that mediate the bystander effect [G8]. The authors antici-
to RDPs in the home also poses a risk of cancer induction. pated that an important next step would be to show whether
He also suggested that, while an inverse dose-rate effect has this work applied in vivo and whether carcinogenesis and
been seen in miners, such an effect may not apply to residen- other disease processes were a result of the bystander effect
tial exposures, since the majority of lung cell nuclei would from ionizing radiation.
experience no alpha hits and only a few cells would receive
even a single alpha hit. 117. Azzam et al. [A15] postulated that the reaction of
non-irradiated cells is due to gap junction-mediated inter-
114. Mutations induced in mammalian cells following cellular communication (GJIC) of a damage signal between
irradiation with alpha particles have been studied using irradiated cells and their neighbours. The levels of a protein
microbeam methods to irradiate the cytoplasm of individual (p21Waf1) induced by stress were compared in cells compe-
humanhamster hybrid cells (AL cells) [W11]. The aiming tent in GJIC and not competent in GJIC. In the competent
point of the microbeam was 8m from the ends of the major cells, more cells showed elevated levels of the protein than
axis of each cell nucleus. The probability of a scattered alpha could have been directly intersected by an alpha particle. The
particle hitting the nucleus was 0.4%. Irradiation of the cyto- expression of p21Waf1 correlated with micronucleus formation
plasm produced gene mutations in the nucleus in a process (indicating DNA damage) and with increased phosphoryla-
mediated by free radicals. While the microbeam irradiation of the p53 gene. While GJIC is certainly one mechanism
tion induced minimal toxicity to the irradiated cells, it was by which a signal is communicated from an irradiated cell to
effective in inducing mutations in the nucleus. An analysis a non-irradiated cell, there is also evidence for soluble fac-
of the mutational spectra induced by nuclear versus cyto- tors being secreted into the culture medium to communicate
plasmic irradiation suggested that different mechanisms of the bystander signal [M43, S73].
cancer induction were operative. Two approaches were used
to investigate whether reactive oxygen species (ROS) medi- 118. A bystander effect and gene induction in non-irradi-
ated the process of mutagenesis through cytoplasmic radia- ated cells occurred for situations where only a small fraction
tion. The first involved the use of an antioxidant (dimethyl of the cell nuclei were traversed by an alpha particle [L5].
sulphoxide) to scavenge ROS, and the second involved Oncogenic transformation can arise from the passage of sin-
the addition of a drug (buthionine-S-R-sulphoximine) to gle alpha particles through cell nuclei [M7]. The role of ROS
deplete endogenous scavenger sulphydryl groups. In the first in mediating DNA damage and cell-related effects is of great
approach, the induction of mutations was suppressed; in the interest in understanding bystander effects. The bystander
second, the induction of mutations was enhanced. Indica- effect and other non-targeted effects are discussed at greater
tors of cellular ability to scavenge ROS may have potential length in annex C, Non-targeted and delayed effects of
as a biomarker of effect. Observations from in vitro studies exposure to ionizing radiation.
further demonstrate that cytoplasmic irradiation is clearly a
risk factor. 119. Little and Wakeford [L35] discussed radon-induced
lung cancer and the bystander effect in C3H 10T cells
115. An earlier study had also demonstrated that radiation exposed to alpha radiation. These authors fitted a model of the
damage from alpha irradiation reflected in the patterns of sis- bystander effect [B21] to experimental data [M7, S47] and
ter chromatid exchange (SCE) in human diploid lung fibro to epidemiological data for various residential radon stud-
blast cells was independent of the number of alpha particles ies, for Colorado Plateau miners [L10] and for the combined
traversing a nucleus [D3]. The much larger cross-sectional analysis of BEIR VI [C20]. The best estimate of the number
of neighbouring cells that contributed to the bystander effect can be predicted on the basis of the markers. A study of the
was between 0 and 1.0 (with an upper 95% confidence limit relationship between residential radon and the occurrence of
of between 1 and 6.5), and therefore the bystander effect chromosome aberrations in peripheral blood lymphocytes
seen in the experimental C3H 10T cell system probably was reported in reference [O3]. This study demonstrated
did not play a large role in the radon-induced lung cancer an excess in the number of cells containing dicentric and/
seen in the epidemiological studies of humans. The authors or centric rings for 61 people living in dwellings with radon
also found that the ERRs in the Colorado Plateau miner data concentrations of above 200Bq/m3 compared with a control
were statistically indistinguishable from those derived from group from the researchers laboratory (53 people). How-
residential radon studies. ever, no statistically significant difference was seen between
the control group and people exposed to radon concentra-
120. One potential biomarker of radon exposure is inter- tions of between 230 and 13,000 Bq/m3. Uncertainty in
leukin-8 [N2]. When alpha particles hit a cell, the produc- exposure was suggested as a possible confounding factor for
tion of ROS increases; this causes the production and release this result [O3].
of interleukin-8 to increase. However, there are triggers for
ROS production other than alpha radiation; asbestos, ozone 124. Another study done on German uranium miners tried
and cigarette smoke can all cause an increase in ROS levels to identify a specific genetic defect caused by alpha radia-
and therefore in interleukin-8 levels. tion that led to lung cancer [W4]. The authors were unable to
find a mutation of the tumour-suppressor gene p53 that was
121. In an early study of chromosome aberrations in characteristic of a radon-induced cancer.
uranium miners, Brandom et al. [B30] studied cultures of
peripheral blood leucocytes in 15 uranium miners and 15nor- 125. Hussain et al. [H28] described studies of the mutabil-
mal age-matched non-miner male controls. The miners work ity of codons 249 and 250 of the p53 gene patterns in normal
experience ranged from 1 to 20 years, and cumulative expo- human bronchial epithelial cells from a 15-year-old male
sures ranged from 10 to 5,400WLM. Chromosome abnor- who had never smoked. The cells were either unexposed
malities were observed in 3 (0.28%) of the control cells and or irradiated to a total dose of 4 Gy (equivalent, accord-
37 (2.3%) of the miner cells. The differences were statisti- ing to the authors, to 1,460WLM of exposure to RDPs). In
cally significant and were considered by the authors to be this study, exposure was from alpha particles from 238Pu in
biologically important. six equal fractionated doses. The authors found that alpha
radiation selectively increased mutation frequency in both
122. Smerhovsky et al. [S58] described a study of chro- codons 249 and 250 but noted that interindividual variability
mosome aberrations in radon-exposed miners in the Czech argues against extrapolation of their results based on a single
Republic. The study included 1,323 cytogenetic assays donor.
of peripheral blood lymphocytes from 225 mine work-
ers exposed to RDPs at levels ranging from about 1.7 to 126. Yngveson et al. investigated the association between
662 WLM. Seventy-five of the workers were reported as residential radon exposure and p53 mutation in lung tumours
non-smokers. In total, some 36 lung cancers were observed [Y6]. Their study included 83 lung cancer cases in non-
in this group. KaplanMeier survival analysis was used to smokers and 250 lung cancer cases in smokers. Lung can-
investigate cancer incidences and Cox regression was used cer cases were selected with time-weighted average radon
to model associations between chromosome aberration fre- concentrations of below 50Bq/m3 or exceeding 140Bq/m3.
quency and cancer incidence. The KaplanMeier survival Molecular analysis was carried out on samples obtained from
analysis indicated a significant decrease in survival times the pathology departments where the cancer cases had been
dependent on frequency of aberrant cells and on frequency diagnosed. Statistical analysis was carried out to investigate
of chromatid breaks. The Cox regression showed that the associations between exposure to radon, tobacco consump-
frequency of aberrant cells was significantly related to the tion and the presence of p53 mutations. A non-statistically-
risk of cancer. significant odds rates (OR) for increased mutation prevalence
was indicated for those exposed to high levels of residential
123. A pilot study on German miners determined the radon (OR = 1.4; 95% CI: 0.7, 2.6), especially among non-
presence of biological markers related to radon exposure in smokers (OR = 3.2; 95% CI: 0.5, 15.5). Mutations of p53
uranium mines [P3]. The researchers looked at two categories were also found to be associated with smoking status and,
of markers: markers in the blood and markers in broncheo in the case of non-smokers, with exposure to environmental
alveolar lavage fluid. They found that former miners leu- tobacco smoke.
cocytes had a decreased ability to repair DNA. In addition,
there were chromosome aberrations in their lymphocytes and 127. Although biomarkers such as mutations in the TP53
an increased frequency of micronuclei in lung macrophages. gene (which encodes the p53 protein) are recognized as
There was an increase in the levels of tumour necrosis factor important biomarkers of radiation damage, not all studies
alpha in the miners compared with the control group, and arrive at this conclusion. Besides the study in [W4], a more
this was weakly correlated to their radon exposure. Further recent study of p53 in serum samples from former uranium
study is needed to establish whether these measurements miners found no correlation between p53 protein concentra-
are reliable biomarkers and whether individual cancer risk tions in serum and exposure to ionizing radiation (measured
in WLM), and the authors concluded that there was no ben- other mutations composed roughly equally of partial dele-
efit in screening for p53 or p53 antibodies at the present time tions and rearrangements (~25%) and undetectable changes
[S7]. A study by Vahakangas et al. [V3] of lung tumours in (~25%). The proportions changed depending on cell type
miners found that their TP53 gene mutations were different [J14].
from those typically seen in lung cancers caused by tobacco
smoke: there were no G:C to A:T transitions in the coding 131. In a study using comparative genomic hybridization,
strand, and the mutations were mostly transversions and Dano et al. investigated gains and losses of genetic mate-
some small deletions, which are very uncommon in human rial in a series of radon-induced rat lung tumours [D13,
lung cancers. D19]. Frequent losses occurred at various locations homolo-
gous to human chromosome bands. These regions are fre-
128. Albertini et al. [A2] studied the viability of using quently (3080%) deleted in human lung cancer and contain
HPRT mutations in human T-cells as markers of the quality tumour suppressor genes or proto-oncogenes such as MET,
of radiation to which a person was exposed. They looked CDKN2A, CDKN2B, FHIT and RB1, and genes yet to be
at the different mutations produced by high- and low-LET identified. Frequently observed gains involved chromosomes
radiation. With high-LET radiation such as that from radon, homologous to those in human encoding MYCN and MYC
the mutations were mostly small partial deletions, with oncogenes. The genetic similarities between rat and human
fewer than 2% being total gene deletions. There were rela- lung cancer suggest common underlying mechanisms for
tively more breaks in the DNA strand because of the energy tumour evolution in both species and provide an opportunity
transferred from the alpha particle to the strand. A high pro- to study early events in carcinogenesis. Moreover, cytoge-
portion of the breaks were lethal, so alpha radiation is effi- netic and molecular genetic analyses of radon-induced rat
cient at killing cells. In the case of low-LET radiation, 10% lung tumours could help to better understand the develop-
of the mutations were total gene deletions and most of the ment and progression of radon lung cancer in humans.
damage to the DNA molecule occurred because of second-
ary ionization, not from the initial collision. These or related 132. Smoking remains the predominant cause of lung can-
differences may eventually allow researchers to differentiate cer. The effects of smoking per se and of exposure to envi-
between high- and low-LET radiation. ronmental tobacco smoke (ETS) [A24] are of great interest
for both miner and residential epidemiological studies of
129. Alpha particles, like other high-LET particles, induce radon [A23]. On the basis of in vitro studies, Piao and Hei
the tumorigenic phenotype into BEP2D cells in the lungs [P7] suggested that the combined effects of radiation and
[Z1]. This is achieved by deleting suppressor genes. Thus, smoking are additive for both low- and high-LET radiation.
by looking at the levels of the products of these genes, it
may be possible to detect the early development of cancer- 133. Bennett et al. [B31] reported a molecular epidemio-
ous cells. logical study of geneenvironment interactions in promoting
lung cancer in women who never smoked. The study was
130. Jostes [J14] suggested that the cellular response designed to assess the risk of lung cancer from exposure to
to alpha radiation may depend on the repair status of the ETS, radon and dust, as well as family history and occupa-
affected cell. This was based on studies by Schwartz et al. tional exposure in 106 white women with lung cancer who
[S8] and Shadley et al. [S32], which compared the induction never smoked. The authors also carried out genetic analy-
of chromosome aberrations in repair-proficient versus repair- sis for cancer susceptibility genes. Odds ratios and 95% CIs
deficient cells. In reference [S8], it was found that a cell line were calculated by multiple logistic regression. A dose
that was repair-deficient for single-strand DNA breaks was response relationship was found between ETS exposure and
more prone to aberration induction than the parental repair- increased lung cancer risk in women with a common genetic
proficient cell line. In reference [S32], the cell line used was deficiency, loss of GSTMI enzymatic activity, with the trend
repair-deficient with respect to double-strand DNA breaks, test significant at the 2% level. This suggested that ETS expo-
and it was less prone to aberration production when alpha sure could possibly double the risk of lung cancer in nearly
particles were used than when X-rays were the inducers. It half of the white women in Western nations. According to
also appears that there is an adaptive response to radiation. Bennett, loss of GSTMI enzymatic activity occurs in about
Jostes [J14] reported that when human peripheral blood lym- 50% of the white population in Europe and North America.
phocytes were exposed to a small priming dose of low-LET
radiation and later to a challenge dose from radon, the number 134. Alavanja [A23] reviewed biological damage from
of chromosome aberrations was smaller than expected [W8, exposure to tobacco smoke and from radon, and concluded
W9]. However, when alpha particles and X-rays were used that strong similarities existed between the biological
at the same time, the number of micronuclei was higher than damage caused by the two agents. He also noted a protec-
the anticipated additive effect [B4]. Taylor et al. [T1] sug- tive effect arising from cruciferous vegetable consumption,
gested a p53 mutation hot spot in radon-associated lung can- at least in part attributable to their antioxidant properties, in
cer, noting that Jostes [J14] had also compiled results from both smokers and non-smokers [A23].
various studies on mutations at the HPRT locus in Chinese
hamster ovary cells exposed to alpha radiation. In general, 135. Traditionally, biological effects from irradiation of
half of the mutations were complete gene deletions, with the a population of cells are considered to arise as a result of
unrepaired or misrepaired damage to DNA in irradiated 136. At the present time, considerable uncertainty
cells. It has been noted previously in this section that radia- remains about the effect on risk estimation of the new
tion effects can also occur in non-irradiated cells (e.g. [L5, biology outlined above and discussed in greater detail
L35, M7]), a phenomenon commonly referred to as the in annex C. Future dosimetry will need to consider the
bystander effect (e.g. [M36, M37, M38]). As the bystander effect of mechanisms of carcinogenesis such as those dis-
effect is thoroughly discussed in annex C, Non-targeted and cussed above. In the meantime, it should be noted that
delayed effects of exposure to ionizing radiation, a detailed the effects of such mechanisms are implicitly included
discussion here is unnecessary, other than to note that while in the results of epidemiological studies. Although sev-
the existence of the bystander effect raises many questions eral potential biomarkers of radon exposure have been
about traditional dosimetric modelling, risk factors derived studied, chromosome aberrations appear to be the most
from epidemiology will already implicitly take into account promising at this time, owing particularly to the possible
any contribution from the bystander effect, thereby support- signature of high-LET exposures and the correlation
ing the use of epidemiological evidence for risk estimation. with cancer risk.
IV. EPIDEMIOLOGICAL STUDIES OF MINERS
137. Studies of underground miners exposed to radon Service (USPHS), in cooperation with the United States
form the current basis for estimating risks from radon and its Atomic Energy Commission and the state health depart-
decay products. The UNSCEAR 2000 Report [U2], BEIR VI ments of Arizona, Colorado, New Mexico and Utah began
[C20] and others have reviewed the epidemiological studies studies of exposures in uranium mines. By 1950, medical
of miners, but scant attention was given to the basis for the studies had been initiated [A12], and uranium miners were
exposure estimates. Miner studies are reviewed in this sec- subject to routine medical examinations. Beginning in 1954,
tion. Particular attention is given to the sources and effects of medical examinations were performed every three years on
uncertainty in estimates of risk to miners. all uranium miners who could be reached and who agreed to
undergo examination [C11].
A. United States: Colorado Plateau miners 142. The initial study population, some 90% of these so-
called Colorado Plateau miners, consisted of all miners
1. Introduction examined in 1954. The USPHS began to collect data on
radiation exposure, smoking history and mortality for these
138. The discovery of radioactive ores in the Colorado miners. Several analyses of these data, with different peri-
Plateau dates to between 1881 and 1887. The ores con- ods of follow-up, were published [A4, A10, A12, A16, A17,
tained vanadium, uranium and a small quantity of 226Ra H17, L13, L14, L15, W1, W2, W3, W12].
[H13]. Before there was a demand for uranium and radium,
vanadium was mined on a small scale. Radium produc- 143. Holaday [H11] recommended that all states adopt a
tion became more important during the period 19161923. tentative working level of 1010 Ci/L of radon in equilib-
However, United States radium production eventually lost rium with its decay products [S31]. For practical purposes,
its competitiveness owing to the availability of radium from the recommended standard was equivalent to 1 WL, or
high-grade ores from the Belgian Congo, and during the 12WLM per year of exposure. Holaday indicated that this
period 19301945, the vanadium content of the Colorado recommendation was adopted as a guide by official agen-
Plateau ores was the principal objective of their mining. Sub- cies in most of the uranium mining states. Holaday [H11]
sequently, through the defence initiatives associated with the documented decreasing exposure to RDPs in the Colorado
Second World War, the emphasis turned more towards the Plateau mines: in 1961, only 21% of the mines studied had
mining of uranium [L13]. WL measurements of below 1WL, but by 1967, 70% of the
mines fell in the <1WL range.
139. The uranium mining industry had expanded some-
what by 1949, and by 1950, some 500 miners worked in the 144. Before 1964, the road systems serving the mines in
Colorado Plateau area mining uranium ores, mostly in small the Colorado Plateau area were inadequate, and since most
underground workings with an average production of about mines were located in remote areas, supplies of fresh water
1ton (907 kg) per person-day [H12]. According to Holaday and electricity were often insufficient [H13]. Holaday and
[H12], employment peaked in 1960, when about 5,800under- Doyle hypothesized that this insufficiency of electrical
ground miners were employed. By 1967, employment had power contributed to high RDP levels during the early days
declined to approximately 2,800 miners, who were then pro- of mining [H13]. In those days (early 1950s), the mines were
ducing approximately 3 tons per person-day. Holaday noted typically shallow [H11], were usually entered by a horizontal
that by 1967, the occupational health field station had some adit or incline, and were almost always ventilated by natural
information on exposures in over 1,200 different mining draught only. In most mining operations, the miners would
operations; however, an unknown additional number of work throughout the mine in a variety of activities drill-
operations were never surveyed. ing, mucking, handling the ore or setting timbers, etc. This
pattern of working was established when the mining was for
140. Cooper [C11], writing in a special supplement of the vanadium.
Journal of Occupational Medicine, noted that in 1953 or 1954,
large deposits of primary uranium ores were discovered in the 145. Uranium was identified in ores in the Shiprock area
Moab, Utah, area and in the Grants area of New Mexico. of New Mexico around 1918. At that time, it received little
attention. By 1950, however, there was considerable inter-
141. In 1949, as a result of concern about the possible health est in uranium, and various uranium outcroppings were
hazards of uranium mining, the United States Public Health discovered in limestone and sandstone areas in the Grants
229
mineral belt [S5]. At various times during the period 1950 19551968, the total number of mine-years for which there
1960, some 60 mines were in operation. Uranium market were more than five measurements was 1,313 [L13]. An
fluctuations starting in the early 1960s resulted in various earlier study by the Advisory Council of the United States
expansions and shutdowns. In the period 19661978, the National Academy of Sciences [N4] observed, Exposure
annual output of uranium in the Grants area of New Mexico values assigned to the period before 1956 are highly unreli-
represented approximately 45% of United States uranium able, being based almost entirely on estimates rather than
production. measurements of concentrations ([N4], p.7]).
146. The New Mexico Health Department began moni- 149. The exposure estimates used by Lundin et al. [L13]
toring RDP levels in New Mexico mines in the late 1950s, were based on RDP concentrations derived in one of three
with the aid of the state mine inspectors office. Accord- ways:
ing to Samet et al. [B47, S1, S3, S4, S5, S74], the maxi- Measured. Values were derived directly from
mum permissible concentration of RDPs decreased from 25 one or more measurements of RDP concentra-
to 10WL in 1960, to 5WL in 1963, to 3WL in 1967, to tions in any given mine in a given calendar year.
1.752WL in 1969, to 1.4WL in 1973, and finally to 1WL Before 1955, such measured data included only a
in 1976. The Grants clinic, which opened in 1957 to serve few of the work areas in the mine.
the miners, handled 8090% of the pre-employment and
follow-up medical examinations of miners, and kept records Extrapolated. Extrapolated concentrations were
of the movements of most miners in this area. The majority obtained by extrapolating between measurements
of the investigations of New Mexico miners were examina- made in the same mine in other years, if not more
tions of morbidity and mortality among uranium miners and than two years before or after the year to which
parallel investigations of the miners exposures, with infor- the extrapolation applied. In some cases, regional
mation on the exposures being published in the third annual extrapolations were also made for mines having
report of the study by the University of New Mexico [S4]. A no direct measurements; this was done by assign-
1989 report provided the results of a casecontrol study to ing a concentration value equal to the average for
investigate lung cancer risk in a cohort of the New Mexico the other mines in the vicinity.
underground uranium miners [S1]. Guesstimates. These were provided by Holaday
for mines in which RDP concentrations could not
be obtained by any of the extrapolation techniques
2. Radon and radon decay products discussed in Lundin et al. [L13]. The guessti-
mates were based on general knowledge of the
147. According to Lundin et al. [L13], radon gas measure- airborne concentrations that occurred in similar
ments in United States mines were first made in 1949, and mines during the same time period and on expert
RDP measurements were first performed in 1951. In 1952, knowledge of long-term trends.
an effort was made to survey all operating uranium mines,
and during that year, RDP measurements were made in 157 150. The miner database of the United States Public Health
mines and radon gas measurements in 79 mines. In 1953 Service/National Institute of Occupational Safety and Health
1954, the number of surveys was limited, but by 1955, many (USPHS/NIOSH) contains a great deal of information on
of the larger uranium mining companies initiated their own miners exposures [S13]. There are significant temporal and
air sampling programmes. By 1956, the mining companies spatial trends in RDP concentrations. Figure III illustrates
were performing most of the mine survey work, while agen- the decrease in RDP concentrations over time. The figure
cies continued their own control programmes [L13]. These is a plot of annual RDP concentration (WL) by years, esti-
measurements were carried out across the four states of Ari- mated using the different methods described by Lundin etal.
zona, Colorado, New Mexico and Utah. [L13]. The WL values estimated by the different methods
are approximately comparable and show a similar temporal
148. Lundin et al. [L13] emphasized the large number of decrease. The high measurement average in 1951 was due to
measurements made in the mines: From the entire 1951 a high WL (895WL) averaged over 8 samples at the Free-
1968 period nearly 43,000 measurements of RDP concentra- dom Mine in Salt Lake, Utah. FigureIV illustrates the extent
tions were available to characterize the approximately 2,500 of variability in measured WL values for Colorado Plateau
uranium mines from which ore was shipped (p. 31). How- miners.
ever, this represented typically less than one measurement per
mine-year averaged over 18 years of study. The distribution 151. Given the uneven distribution of measurements on a
of these WL measurements, moreover, was far from uniform per-mine basis and the large variability between mines, it
(from no measurements to a fairly large number of measure- may not be possible to estimate exposures for a specific year
ments in a single mine). Lundin et al. tabulated the number in those mines where no measurements were taken. SENES
of mines in which five or more RDP measurements were [S13] estimated variabilities at the four levels of area esti-
made in any one year. This amounted to 116 mine-years for mate by the pooled standard deviation of measurements,
the period 19511954, during which more than half of the under the assumption that there was no spatial or temporal
cumulative exposure of miners was received. For the period trend in the variation of exposure rate. At each level (i.e.
Figure III. Average radon decay product concentration for underground uranium mines in the Colorado Plateau area from
1950 to 1968, inferred using different methods [L13].
1 000
AVERAGE RADON DECAY PRODUCT CONCENTRATION (WL)
100
10
0.1
1950 1955 1960 1965 1970
YEAR
Legend Measurement Extrapolation
Guesstimate
Figure IV. Range of average radon decay product concentrations measured in underground uranium mines in the Colorado
Plateau area [S13].
1 000
AVERAGE RADON DECAY PRODUCT CONCENTRATION (WL)
100
10
0.1
1950 1955 1960 1965 1970
YEAR
local, district, etc.), only areas that met the criteria of having was used with sample size as a weighting factor. The results
more than three mines and 10 samples were included in the are listed in table6 together with the equations used in the
calculation; the natural logarithm of measured concentration calculations to rate the large variability in WL values.
Table 6 Estimated variabilities at different levels of area estimate [S13]
Level of area estimate Symbol Standard deviation of natural logarithm (WL)
Localitya SL 3.16
Districtb SD 3.23
Statec SS 3.39
Coloradod SC 3.66
(E m E )
2
S =
2 m
,
( Ny 1)
X

where
E is the natural logarithm of measured concentration (WL);
is an average over E weighted by sample size;
N is the number of measurements;
X = L, D, S and C, denoting locality, district, state and Colorado levels, respectively;
= (ly), (dy), (sy); m = mine; y = year.
Summation over denotes summation over both indices indicated in parentheses. In the case of the Colorado level, summation over reduces to a single summation
over variable y only.
a Locality: reflects variability among mines within the local mining area. c State: reflects variability between states (Arizona, Colorado, New Mexico, Utah).
b District: reflects variability between mines within an entire mining district. d Colorado: reflects variability among Colorado mines.
152. Schiager and Hersloff [S6], reporting on interviews more reliable. However, there is still likely to be consider-
with Holaday, noted that, while large uncertainties existed in able uncertainty in exposure assessment up to what one might
the estimates of the RDP concentrations, these were the best refer to as the modern period, i.e. 1967 to the present.
that could be made and there was no conscious bias injected
into the estimates of the early exposure conditions. This is
in contradiction to other statements, which indicated that,
where uncertainties existed, WL were deliberately overesti- 3. Exposure estimation
mated [L13]. If, on average, exposures were overestimated,
then on average the risk per unit exposure would be under 154. Wagoner et al. [W2] concluded that the excess respi-
estimated. As noted previously, mining companies began ratory cancer rates among uranium miners were not attrib-
conducting the majority of exposure measurements after utable to age, smoking activity, heredity, urbanization, self-
1956. Lundin et al. [L13] felt that during this period, i.e. the selection, diagnostic accuracy, prior hard rock mining or
1950s and 1960s, there was a possibility of a bias towards ore constituents. They attributed the excess risk to airborne
underestimation of exposure, and therefore these authors radiation.
tried to avoid this potential bias: ...efforts were made to
exclude company measurements from data after 1960 from 155. Miners who were examined in the Colorado Plateau
use in the epidemiological study of uranium miners (p. 31). area during the period 19511960 and for whom sufficient
However, since the bulk of the exposures upon which risk records existed made up the cohort studied by Wagoner et al.
estimates are based occurred prior to 1960, this selection had [W2]. The exposure calculation was performed individually
very little impact on the results overall. for each miner; the miners were then categorized into groups
according to exposure levels. The average RDP concentra-
153. In summary, most WL exposure estimates for Colorado tion (WL) and duration of work underground in working
Plateau miners for the period before 1950 seem unreliable, as months (one working month is taken as 170 hours) were mul-
essentially no data exist and all the estimates were based on tiplied to arrive at average exposures (WLM) for each group
extrapolation or guesstimates. Exposures estimated for the of miners; additional details were provided in a subsequent
period 19501956 were considered more reliable, although paper by Wagoner et al. [W1]. At that time, approximately
still highly uncertain. After 1956, the mining companies 12,000RDP measurements were available for the approxi-
themselves started to make measurements on a systematic mately 1,200 mines under study. The RDP concentrations
basis and, at least in the large mines, measurements became used in the calculations were derived as follows:
When there were multiple measurements in the mine RDP concentrations averaged throughout the mine in which
during a calendar year, an average annual exposure was each miner worked. For calculating annual exposures, it
calculated. Measurements from non-work areas were was assumed, unless we had information to the contrary,
excluded from all calculations. When no measurements that a man worked in the mine at which he was found for
were available for a mine during a calendar year, esti- six months before and six months after the census or ques-
mates were made from the average of measurements tionnaire date (6 month rule). When a man was known to
for the same mine during the preceding and following work in two different mines at less than a one year interval,
calendar year or other mines on the basis of geographic the period of employment during the interval was equally
proximity, similar ore bodies, physical layout, ventila- divided between the two mines [L13].
tion and control efforts of regulatory agencies ([W1],
p.184). 160. Full-time mining was assumed to consist of 12 full
months underground with no adjustment for vacation or ill-
156. More detailed measurements began in 1967 with the ness. This assumption was an important reason for believing
intention of presenting these data for review by the Federal that exposures were overestimated; however, no adjustments
Radiation Council (FRC) [F2] so that the FRC guidelines for were made for overtime work or moonlighting by any of the
the control of radiation hazards in uranium mining could be miners [S6]. People familiar with the uranium mining indus-
updated. The results of this update were presented in a paper try in the 1940s and 1950s recalled that many miners worked
by Lundin et al. [L14], who examined a cohort of 3,414 white exceptionally long hours. A standard working week until
and 761 non-white underground uranium miners who had 1960 was at least 48hours. Many miners working entirely
undergone medical examinations in 19501961. The results under production contracts spent 5060 hours underground
indicated that uranium miners who smoked had an excess each week. It was not unusual for a miner to work a regular
lung cancer risk ten times greater than non-smoking miners. full-time shift for an established company and then spend his
Prior hard rock mining experience had little effect on lung days off developing a mining claim of his own. Since esti-
cancer mortality overall but was suspected of contributing mates of cumulative exposures (i.e. WLM) were based on
more significantly to risks in the lower exposure categories. months rather than actual hours worked, the method tended
to underestimate exposures. It is likely that any potential bias
157. In 1971, Lundin et al. [L13] reported on the cohort in exposure estimates resulting from not making allowances
with exposures updated from the start of mining up to the for vacation and sickness was more than compensated by
end of September 1969. The cohort contained 3,366 white not making allowances for underground time exceeding the
and 780 non-white uranium miners with at least one month normal (48hour) working week.
of underground mining prior to 1January 1964. Procedures
were also developed by Lundin et al. [L14] for estimating 161. The 1968 report of the National Academy of Sciences
RDP exposure from hard rock mining other than uranium [N4] suggested that the problem of determining radiation
mining. exposure for individual uranium miners was also compli-
cated because official mine records did not necessarily show
158. As previously noted, radiation levels in uranium the actual job assignment. Only the miner himself, and to
mines dropped sharply after 1967. This fact, combined with a lesser extent his immediate supervisor, knew the areas in
a drop-out rate of 10%50% per year for the original cohort which he worked. The report also raised the possible prob-
after 1960, justified the assumption that exposures received lem of exposure from previous mining, and further noted,
after September 1969 contributed only a relatively small there is some uncertainty in the average working values
additional exposure to this cohort. even in mines in which numbers of measurements have
been made. Measurements consisted of spot sampling at
159. According to Lundin et al. [L13], more than 50% of a particular time and location, and therefore reflected only
the collective exposure of some 2.8 106person-WLM was the conditions that existed at that time and location. (This is
received prior to 1955. For the calculated cumulative expo- important since exposure in WLM is the product of time in
sures (expressed in person-WLM) received up to 30 Sep- working months, a working month nominally being taken
tember 1960 by 3,325 men, more than 25% was received by as 170 hours, and RDP concentration in WL.) The report
1,325 men and was based on actual measurements [L13]. recognized that workplace conditions (dust levels, WL, etc.)
Although the converse was not explicitly stated, it may be varied with the nature of the operations being carried out,
inferred from reference [L13] that, for the other 2,000 men e.g. blasting, the ventilation provided and the amount of ore
in this cohort, less than 25% of the cumulative exposure was uncovered.
based fully on measured data. This emphasizes strikingly the
uncertainties in the early exposure data; however, it does not 162. According to a review by the USPHS epidemiological
necessarily imply any bias in exposure estimates and hence study ([J10], p.1,266), the basic information examined for
in risk estimates. The duration and periods of exposure of individual uranium miners was the following:
individual miners were determined in some cases from
Mines worked;
employment records, but in most instances they were deter-
mined from interviews with the miners themselves. Annual Dates of employment in mines;
exposures for full-time miners were assigned on the basis of Fractional time in mines;
Radon decay product concentration levels meas- about mining experiences during medical examinations.
ured or estimated for each mine as a function of In addition, supplemental information from subsequent
calendar year. annual uranium miner censuses, records of official agen-
cies and mail questionnaires was available [L13]. Efforts
From these data, cumulative WLM values were calculated were also made to account for other hard rock (OHR)
for each individual miner. Cumulative WLM values were mining experience, as many of the underground uranium
calculated for both underground uranium mining alone and miners in the Colorado Plateau had previous mining expe-
for uranium mining plus other hard rock mining. The aver- rience. For example, some had hard rock mining experi-
age exposure of the group of miners in the USPHS study was ence from other western mines, while others were coal
of the order of 800WLM [C18]. miners from the eastern United States. However, the lack
of radon or RDP measurements from these other mining
163. Some effort was made to estimate the exposure of activities may result in an underestimate of the miners
miners to RDPs accumulated since 1967. As reported in actual exposure.
reference [S13], exposure data were collected and exam-
ined at 23 separately managed large mining operations and
also for more than 180 small mines representing in total 4. Other hard rock mining exposures
some 25,000 miners. The major conclusions of this study
(for 19671985) were: the average working time for the 167. Radon is a normal constituent of mine atmospheres,
underground uranium miners studied was 3.3 years, and including those of non-uranium mines. For example,
was 5.9years for those who worked more than 2years; the Holaday [H14] reported the results of several early meas-
average lifetime exposure (i.e. 19671985) of underground urements of radon in non-uranium mines in Colorado and
uranium mine employees was 3.6 WLM; and the average New York. Radon levels surveyed in 35 metal and clay
yearly exposure per employee who worked in underground mines in Colorado ranged from 10 to 2,100pCi/L. In the
uranium mines in this period was 1.2WLM. New York mines, radon concentrations ranged from 2 to
110pCi/L. According to SENES [S9], about 40% (1,433
164. Many New Mexico miners were included in the cohort out of 3,359) of white male Colorado Plateau miners accu-
study above. An independent epidemiological study of New mulated radiation exposures from OHR mining. To inves-
Mexico uranium miners was initiated in 1977. This study tigate this, exposures from OHR mining were calculated
was performed by the University of New Mexico under the for miners whose exposures in uranium mines were less
direction of J.M. Samet. The focus of Samets study group than 120 WLM. Following the procedure employed in
was retrospective analyses of a cohort of 3,055 under- the USPHS investigations as described by Lundin et al.
ground uranium miners whose first underground experience [L14, L15], a miner was assumed to have completed his
occurred prior to 1971. An outline of the approach used to OHR mining activity by the year preceding the start of
estimate exposure in the New Mexico study is provided in his underground uranium mining. Exposures were based
references [M34, S4, S75]. According to Samet et al. [S75], on assumed RDP concentrations in OHR mines of 1.0WL
two large databases were developed to profile exposures to prior to 1935, 0.5WL from 1935 to 1939 and 0.3WL from
RDPs of Grants area miners: 1940 onward.
The first comprises WLM measurements from 1957 168. When these OHR mining exposures were added
to 1967. A total of 20,086 individual readings are to the exposures from uranium mining, the dates used
available from the 186 visits made during the 11 years; in the previous analysis (i.e. the dates when each miner
after 1960, mine index values, which weight individual reached the limit of each exposure category) had to be
measurements by number of persons exposed, were recalculated. The assumed starting date of OHR mining
generally reported. The second includes all individual was calculated on the basis of the total exposure and the
WLM reports by companies for 1967 through 1982 appropriate rates. Next, from the OHR mining exposure
[S75]. rate and the known dates at which different uranium min-
ing exposure levels were reached, the miners exposure
165. The mean WL values reported by Butler et al. [B47] history was classified according to exposure rates and
were 42 in 1954, decreasing greatly to about 4.3 in 1955, and the number of months at each rate. The exposures were
subsequently generally declining to about 1.7 in 1967. These assumed to be accumulated at a constant rate during each
authors also reported that the mean annual WLM exposure period at a particular exposure level. The dates on which
was below 10 from 1969 onward [B47]. It is perhaps worth each miner reached a certain level of accumulated expo-
noting that the (weighted) mean of the WL measurements sure were seen to be earlier when the OHR data were
was found to provide the best indicator of the total mine taken into account. The addition of OHR mining expo-
index values, which weight measurements by numbers of sures caused a shift of the miners, and hence the lung
personnel exposed [B47, L35, S1, S4]. cancers (and person-years), into the higher exposure
categories. The average uranium and OHR mining expo-
166. The employment history of United States miners was sures from the NIOSH cohort (with follow-up through
documented by various means. Miners were interviewed 1985) are shown in table7 [S13].
Table 7 Average uranium and OHR mining exposures by exposure category white miners [S13]
Exposure category for Average time spent Average exposure for Average exposure for Average exposure rate while underground
uranium mining (WLM) underground uranium mining (WLM) uranium and (WLM/year)
(years) OHR mining combined
(WLM)
<120 1.11 51.7 68 46.58
120359 3.33 233.4 249 70.09
360839 5.24 572.6 594 109.27
8401799 7.47 1229.6 1252 164.61
18003719 10.66 2515.5 2534 235.98
3720+ 14.22 5787.3 5808 406.98
169. Although the impact of OHR mining on the over- from 51 to 101WLM. These data suggest that, particularly
all cohort average WLM is small, the effect for individual in the low exposure categories that are of greatest interest
miners can be appreciable. Table 8 summarizes the esti- to present-day miners, a potential bias towards underestima-
mated exposures of miners from uranium mining only and tion of exposure is introduced if OHR mining exposure is
from OHR mining, for those whose uranium-only expo- neglected. In the absence of an agreed procedure for esti-
sure was estimated at less than 120WLM [S9]. When OHR mating OHR mining exposures, studies could be done either
mining exposure was added, 5 of the 10 miners shifted on miners with no pre-1950 exposure (which minimizes this
from the 0120WLM category into the next higher expo- effect) or with the use of categorical variables denoting the
sure category. The average exposure of this group increased presence or absence of pre-1950 exposure.
Table 8 Effect of OHR mining for lung cancer cases with less than 120WLM uranium mining exposure [S9]
SENES ID number Uranium mining exposure (WLM) OHR mining exposure (WLM) Total exposure (WLM)
1911 8 0 8
1011 13 136 149
1092 28 0 28
4017 30 0 30
3321 33 0 33
3633 42 0 42
3297 42 187 229
3588 44 62 106
2023 68 29 97
1563 73 68 141
50 82 0 82
534 83 122 205
560 119 44 163
Average 51 50 101
170. Limited data are available on the characteristics of G1, N7, N10, S23]. A 1957 report on the control of radon
mine atmospheres in the past. For example, the attached and its decay products [H27, U16] compared the operating
fraction of RDPs will depend on a number of characteris- conditions in uranium mines with those in conventional hard
tics of the mine atmosphere, among them WL, dust levels, rock mines. While few data were presented, the report states
dust particle size and humidity. Such data are important for that dust counts in uranium mines indicate concentrations
both dosimetry and epidemiology. Useful data are summa- from 5 to 20 million particles per cubic foot of air and the
rized in various publications, including references [C10, silica content of uranium ore (carnotite) ranges from 50 to
75 percent [H27]. It is important to remember that the exposures (<800WLM). The authors also briefly discussed
majority of measurements in mines are from the mid-1960s the potential for errors in the exposure estimates to bias epi-
onward, and that the major portion of exposure of miners demiological analysis, and suggested that such errors might
dates from earlier times when few actual measurements were result in the underestimation of the ERR.
made.
173. A 1992 report [S9] described exploratory analyses
performed on white male underground uranium miners with
5. Epidemiological analyses follow-up to 31 December 1985. The purpose was to inves-
tigate the effect of other hard rock (OHR) mining experi-
171. In 1950, the United States Public Health Service ence and smoking on the risk of lung cancer. The report
(USPHS) began to collect various data on uranium miners in also included an analysis of a subgroup of miners with
Arizona, Colorado, New Mexico and Utah, including radia- cumulative exposures of below 2,000WLM, using Poisson
tion exposure, smoking history and mortality. Numerous regression to estimate model parameters using iteratively
analyses of the data have been published [G4, H9, H17, L13, reweighted non-linear regression. Simple linear ERR and
L16, W12]. The miner data were incorporated into analyses absolute risk models were among the dose responses evalu-
carried out by BEIR IV [C19], Lubin et al. [L10] and BEIR ated. The results are shown in table 9. While the regres-
VI [C20], among others. sions in table9 are all significant (p<0.01), on the basis
of the F-ratio (a statistical test to see whether the amount
172. Hornung and Meinhardt [H17] reported a propor- of variation explained by the regression is significant), the
tional hazards analysis of the Colorado Plateau cohort, origi- absolute risk model accounts for more of the variability in
nally described by Lundin et al. [L13], with follow-up to the data for all miners and smoking groups than the relative
31 December 1982. The cohort consisted of 3,366 (white) risk model. The effect of OHR mining and the joint effect of
miners with 256 lung cancer deaths, a median (cumulative) OHR mining and smoking were also investigated (table10).
exposure of 10.3WLM and a median duration of employment The miner groups included all of the miners with no expo-
of 48months underground. This study evaluated several risk sure from OHR mining, those with OHR mining experi-
models and chose a power function model since it provided ence but no uranium mining exposure prior to 1950, those
the best fit to the data, and permitted analysis of the effects of with neither OHR mining experience nor pre-1950 expo-
several temporal factors and smoking. The study estimated sure in uranium mines, and those with only OHR mining
excess relative risk (ERR) to be 0.91.4%WLM1, compared experience. All of the regressions in table10 are significant
with a previous smoking-related estimate of 0.31%WLM1 (p<0.01). On the basis of the F-ratio, the results in table10
reported by Whittemore and McMillan [W12]. The rela- show that, in this case, the relative risk model accounted
tive risk increased with age at exposure and decreased with for more of the variability in the data than the absolute
increasing time since exposure (a reduction of about 55% risk model. The absolute risk to miners who never smoked
10 years after cessation of mining compared with miners (2.8 106 a1WLM1) was about half that calculated for
with the same exposure, smoking history and age) [H17]. all smokers (6.6 106a1WLM1). In this analysis, the
Hornung et al. [H9] conducted further studies of modifiers risk was calculated relative to the baseline risk in a non-
of lung cancer risk in the Colorado Plateau miner cohort; smoking reference population. Finally, the authors fitted
follow-up to 31 December 1990 added an additional 121 the parameters of the BEIR IV model with the exposure
lung cancer deaths, bringing the total number of lung cancer response model using the data for white Colorado Plateau
deaths to 377. This analysis confirmed the earlier finding of uranium miners. The parameter estimates for time since
a strong interdependence of relative risk and age. It also sug- exposure and attained age were comparable to factors pre-
gested an exposure-rate effect resulting in a concave down- sented by BEIR IV; however, the basic risk factors (b2
ward dose response; i.e. the relative risk was reduced at low in BEIR IV terminology) estimated in the regressions of
exposure rates and low cumulative doses. For risk estima- Colorado Plateau data alone (not correcting for exposure in
tion, the authors recommended the use of ERR after strati- OHR mining) were an order of magnitude lower than those
fication to lower exposure rates (<10WL) and cumulative estimated for the combined cohorts by BEIR IV [C19].
Table 9 Summary of regression analyses by smoking category [S9]
Category Number of Number of lung Excess absolute risk Excess relative risk
miners cancers
Slope Intercept F-ratiob Slope Intercept F-ratiob
(PY/WLM)a (PY1)a (WLM1)
All miners 3359 305 5.0 106 0.18 103 3960 2.3 103 0.30 619
Non-smokers 493 14 3.1 106 0.61 103 139 21.1 103 3.8 203
Ex-smokers 318 38 7.5 106 1.1 103 45 9.2 103 1.2 55

miners cancers
All smokers 2754 282 5.7 106 0.30 103 1954 2.2 103 0.30 607
Light smokers 501 29 5.2 10 6

0.35 10 3
63 3.5 10 3
1.3 11
Heavy smokers 1910 215 5.5 106 0.0035 103 7882 1.8 103 0.29 264
a PY = person-year.
b A statistical test to see whether the amount of variation explained by the regression is significant.
Table 10 Summary of regression analyses by smoking category for miners with no OHR mining exposures [S9]
miners cancers
All miners with 1926 152 5.5 106 0.92 103 599 2.6 103 0.031 1266
no OHR mining
Never smoked 338 9 2.8 106 0.64 103 344 20.7 103 4.1 438
Ex-smokers 177 22 8.6 106 1.7 103 56 9.7 103 3.4 27
Light smokers 318 15 5.1 10 6

0.80 10 3
108 3.3 103
1.1 11
Heavy smokers 1015 99 5.9 106 0.84 103 977 2.4 103 0.15 498
All smokers 1528 138 6.6 106 1.3 103 310 2.6 103 0.033 1034
a PY = person-year.
b A statistical test to see whether the amount of variation explained by the regression is significant.
174. Stram et al. [S60] reported an analysis which used a the simple linear risk model, the authors report = 0.28
measurement error correction of lung cancer risk based on (SE = 0.075), and for the exposure error adjusted model,
fitting a multilevel statistical model to the Colorado Plateau = 0.44 (SE = 0.14), both for the 1950 cohort. Similarly, for
uranium miner cohort data within the same mine, locality the 1952 cohort, the authors report = 0.33 (SE = 0.1) using
and mining district. The authors used two subcohorts from the uncorrected exposure and = 0.54 (SE = 0.2) for the
the cohort of 3,347 white miners employed for at least one exposure error adjusted model. For both cohorts, the error
year in the period 19501960 as defined by Roscoe [R8]. correction increased the risk estimates by about 60%. The
The first cohort (referred to as the 1950 cohort) included authors found a submultiplicative relationship between radon
2,074 miners with 263 lung cancer deaths who had their exposure and smoking, both with and without error correc-
initial mining experience commencing in 1950 or later. The tion. The authors also observed an exposure-rate effect; this,
second cohort (referred to as the 1952 cohort) included however, diminished after correction for exposure measure-
2,388 miners with 209 lung cancer deaths. The authors ment error. With their simplified BEIR VI model, the effect
noted that the reason for the selection of the 1952 cohort of low exposure rate (015WL) was essentially the same
was that systematic measurement of radon in mines did not with and without measurement error correction.
start until 1952. The approach to (exposure) error correc-
tion was based on a computation of the exposures (WLM) 175. Gilliland et al. [G4] reported a study of the exposure to
for each year and mine of interest. The authors investigated RDPs and lung cancer risk in non-smoking uranium miners.
a number of models for lung cancer mortality, including a The authors used casecontrol methodology and conditional
simple linear ERR model of the form 1 + (t), where logistic regression analysis to investigate the relative risk of
is the ERR per 100WLM and (t) is the miners cumula- death as a function of cumulative exposure to RDPs. Their
tive workplace radon exposure up to 2 years prior to the findings are in close agreement with a parallel analysis of
attained age. In addition, the authors investigated several miners reported by Lubin et al. [L10]. The authors con-
models, including a simplified BEIR VI model, of the effect cluded that non-smoking miners were indeed at increased
of smoking, attained age and time since exposure. For risk of developing lung cancer.
176. Luebeck et al. [L16] noted that with their biologically each and the remaining 24 cases with fewer than 40 con-
based model and parameters applied to the Colorado Plateau trols (all controls were used). The relative risk of lung cancer
miner cohort, an inverse dose-rate effect was not seen with lev- increased for about 8years and then decreased, reaching
els of exposure typical in residences. The ERR was estimated background levels after about 34years. The decline in risk
to be about 0.0078 (95% CI: 0.0036, 0.0165) per WLM for with increasing time since exposure was much more pro-
25years of residential radon exposure at a level of 150Bq/m3. nounced in persons over 60years of age. Hauptmann etal.
This is consistent with the value reported from a ratio analysis [H30] reported on the use of splines (piecewise polyno-
of eight epidemiological analyses of residential radon exposure mial functions) to analyse latency in the Colorado uranium
[L4]. Finally, Luebeck et al. [L16] noted that the comparable miner cohort and reported similar results, with ERR>0 for
risks in the BEIR VI report, expressed as lifetime risk, were the period from 9 to 32 years prior to the identification of
higher than their own estimates by a factor of 24. lung cancer. The ERR reached a maximum of about 0.6 for
100WLM about 14 years after exposure and decreased to
177. The Navajo of the south-west United States were about 0.02 thereafter [H30].
involved in the mining and milling of uranium ores in the
Colorado Plateau area from the 1940s to the 1970s. The 1995
study of Roscoe et al. [R9] updated an earlier study [A4] of 6. Evaluation
mortality among Navajo uranium miners. The 1995 study
reported on a cohort of 757 Navajo miners with vital status 180. Estimated exposure rates for individual miners in the
followed from 1960 to 1990 and a mean cumulative expo- Colorado Plateau area have large uncertainties due to: varia-
sure of 755WLM accumulated over an average of 8.3years tions between workplaces within mines (even for those mines
of underground work. The exposures were based on the work where RDP concentrations were measured); the necessity to
of Lundin et al. [L13]. A life table approach based on mor- use guesstimates, extrapolations or estimates from other
tality data for non-white men in New Mexico and Arizona, mines in the area; uncertainties in OHR mining exposures
direct standardization of rates and internal comparisons before (and possibly after) employment at uranium mining
between the exposure categories were used to analyse the facilities; and discrepancies in the work histories of those in
cohort. All exposures were lagged five years, to represent a the sample group examined. There are significant discrep-
reasonable minimum period for the induction of lung cancer. ancies in the work histories of workers who worked under-
A Cox regression analysis was used to account for simulta- ground part-time. Furthermore, the average WL values may
neous risk factors and the use of external mortality rates. The not apply to this type of worker, as they may have worked
time-dependent regressors considered in the model included in areas subject to lower ventilation rates than those for the
cumulative exposure, log cumulative exposure, duration of other workers. Reconstruction of exposure histories from
exposure, log exposure rate, log cumulative pack-months of company records is probably not feasible, because work-
smoking, time since first exposure and others. ers tended to work in numerous mines, for which few or no
records are available. However, it should be possible to study
178. Standardized mortality ratios for a number of causes a statistically valid sample of miners and from these investi-
of death (heart, circulatory and digestive diseases) were low- gations to draw conclusions concerning the uncertainty asso-
ered. Of the diseases examined, only the values for lung can- ciated with the estimates of exposure for the cohort per se.
cer, pneumoconiosis and other respiratory diseases were
elevated. The mean exposure to RDPs among the 34 deaths 181. Overall, notwithstanding limitations in the exposure
observed from lung cancer (versus 10.9 expected) was data, the Colorado Plateau cohort of uranium miners is an
1,517WLM. Smoking status for the miners with lung cancer extremely valuable resource for risk estimation. It provides
was similar to that for the entire cohort of Navajo miners. A one of the most substantial bases for risk estimation for groups
log-linear model and a linear model in cumulative exposure exposed to RDPs, and the best information on smoking histo-
fitted the data equally well, and yielded ERRs of 13.8 and 9, ries. The prominent strengths of this group include: the size of
respectively, for a cumulative exposure of 400WLM relative the cohort; the extent of follow-up; the considerable amount
to no exposure. Unlike the case of the white miners, smoking of exposure information for the periods of interest (prior to
was not strongly associated with lung cancer risk in the Nav- the mid-1960s); information on smoking; and the possibility
ajo cohort. The authors attributed the excess non-malignant to assess the effect of OHR mining. Although no systematic
respiratory disease (standard mortality ratio of 1.4) to be due bias was identified in the estimates of the exposures for this
mainly to pneumoconiosis and exposure to silica and other cohort, the uncertainties in the exposures of individual miners
workplace contaminants rather than to radon. are very large, particularly for the early years of mining.
179. Latency is an important consideration in evaluating

potential lung cancer risk following exposure to RDPs (e.g. B. Canada: Ontario uranium miners
[C20, L10, N7, N11]). Langholz et al. [L39] reported on
an investigation of methods to assess latency effects and 1. Introduction
an analysis of latency in Colorado Plateau uranium miners
using a nested casecontrol methodology with 263lung can- 182. Uranium mining in Ontario started in the early to mid-
cer deaths. Of these, 239 cases were matched to 40controls 1950s in the Elliot Lake area. Uranium production developed
rapidly to reach a peak during 19571960, and declined just methods of mining and ventilation were incorporated. Con-
as rapidly after 1960. To illustrate this, there were 2 oper- siderable information about exposure conditions in Ontario
ating uranium mines in 1955, 15 in 1958 and 5 in 1964. mines is given in Ham [H1] and in Muller et al. [M19].
The period during which the largest exposures occurred for
Ontario uranium miners was relatively short (10 years or 185. Ventilation flows changed in Ontario mines over the
so). In total, more than 16,000 men were employed in the same time period. McCrodan [M4] reported ventilation rates
Ontario uranium mines at various periods between 1955 and for two of the Elliot Lake mines (table11).
1977 [M8]. By 1988, only two uranium companies, both in
Elliot Lake, remained in operation, and by 1993, only one of 186. The Ontario investigators recognized that estimates
these, Stanleigh, remained in operation. It ceased operations of RDP concentrations involved some uncertainty, espe-
in 1996. cially for the early years of mining for which relatively few
reliable measurements were available. The epidemiological
183. Muller and co-workers have carried out a number of investigators worked together with mine ventilation engi-
studies (e.g. [K13, M3, M8, M15, M19, M21, M22, M23, neers who were familiar with the Ontario uranium mines
M24, M25, M26]) on some 50,000 men who worked in one over the early years of operation to develop two estimates
or more mines in Ontario. The Ontario miner population was of RDP concentrations, standard WL and special WL,
subdivided into gold miners, nickel/copper miners, iron ore in an attempt to bracket the uncertainty [M19]. Muller and
miners, uranium miners, other ore miners and a mixture of his co-workers suggested that the standard WL estimate was
miners. Men who worked at the Eldorado Mining Companys more representative of a miners exposure, while the special
Port Hope plants or in Eldorado mines in Saskatchewan or WL estimate was probably on the high side.
the Northwest Territories, as well as those with documented
exposure to asbestos, were treated separately. This left a 187. In 1985, a reconstruction of early underground ura-
cohort of about 15,000 miners with exposure in Ontario nium mining environments was undertaken [D7]. Mining
uranium mines. Men were considered to have entered the practices during the late 1950s and early 1960s in the Elliot
study at the time of their first medical examination (between Lake area were reproduced in reconstructed underground
1 January 1955 and 1 January 1978) if they reported having mine areas. Extensive measurements were made during these
worked for a half-month or longer in dust exposure in an tests. RDP levels were recorded under a variety of operating
Ontario uranium mine. Miners left the study on 31 Decem- conditions. Under continuous ventilation with compressed air
ber 1981, or at death if this occurred earlier. Miners with ura- (the most favourable condition), exposures during the 1950s
nium mining exposures outside Ontario and asbestos miners were likely to have been not more than double the exposures
were excluded. received by miners today. However, in unventilated areas, the
exposure levels could be as much as 10 times higher than in
mines today [D7]. While this work reduced the uncertainties
2. Radon and radon decay products associated with the concentrations of RDPs, the uncertain-
ties in ventilation practice and in the times spent in different
184. A certain number of workplace exposure data for oper- locations in the mine remained. The 1985 study concluded
ating uranium mines in Ontario became available starting in that a typical raise miner in the 1950s, relative to miners of
1955, although systematic measurements were not started around 1985, would have been exposed to RDP levels three
until 1958. According to Ham [H1], the Ontario Department times higher, about equal levels of thoron decay products
of Mines issued codes in 1957 requiring that various meas- and gamma radiation, and much higher levels of uranium
urements, including measurements of RDPs, be taken in the and quartz dust. Further information concerning the atmos-
mines. Thus, however infrequent, measurements were made pheres of the Elliot Lake mines and the levels of radon and
in each operating mine from that time on. Records of RDP thoron decay products is given in reference [D8]. The meas-
levels for 19541955 show that average RDP concentrations urements made during the reconstruction also confirmed that
ranged from 3 to 7WL and the average exposures of full-time the exposure values used for the early years (specifically for
underground miners from 36 to 84WLM/a. The levels varied raise miners) did not overestimate the working exposures at
(up and down) over time as new mines developed and new that time.
Table 11 Ventilation rates at Elliot Lake mines (adapted from reference [M4])
Year Denison Quirke I
cfmc cfm/tond cfmc cfm/tond
19571958 200000 33 300000 54
1960 300000 70a
1961 350000 59
Year Denison Quirke I
cfmc cfm/tond cfmc cfm/tond
1965 450000 75 85
1965 530000 88
1965 530000 150a
1968 250000 125a
1969
1971 650000 108 400000 200b
1975 650000 108
a Reduced tonnage. d Cubic feet (of ventilation air) per minute per short ton (907.19kg) hoisted to
b Mine reopened. surface.
c Cubic feet (of ventilation air) per minute (1 cfm = 4.72 104 m3 s1).
3. Exposure estimation The key observations concerning exposure estimations for

the Ontario study taken from references [M23, M24] are
188. According to Muller et al. [M19], some 131,000 summarized below:
measurements of RDP concentrations were made over the
1955: 2 uranium mines; sporadic measurements;
period 19551981, using the Kusnetz method. These data
were obtained over a period representing some 141mine- 1958: 15 uranium mines; systematic measurements,
years of operation, which corresponds to 929 measure- assuming 80% of time spent in working
ments per mine-year of operation. Up to 1977, there were areas (headings, stopes, raises) and 20% in
approximately 55,000 measurements representing some travelways;
126mine-years of operation; this corresponds to approxi- 19551981: 131,000 RDP concentration measurements
mately 430 measurements per mine-year of operation over 141 mine-years of operation (an aver-
over this period. Expressed another way, in the period age of 929 per mine-year, though fewer in the
19551977, approximately 1.7 measurements were made early years); mean extrapolation period (pre-
per average man-year worked, or, on average, one WL 1958) of 1.1 years (representing 23% of the
measurement for every 9WLM accumulated by the study total collective exposure expressed in person-
cohort. WLM); standard WL and special WL by
mine and calendar year, with standard WL
189. About 23% of the assigned WLM exposure of the considered more representative.
cohort was based on extrapolated values of RDP concen-
trations, particularly during the early years of mining. The Table12 shows the distribution of collective exposure based
mean period of extrapolation was approximately 1.1 years. on extrapolated and measured WL values.
Table 12 Exposure (WLM) of Ontario miners based on extrapolated WL values [M23, M24]
Calendar year Extrapolated standard WLM Total standard WLM Per cent WLM based on extrapolation
1954 843 843 100
1955 4276 4276 100
1956 20806 20806 100
1957 52263 52263 100
1958 9736 87048 11
1959 10617 81733 13
1960 12902 55275 23
19611977 0 185079 0
TOTAL 111443 487323 23

190. It is not clear how the upper bounds for the expo- excess of lung cancer could be identified in gold miners who
sures of uranium miners from 1955 to 1977 in reference began mining gold after 1945 [K12].
[M19] were generated. Unfortunately, no justifications or
explanations were given; however, as noted earlier, the 195. According to reference [K12], no RDP concentra-
exposures used for the early years were not likely to have tion measurements were made in Ontario gold mines prior
been overestimated [D7]. to 1961. RDP levels in gold mines were variable. In some
mines, average WL values in inactive areas were 0.3WL,
191. The Ontario mining industry experienced frequent while in other mines, levels were below 0.02WL.
changes in market conditions. Mining companies and miners
moved from mining one type of ore to mining another, and 196. Increased ventilation rates and related practices intro-
from one location to another [M19]. According to Muller duced since the 1950s may have had less effect on ore dust
etal. [M15], the miners were all requested to fill in detailed concentrations than on the concentration of RDPs in the
employment information concerning their first 60 months mine air. According to Ham, dust levels in Ontario uranium
of mining experience so that those involved in mining other mines decreased by only about a factor of 2 between 1960
ores could be identified and excluded from the study. and 1975 [H1], while the estimated concentrations of RDPs
decreased by about a factor of 5 over the same period [M21].
192. For the period 19551977, full-time miners were On the other hand, data reported by DSMA Atcon Ltd. [D7]
assumed to spend 80% of their working time underground and by Duport and Edwardson [D10] suggested that the
and 20% on travelways. Part-time miners were assumed to levels of ore dust and/or RDPs in the mine air diminished by
spend 50% of their time underground in areas with higher comparable amounts over the years in the Ontario mines.
than average concentrations of RDPs. Up to the end of 1967,
and in one mine up to 1 April 1968, WLM exposure values 197. In the Elliot Lake mines, thoron decay products also
for each miner were estimated as WLM = WL WHF contributed an appreciable radiological exposure; their
Months, where WL is the weighted average of WL meas- concentrations, however, were less affected by increased
urements in stopes, raises and travelways; WHF is a work ventilation than the concentrations of RDPs [J9]. Data for two
history factor introduced to account for overtime or work Elliot Lake mines reported by Chambers et al. [C2] showed
stoppages; and Months are the total number of actual months thoron decay product levels ranging from 0.1 to 0.3 WL,
worked underground. The Ontario investigators set WHF with parallel RDP levels ranging from 0.2 to 0.5WL. This
equal to unity if normal working hours were maintained. suggests a ratio of thoron decay product exposure to RDP
The WHF was increased or decreased as appropriate if overexposure of about0.5.
time hours were worked or if work stoppages occurred in
a particular calendar year. After 1967, the individual expo- 198. A great deal of information is available concerning
sure estimates were based on time cards, filled out daily by the working environment in the Elliot Lake mines. Some
miners, and on WL measurements made in the particular data were developed by the mining companies for engineer-
work locations reported by the miner on his time card. ing or regulatory purposes, while other data were developed
through the various research activities of the Elliot Lake
193. Smoking information on the Ontario uranium miners Mining Research Laboratory operated by Energy Mines
is very incomplete. The most recent studies of Muller etal. and Resources Canada, the Atomic Energy Control Board
[M23, M24] reported the results of a 3% sample of men born (AECB) of Canada and the mining companies themselves.
prior to 1939. Smoking information was sought on 226 ura- Data are available on various subjects, including: the effects
nium miners who had no former gold mining experience. of using diesel equipment on the characteristics of mine air
Smoking information was also sought on 80 lung cancer [B8, K2, K3]; the composition of the mineral dust (70%
deaths that occurred between 1955 and 1981 in the cohort quantity) [B7, K4]; particle and activity size distributions
of uranium miners with no former gold mining experience. [B6, B9, D10]; gamma radiation levels [C5, C6]; and arsenic
Of the 80 lung cancer deaths, smoking information was levels in Ontario gold mines [O1]. A 1986 study [S11] exam-
obtained on 73 men; of these, 72 were smokers or former ined the potential to use electrostatic precipitation to reduce
smokers [M22]. radioactive aerosols in underground uranium mine atmos-
pheres. This study further summarized available data on dust
194. Studies of lung cancer incidence and mortality in loadings, particle size distribution and the attached fraction
Ontario gold miners reported by Kusiak et al. [K11, K12] of the RDPs. Overall, detailed information is available to
suggested that both radon and arsenic might be causative characterize the mine environment for the 1970s onward, but
factors in lung cancer. Kusiak et al. [K12] noted that avail- little information is available for earlier times.
able data indicated that dust concentrations in some gold
mining occupations in the 1930s and 1940s were often
above 1,000particles/mL (p/mL), decreasing over time to an 4. Epidemiological analyses
average of 400p/mL by 1959 and 200p/mL by 1967. Geo-
logical data confirmed the anomalously high arsenic levels 199. In the Ontario uranium miner cohort, the average
where gold is found... and that arsenic concentrations...are miner had, in 1984, 1 years of mining experience and a
regionally enriched. The authors noted, however, that no median age of 39 years. Overall, there was an average of
15.1person-years at risk per man. Muller et al. [M26] reported 203. One of the most important observations from the
mean exposures for this group in the range 4090WLM. Ontario miner study was the use of a time since exposure
effect, where the risk of lung cancer decreased with increasing
200. The present cohort consists of men who worked a time since exposure [M22]. NCRP Report No.78 [N7] previ-
half-month or longer in an Ontario uranium mine between ously reported a doseresponse model where the excess abso-
1January 1955 and 31 December 1977 [M19]. The exclu- lute risk of lung cancer was assumed to be zero before 40years
sion of those with known asbestos exposure or with expo- and then, following an initial latent period of five years, to
sure in uranium mines other than in Ontario reduced the decline exponentially with time since exposure. The concept
cohort size to 15,984 men. It was discovered that 66% of of declining risk with increasing time since exposure was sub-
these miners had OHR mining experience and that OHR sequently incorporated in the analyses of others, including
mining, particularly gold mining, increased the risk of Lubin et al. [L10], BEIR IV [C19] and BEIR VI [C20].
lung cancer significantly [M23, M24, M26]. Exclusion of
miners with OHR mining experience reduced the cohort
size to 5,443 [M19]. The Ontario studies demonstrate the 5. Evaluation
importance of identifying OHR mining experience, since
uranium miners with previous gold mining experience 204. The Ontario miner study is a large well-defined study
exhibited excess risk of lung cancer even at zero expo- cohort with considerable information available on which
sure from uranium mining. In men who worked as gold to base exposure estimates. Researchers have attempted to
miners before becoming underground uranium miners, assess the effect of uncertainty in exposure through the use
92deaths from lung cancer occurred, compared with the of standard and special working levels, which are mainly
55.7 expected [M22]. estimates. While more could be done in quantitatively evalu-
ating the effect on dose response of uncertainty in exposure
201. In a follow-up analysis of mortality from lung cancer estimates, the cohort provides one of the highest-quality
in Ontario uranium miners, Kusiak et al. [K13] re-examined studies available for radon risk estimation. Future updates
the Ontario uranium miner cohort; mortality follow-up was will further increase the value of this cohort.
extended from 1981 to 1986. An association between excess
lung cancer and RDP exposure was found in the miner
cohort; this was similar to that found in the same cohort with C. Czechoslovak miners
follow-up to 1981. The study found that lung cancer mor-
tality in Ontario uranium miners who also mined gold was 1. Introduction
related to exposure from both RDPs and arsenic.
205. Mining in Jachymov (Joachimsthal), Bohemia (now
202. In a cohort and casecontrol analysis of Ontario in the Czech Republic), started at the beginning of the 16th
miners, Finkelstein [F13] investigated the presence of sili- century. Thousands of silver miners were involved. Mining
cosis as a risk factor for lung cancer. A cohort of 382 min- for cobalt, bismuth and arsenic started later in the 16th cen-
ers with silicosis and 970 controls were developed from tury. In the middle of the 19th century, uranium was mined
the 68,000 workers in the Ontario database. Data were for use in the glass and porcelain industry. Between 1909
available for 94% of the silicosis cases and for 99% of the and 1925, Jachymov was devoted to pitchblende mining in
controls. In discussing his cohort analysis, Finkelstein noted pursuit of 226Ra, with an average annual production of about
that there was a significant excess of cancer (mainly lung 26g of radium [L6].
cancer) in miners with silicosis and that men with normal
radiographs had a lower cancer incidence than the Ontario 206. Mining conditions in the early years were poor. The
average. Finkelstein used a casecontrol methodology and mines were usually damp (especially in the spring when the
logistic regression to assess the risk of cofactors. He found snow was melting) and cold. Miners had to descend ladders
that silicosis is a highly significant risk factor for lung can- hundreds of metres to their working areas. Natural ventila-
cer. In an analysis of cumulative risk, Finkelstein calculated tion was provided by a gallery between all the mines, and,
a weak association between silicosis and lung cancer with according to Lorenz [L6], it was generally sufficient,
OR= 1.004 (95% CI: 0.9967, 1.011), while in his model of except in dead-end shafts.
the joint effect of cumulative radon exposure and silicosis, he
found no association of lung cancer with radon (OR =0.995; 207. Although high death rates among miners in their
95% CI: 0.986, 1.004) and a strong association with silico- prime years caused by lung-related diseases were recognized
sis (OR = 6.99; 95% CI: 1.91, 25). BEIR VI [C20] and the and recorded as early as the 1550s, no detailed studies of this
UNSCEAR 2000 Report [U2] reviewed the available data on were performed. In 1879, Harting and Hesse (as reported
the effects of exposure to silica in underground miners and in reference [L6]) became the first to conduct organized
commented on various studies, including that of Finkelstein investigations on workers at the Schneeberg mines, which
[F13]. Overall, there is a range of opinions on the effects are across the border from Bohemia, in Saxony (Germany).
of exposure to silica in the mining environment, and some They found that 75% of the deaths were caused by malig-
uncertainty remains concerning the influence of silicosis on nant growths in the lung, and that the incidence was greater
risk of lung cancer. among miners than among masons or carpenters working
in the mines [L6]. From 1869 to 1877, 150 deaths due to 213. Working conditions were improved as the knowledge
miners disease were identified in a workforce of 650 men. of the risks of lung cancer in miners from exposures to short-
The onset of the disease occurred after about 20 years of lived RDPs increased. According to Vesely and Sada [V1],
work in the mines. According to Lorenz [L6], Harting and a dramatic reduction in radon concentrations took place in
Hesse were the first to diagnose miners disease as lung can- Czechoslovak mines during the 1950s. Mean cumulative
cer but, owing to the high levels of dust in the mines, they exposures of about 310WLM were reported for a cohort of
assumed that the inhaled arsenic and poor nutrition were the miners who started work in 19481952. The mean cumula-
predisposing factors for the disease. tive exposure of miners starting work in the years 19681972
was 40 times lower [S24].
208. A more recent paper by Greenberg and Selikoff [G7]
reappraises the data reported by Harting and Hesse in 1879,
and of the early efforts to identify the cause of lung disease 2. Radon and radon decay products
among the miners and to measure how much dust the miners
inhaled. One experiment (as reported in reference [G7]) con- 214. Pirchan and Sikl [P5] reported three active pits in
cluded, a miner inhaled 0.231g [sic] of dust in a 7h shift. Jachymov prior to 1930. The quantity of radium emana-
Unfortunately, it is not clear whether the studies of Harting tion (radon) found in the air discharged from the Svornost
and Hesse led to any improvement in working conditions. (Harmony) pit (depth 500m) was 4 Mache units, from the
The identification of RDPs as the primary causal agent was Werner pit (depth 476m) 15 Mache units and from the Saxon
left to later investigators. Nobility pit (depth 120m) 10 Mache units. (One Mache unit
is approximately 10Bq/L, see Behounek [B3]). Pirchan and
209. More investigations followed. Rostoski and Saupe, in Sikl realized that radioactivity levels varied throughout the
a 1921 study of selected miners and non-miners (507 people mine and suggested taking measurements at various loca-
in all), identified lung cancer as a common cause of death tions to assess the exposures to miners [P5]. Lorenz [L6]
among miners [L6]. made a similar observation.
210. Pirchan and Sikl [P5] observed the first case of lung 215. Water is a significant source of radon in under-
cancer in Czechoslovak radium workers in 1926. In 1929, ground mines. The Czechoslovak mines were no exception.
Lowy [L48] reported two deaths of Jachymov miners from Behounek [B3] reported radon in groundwater at levels of up
lung cancer. Further study of the issue was commissioned by to 426,000pCi/L in the Jachymov mining district.
the Czechoslovak Ministry of Public Works. In 19291930,
Pirchan and Sikl [P5] examined necropsies in 13 of the 19min- 216. Systematic radioactivity measurements were not per-
ers who died during that period. They stated that lung cancer formed in Jachymov until the late 1940s. From 1949 to 1960,
incidence was highly prevalent in Jachymov miners and sug- radon concentration measurements were recorded. Hundreds
gested that radium emanation (radon) was the most probable of readings for each uranium mine for each year during this
cause. Lorenz [L6], however, later suggested that genetic sus- period are available [S18]. The classical method was used
ceptibility to lung cancer in miners must be unusually high. to measure radon, i.e. measuring the current with an elec-
trometer in an ionization chamber [S20]. The measurement
211. Once radioactivity was recognized as a major cause of RDPs did not begin in Jachymov until 1960 [S20]. In
of lung cancer deaths among miners, measures were taken 1968, personal exposure records, which took working place
to reduce exposures. Drilling with water wash-out was and work time into consideration, were established. The
introduced around 1930 to reduce the amount of airborne records were reported quarterly for each individual [S29].
radioactive dust [S24].
217. Data on attached/unattached fractions are sparse. Some
212. Prior to 1932, the mines were ventilated using natural data were collected from 1963 to 1965 by the Czechoslovak
ventilation alone. Beginning in 1932, this was in some cases Academy of Sciences. These measurements indicated that,
reinforced by mechanical ventilation. After the Second World typically at that time, the fraction of free unattached radium
War, mining started again. As early as 1946, the Czecho- A (historical name for 218Po) atoms was approximately 10%
slovak Ministry of Health started collecting miner mortality in the Czechoslovak mines. The AMAD (activity median
data to better understand the hazards of exposure to RDPs. aerodynamic diameter) was estimated to be between 0.05
Up until 1952, ventilation continued to be mainly by natural and 0.2m, with the mean at about 0.1m [H2].
means; however, in the 1950s, artificial ventilation, both gen-
eral and local, was systematically introduced into all mines. 218. In 1968 and again in 1973, there were ventilation
From 1955 onward, all mines were mechanically ventilated. incidents in underground uranium mines in Czecho-
From 1956 onward, auxiliary ventilation was also provided slovakia [H2]. In both incidents, mechanical ventilation
in selected areas where appropriate. In 1954, the Czecho- stopped for a period of time. During these periods, radon/
slovak Hygienic Service started undertaking inspections of radon decay product levels were measured to assess the
working conditions in uranium mines. Increased efforts to equilibrium conditions that might have existed in the early
reduce radioactive contaminants by increased ventilation days of mining, prior to the introduction of mechanical
and tighter safety regulations commenced in 1966 [V1]. ventilation. On the basis of data collected during these
two incidents, an overall equilibrium factor of approxi- 219. During the period 19481952, when the uranium
mately 86% for the period 19481952 was estimated. It mines in western Bohemia were naturally ventilated, 40%
was noted, however, that in some of the newer mines, the of the measurements indicated radon levels in excess of
situation was better. From 1953 to 1959, a nominal equi- 1,000pCi/L. The early high radon levels and the improve-
librium factor of approximately 55% was assumed. For ments that took place are illustrated in figureV. The break
the period 19601966, a radon equilibrium factor of 36% in the curve shown in figureV indicates the change from
was assumed; some of the older mines had higher equi- routine radon measurements to routine RDP measurements
librium factors and some of the newer mines had lower as the primary basis for the estimation of exposure.
equilibrium factors.
FigureV. Evolution of the average radon concentrations, 19491968 (right ordinate axis), and the average potential (alpha)
energy concentration, 19691981 (left ordinate axis) [H2, K7].
60
35
CONCENTRATION OF POTENTIAL ENERGY (10 MeV/L)
ACTIVITY OF RADON PER UNIT VOLUME (kBq/m)

50
30
25 40
20
30
15 Radon
20
10
Potential energy 10
5
0 0
1945 1950 1955 1960 1965 1970 1975 1980 1985 1990
YEARS
220. The free unattached fractions of RDPs shown in table13 ventilated) showed low unattached fractions. In one
were obtained from a series of measurements in uranium mines series of measurements, 1.6% 0.8%, and in a second,
in Pribram, Czechoslovakia, in 1988 and 1989 [H2]. larger series, 2.3% 1.3%, of (equivalent) RDPs were
unattached [H2]. According to investigators, Jachymov
221. Measurements made more recently in an east- mines were thought to have unattached fractions of
ern Slovak iron ore mine with high dust levels (poorly 610% [H2].
Table 13 Unattached fraction of RDPs in Czechoslovak mines (adapted from reference [H2])
Range (%) Mean (%)

218
Po 12.043.0 27.5
Pb
214
4.015.7 9.4
214
Bi 0.610.0 5.3
Overall 5.923.0 14.4

3. Exposure estimation miners with pre-1948 exposures, and therefore this aspect
is not important.
222. Sevc et al. carried out the main Czechoslovak epide-
miological studies on uranium miners. The first study was 227. The employment history of the miners is another very
in 1971 [S17] and there have been several updates [K8, K9, important factor in estimating exposures. Jachymov is situ-
S18, S19, S20, S25], the most recent being in 2004 [T40]. ated in the Erzgebirge (Ore Mountains), where abundant
The study involved miners who started uranium ore mining minerals are found. As discussed earlier, there was a long
between 1948 and 1957. Sevc et al. [S20] reported that history of mining prior to 1909, when pitchblende was first
estimates of working levels of RDPs (WL) or radon gas mined. The early miners probably had previous mining expe-
concentrations were made on the basis of records of the ven- rience (e.g. [L6, P2]). On the other hand, tin mines in the
tilation conditions and practices, emanation rates from dif- Erzgebirge were not operated between 1931 and 1939, and
ferent types of ores, and RDPs measurements made in 1960 during the Second World War, the mines employed mainly
and later and also the values for working level months prisoners [T40]. These facts limit the possibility of previ-
(WLM) were estimated on the basis of radon gas measure- ous mining experience among cohort members, and this is
ments and from data on the number of months of employ- consistent with Sevcs claim that less than 2% of the epide-
ment with each mine and within each calendar year of the miological study group mined non-uranium ores before they
whole employment period for each miner. No further details mined uranium [S24].
were given of how each factor was accounted for. However,
the authors estimated the coefficients of variation for WL 228. By definition, a working month conventionally now
estimates to be <27%, and <30% for WLM estimates. means 170 hours of work. If a miner held more than one job
with a mine in the 1920s1950s, the working hours spent in
223. The average annual RDP concentration (WL) in each each would need to be taken into account in order to deter-
shaft was used to calculate each mans exposure on the basis mine his exposure. Sevc et al. [S20] stated, however, that
of his working time. Payroll cards were available for all men only the number of months of employment during a year
in the study groups. Beginning in 1968, individual personal was taken into consideration. There was no evidence that
dosimetry cards recorded each miners exposure. Discus- the miners actual working patterns were incorporated in the
sions with the Czechoslovak investigators indicate that the WLM estimations. In discussions held in 1988, the Czecho-
exposures estimated using time-weighted area measure- slovak investigators commented that the workers spent about
ments are unlikely to differ by more than a factor of 2 from 80% of their time in the workplace and 20% in the trans-
those obtained from personal dosimetry [H2]. port ways. In the early days, the men worked 8hour shifts
(3 shifts per day), 6days per week. After 1968, the normal
224. Radon measurements were obtained for four types working week was reduced to 5 days. Uranium miners had a
of working area: mine workplaces in close proximity to the total of 5 weeks of leave per year. By 1990, retirement from
ore (stopes), where the levels were the second highest in the uranium mining was mandatory at age 50, but some retired
mine; hallways and corridors where there was no ore; chim- uranium miners often continued to work in other (especially
neys (raises), where the levels were the highest; and transport coal) mines. After 1966, people over 40 years of age were not
ways. Where no data existed on a working area, the average accepted into uranium mining as new miners. Later reports
value for the entire mine in a given year was used. Typi- [T37, T38] on the Group S cohort gave more details on how
cally, 20% of the total number of measurements was made information on jobs was used.
in transport ways and 80% of the measurements were made
in the other working areas. 229. On the basis of more recent (preliminary) surveys
[T29], Czech investigators estimate the exposure of the gen-
225. Individual miner exposures were calculated on the eral population to RDPs in typical areas of the Czech Repub-
basis of job descriptions recorded in personnel cards for lic to be about 0.34WLM/a, whereas some residents of the
all miners (the use of which was begun in 1948 for payroll Jachymov area could be exposed to 34WLM/a. However,
purposes). The estimates of time spent in the workplace are preliminary evaluations suggest that correction for at-home
thought to be reasonable, since the miners were under sur- exposure, which would have shifted miners to higher expo-
veillance by a controller and a mine technician, the latter sure categories, did not affect the risk estimates significantly.
being responsible for rating the workers pay. The effect of exposure away from work is subject to ongoing
investigation.
226. Very few measurements of the concentrations of
radon in the workplace are available for the years before
1948. Estimation of the exposures of miners before this 4. Epidemiological analyses
date would require consideration of many factors, includ-
ing the radon levels recorded in later years and knowledge 230. Czech investigators have studied several groups of
of early mining practices and ventilation systems. How- underground uranium miners. The most studied group is
ever, according to Hamilton et al. [H2], Group S consists of the Group S cohort. These miners represent approximately
Czech miners who began mining in the period 19481959 11% of the underground miners employed in the Jachymov
and worked for four years or more; it does not include and Horni Slavkov mines. The cohort originally included
4,364 men [S17]. Reported differences in the size of this differ from that of the general population. This approach is
cohort are due to whether or not emigrated miners were close to the internal approach if additional stratification for
included. The most recent results for the Group S cohort age and calendar year is used [T2, T26].
included 4,320 miners [C20, T37].
233. In the past, papers on epidemiological studies of
231. In discussing the accumulation of WLM exposure, Czech miners did not usually indicate the numbers of min-
Sevc et al. [S20] indicate that person-years at risk were ers involved, and therefore it has sometimes been necessary
assigned totally to the final WLM category reached by each to back-calculate from reported data to obtain the number of
individual miner, rather than being distributed across each miners in the various groups. However, in the first paper [S17]
WLM interval as they accumulated. This affected the esti- and since 1988 [S25], the numbers of miners were reported.
mation of the expected number of lung cancer cases in each
exposure category. This difference was discussed by Kunz 234. In 1988 [K7, S25], investigations of other study
et al. [K8], who re-evaluated the epidemiological data of groups were reported (table 14). These include Group S,
reference [S20] and concluded that the distortion caused by with subgroups A and B covering the underground uranium
earlier methods was not large. Since 1978, all analyses [K8, miners whose exposure began during 19481952 and 1953
K9, S25] have used the conventional approach. 1957, respectively. These two subgroups represent the main
cohort for epidemiological investigations. In addition, inves-
232. In earlier papers (19711988), the observed numbers tigations of a number of other study groups are also reported:
of deaths from lung cancer were compared with the numbers study Group N, which comprised uranium miners who
expected from general mortality data. This was justified by an started exposure at levels lower than those in study GroupS;
investigation of a random group of 700 miners that showed a small study group, GroupK, which comprised miners in
that 70% were smokers, similar to the general male population iron mines in eastern Slovakia; and study Group L, which
of Czechoslovakia. However, in publications since 1991, the comprised miners from the Czech shale clay mines. Studies
expected numbers were modified by incorporating a multi of non-uranium miners were completed with a Czech study
plicative parameter that allowed the background mortality to of tin miners [T40].
Table 14 Czech and Slovak studies of miners exposed to radon [S25, T40]
Study group Type of mine Location Cohort size Exposure (WLM) Latest reference
S* (= A + B) Uranium Western Bohemia 4320 152 [T38]
N* (= C + D) Uranium Central Bohemia 5622 7 [T38]
K Iron Eastern Slovakia 1056 40 [S25]
L Shale clay Central Bohemia 916 25 [S25]
C Tin Northern Bohemia 2466 54 [T40]
235. A more recent study by Tomasek and Placek [T2] on individual dosimetric records. For the newer subcohort
investigated risks to a subgroup of miners whose exposures (N), smoking data were available for most (about 85%) of
were restricted to lower exposure rates. This subcohort had the miners. For the older subcohort (S), smoking data were
a total of 419 lung cancers to the end of 1995. A decrease in available retrospectively for 279 cases and 410 (nested-in)
relative risk with time since exposure and age at exposure controls. Follow-up was to the end of 1999. The analysis
was observed. Differences in the risk estimates for epider- was based on a relative risk model that allowed considera-
moid and small cell cancers were also identified, although tion of time since exposure and attained age or age at expo-
each had a pattern of risk similar to that of lung cancer sure. Excess relative risk (ERR) was linearly dependent
overall. The authors found no evidence for non-linearity on cumulative exposures received more than 5 years pre-
or dependence on exposure rate (at RDP concentrations of viously. The ERR was 0.045 (90% CI: 0.017, 0.140) per
below 8WL), although the average dose-rate effect was seen WLM among non-smokers (42 cases) and 0.02 (90% CI:
in the GroupS cohort as a whole. 0.011, 0.035) per WLM among smokers (309 cases); the
differences between the two estimates were not statistically
236. A subsequent study by Tomasek [T26] investigated significant. The lung cancer risk in miners who smoked was
lung cancer risk in a cohort of 5,002 miners exposed in about 10.8 times that in non-smoking miners (this included
two different periods. Exposures of the 2,552 miners in those who had not smoked for the previous 20 years). The
the older cohort (S) were derived from workplace radon ERR was found to decrease by more than 60% per decade of
measurements commencing in 1949. For the 2,450 miners time since exposure and simultaneously by more than 40%
in the newer group of miners (N), exposures were based per decade of age at exposure.
5. Evaluation the survey in a relatively short time. I agree that the

error may be great but it should not be more than 50%,
237. In comparison with studies reported in BEIR VI, the which is acceptable compared to other potential sources
S-cohort had (by 1990) the second largest number of lung of error, even with a very sophisticated method, as local
cancer deaths. Exposure information in the S-cohort is among variations, seasonal variations etc. But we have tried to
the most extensive ([C20], p. 322). Extensive measurements make all necessary corrections for these errors too as
of radon in all shafts are available almost from the first years far as we know them. The result of that survey is seen
of exposure. In results published in 2003 [T30], only 4% of in the table.
all exposure years are not based on radon measurements. The
most recent results on the Czech uranium miners [T39, T40] Radon decay Number of Number of
are based on a total of 929 lung cancer cases. This combined products mines workers
cohort includes a large proportion of miners with exposures
based on detailed personal dosimetric data and provides an <0.1WL 25 1121
opportunity to investigate the role of potential modifiers of 0.10.3WL 13 1740
effect.
0.31WL 17 1739
13WL 5 133
D. Swedish iron ore miners
This was the situation in 1969 and 1970. My part of
1. Introduction the work is to make a qualified estimate of the radon
decay product exposure during the last 20 years, which
238. Iron ore has been mined in Sweden since medi- will be rather problematic I suppose.
eval times. Originally, there was only open-pit mining, but
around 1910 underground mining started [E1, E2]. Before 241. The Malmberget mine, as it now exists, is actually a
1945, ventilation was entirely natural. According to Axel- combination of several mines that initially were separate. The
son [A11], some mechanical ventilation was developed dur- iron ore deposit at Malmberget consists of about 20distinct,
ing the 1940s and 1950s to prevent water freezing under- large ore bodies that outcropped to the surface; in these ore
ground. Air was warmed by taking it through old shafts bodies several open pits were started. Most of these mines
before it reached the workplaces. Snihs [S36] commented were in line with each other, separated by low-grade iron ore
that in some mines, ventilation air was brought into the mine formations.
through crushed rock; this method, although reducing air-
borne dust and raising the inlet air temperatures, also picked 242. Open-pit mining in the Malmberget mine area first
up any radon emitted from the old shafts or crushed rock. In began in about 1890. Even later, when the depth required
addition, travel time resulted in the ingrowth of RDPs. for mining forced a change from open-pit mining to under-
ground mining (by about 1930 all mines were underground),
239. According to Snihs and Ehdwall [S36, S39], the the bottoms of the mines were still above the general level of
primary sources of radon in the Swedish iron mines were the surrounding terrain. The adits could therefore be driven
incoming radon-rich water and, to a lesser extent, radon from the side of the mountain to the bottoms of the under-
from radioactive minerals. The uranium content in the waste ground mines, which in turn were connected to the bottoms
rocks in the iron mines was of the order of 1520 ppm [S39]; of the open pits, thereby permitting natural ventilation of
however, relatively high emanation coefficients (3040%, the mines. By 1955, the bottom levels of the mines reached
measured in accordance with the procedures set out in refer- below the level of the country surrounding the mountain, and
ence [A20]) for some of the rock were a contributing factor the efficiency of natural ventilation declined as progressively
to elevated radon levels in these mines. The radon problem lower levels were developed.
having been identified in about 1968, ventilation in the Swed-
ish mines was gradually improved. The ventilation path was
changed to bypass crushed rock and incoming groundwater,
thereby leading to reductions in exposure [S37]. 2. Radon and radon decay products
240. Snihs [S16] summarized the status of knowledge 243. Early Swedish mine and miner data are summarized
about RDP levels in Swedish mines around 1972: in annex G of the UNSCEAR 1977 Report [U9].
We measured only the radon concentration in many 244. According to Snihs [S36], the first radon measure-
mines to get a rough idea of the radiation problem in ments were made in the early 1950s in the Boliden mine.
the mines. To get the corresponding radon decay prod- However, limited knowledge about radon problems in
uct concentration we then applied the factor 0.5. The non-uranium mines and a lack of experience in taking
reason why we measured radon only, is that the mine measurements delayed the institution of routine radon or
companies were asked to send samples (in pre-evacuated RDP measurements. A general awareness that many non-
bottles) by post. By that method we were able to make uranium mines had significant radon levels arose in about
1968. This led to radon surveys in which the general proce- the mining areas by these two methods; while the princi-
dure was to take 312 radon gas samples per mine during pal source of radon in the Malmberget mine was likely to
both winter and summer periods. Samples were collected in have been radon-rich mine water, it is likely that additional
evacuated bottles and sent to the National Institute for Radi- radon entered the mine air because of this and the method of
ation Protection (NIRP) in Stockholm for analysis. ventilation.
245. Each mine with RDP levels of 0.3 WL or greater 250. Extensive recirculation of air was widely practised in
was investigated further by NIRP staff. They visited the the Malmberget mine in the 1950s and 1960s. This recircu-
mine and took RDP samples using the Kusnetz method, lation could have permitted the buildup of both radon and
as well as many additional radon gas samples. Typically, the equilibrium factor during that period. Changes in min-
more measurements of radon gas concentrations than of ing methods in the mid-1960s made it necessary to intro-
RDP concentrations were taken. According to reference duce diesel equipment, which in turn led to the requirement
[S28], the equilibrium between radon and RDPs was found to improve mechanical ventilation. Overall, Swent and
to vary greatly but was typically 50%. Chambers [S28] concluded that the pre-1969 WL values
given by Radford and Renard [R2] were likely to have been
246. To provide a basis for estimating the equilibrium underestimated by a factor of above 2, as they did not take
factor, simultaneous measurements of radon and RDP con- into account: the earlier practice of recirculating air in the
centrations were taken. Typically, an average equilibrium mine; the lower volumes of air circulated through the mine
factor was applied to all working areas in a mine or parts in earlier decades; periods of stagnant ventilation airflow,
of the mine [S37]. According to Snihs and Ehdwall [S39], which occurred during the years when natural ventilation
the equilibrium factor varied widely, ranging from 0.15 at was the only ventilation method; and the pattern of decline
the air inlet of the mine to nearly 1 at the air outlet. Average in the incidence of silicosis in later years, confirming the
equilibrium factors in workplaces were typically between improvement in ventilation.
0.4 and 0.6 [S39]. Axelson [A11], however, felt that a more
appropriate typical equilibrium factor was0.7.
3. Exposure estimation
247. Swedish measurements of radon were typically made
by the NIRP using 4.8 L conventional propane contain- 251. Snihs [S36] developed his estimate of risk of lung
ers. The containers were evacuated by the NIRP and sub- cancer by assuming that RDP levels in Swedish mines meas-
sequently opened at places of interest in the mines. After ured since 1969 were representative of earlier years. Snihs
sampling, they were sealed and mailed back to the NIRP for [S36] made qualified guesses for exposures that may have
analysis in ionization chambers [S39]. occurred in relation to the observed mortality from lung can-
cer. Snihs and Ehdwall [S39] provided further discussion of
248. Following the first measurements of radon, the mines the measurements of radon and RDPs that were started only in
were divided into zones by radon or RDP level and subse- the late 1960s in Swedish non-uranium mines. These authors
quently checked according to the following frequency: noted that the earliest measurements of radon in mine air at
Malmberget were in 1968 but that subsequently extensive
Zone 1: <10 pCi/L (<0.1 WL), once every measurements of radon and radon decay product concentra-
twoyears; tions in air were made by the NIRP and the Swedish min-
Zone 2: 1030pCi/L (0.10.3WL), every year; ing company LKAB. Radford and Renard [R2], noting that
the new ventilation system for mines became operational in
Zone 3: 30100 pCi/L (0.31 WL), once every 1972, stated that the reconstruction of past concentrations
sixmonths. depended on the measurements made during the period
For areas with levels of greater than 1WL, measurements 19681972 and on knowledge of the natural and mechanical
were to be taken every three months, according to Snihs and ventilation used previously. However, the authors noted that
Ehdwall [S37]. the reconstruction of Malmberget exposure data depended
on the assumption that ventilation conditions in the mines
249. In 1986, Radford and St. Clair Renard reviewed the in 19681972 were not greatly different from those in the
history of mining methods and of general ventilation in the past [R2].
mines (reported in reference [S28]). When the mines were
first converted from open pits to underground mines, the 252. Key features of the exposure estimation for Swedish
underground method of extraction was by shrinkage stoping. iron miners in the study of Radford and Renard [R2] were:
Small pillars were left between the large shrinkage stopes. 1930: nominal start of the study;
After the shrinkage stopes were drawn empty of broken ore, 1969: first (NIRP) radon measurements;
the hanging wall was allowed to cave in and fill the opening.
Mining methods evolved from shrinkage stoping, followed Until 1973: fresh air drawn through broken rock
by sublevel stoping, and in 1965 by sublevel caving, which (preheated);
allowed even larger quantities of wall rock to cave in. Until 1955: mechanical ventilation introduced to replace
1973, fresh air was drawn through the broken rock left above natural ventilation;
Until about 1965: some air recirculation 4. Epidemiological studies

occurred;
1965: diesel engines introduced into the mines; 257. A number of authors reported epidemiological studies
of Swedish miners, including references [A6, A7, A8, A9,
All exposures guesstimated. A11, A13, C7, D1, D2, E1, E2, J11, J12, J13, L2, R1, R2,
Radford and Renard [R2] assumed constant exposures prior S21, S22, S36, S38, S39]. However, the basic reference for
to 1968. This is unlikely because of the changing ventilation the study of Malmberget iron miners is the paper by Radford
practices (e.g. increased volume and elimination of recircu- and Renard [R2], which included a description of the basis for
lation) and the introduction of mechanical ventilation prior the estimates of exposure to RDPs. This was a retrospective
to the first radon measurements. study of lung cancer mortality in a group of 1,415 Swed-
ish iron miners. The total cohort represented 24,083 person-
253. As discussed above, the data available from meas- years at risk, with an average exposure of approximately
urements of radon and radon decay product concentrations 81.4WLM. The study cohort included men born between
make it possible to estimate relatively well the exposure in 1880 and 1919, who were alive on 1 January 1970, and who
mines after 1970; however, few if any measurement data had worked for more than a calendar year between 1897 and
are available from the period before 1969, and early data 1978. Follow-up of these miners was reported for the period
must be estimated from a combination of later exposure 1 January 1951 to 31 December 1976. The authors estimated
data, reconstruction of measurements and consideration an ERR of 3.6%WLM1, and an excess absolute risk of lung
of ventilation practices, radon sources and other factors. A cancer of 19 per 106 person-years per working level month.
paper by Bergdahl et al. [B45] provides a comprehensive Miners were identified from company and union records of
re-evaluation of radon exposures in the Kirunavaara and active and pensioned miners, which were available for the
Malmberget iron ore mines. The re-evaluation suggests that years since 1900, as well as from medical records and, in a
radon levels were higher than in the estimate by Radford few cases, from parish records. The Swedish Government
and Renard [R2], but not as high as suggested by Swent gives every person a code at birth; this code is included in all
and Chambers [S28]. work and hospital records. Every citizen is also required to
register in a local parish of the state church. These require-
254. In the epidemiological study of miners in Malmber- ments helped in locating the miners and their records. Also
get by Radford and Renard, undertaken in 1984, the his- available from company records dating back to 1900 was
torical exposure was estimated from data from 19681972 the total number of man-hours worked underground each
[R2]. Also in this study the equilibrium factor Feq was year in each section of the mine. However, the exact loca-
assumed to be 0.7. The same exposure estimate was used tion of the work within the mine was not available. There is
for all underground workers except those that worked in some uncertainty as to work status for miners who started
Koskullskulle (these workers seldom changed their work- or stopped work or who changed work function midway
ing place; Koskullskulle was a separate mine that was not a through the year. Miners were assumed to work 173 hours
part of LKAB until 1953). The radon exposure (expressed as per month on average in the period 18901930; 162 hours
WLM/a) was estimated in reference [R2] for Malmberget as per month during the period 19301950; and 144 hours per
follows: 19701972: 3.2; 1960s: 4.9; 1950s: 6.2; 1940s: 6.9; month from 1950 onward.
1930s: 4.6; 1920s: 4.8; and 1910 and earlier: 4. For Koskull-
skulle, the authors [R2] estimated the exposure for the period
19201969 as approximately 2WLM/a and for 19701972 5. Evaluation
as approximately 1WLM/a.
258. There were few radon measurements in Swedish
255. Bergdahl et al. [B45] estimated the exposure during mines and none in Malmberget mines prior to 1969. It was
the period 19251972 to have been constant at between 0.8 only after this date that investigations were initiated by
and 17 WLM/a, depending on the ore body in which the the National Institute of Radiation Protection, Stockholm.
work took place. In cases where the location of the work was Therefore epidemiological studies of Swedish miners were
unknown, the exposure was estimated to have been 6WLM/a. based on reconstruction of the radon and radon decay prod-
In Koskullskulle, the exposure in the period 19251972 was uct concentrations to determine the exposure of miners.
estimated to have been 5WLM/a, with values before 1925 Since underground work began in 1932, investigators under-
gradually increasing from the 1910 value of 0.8WLM/a. took this reconstruction for a period of 36 years. During
this period, the conditions in the mines would have changed
256. The principal differences between the exposure matrix owing to changes in the mining methods and ventilation
proposed by Bergdahl et al. [B45] and the earlier exposure procedures. Two attempts were made to estimate the expo-
estimates of Radford and Renard [R2] are that Bergdahl et al. sures [B45, R2]. The estimates obtained in reference [B45]
used a lower exposure value for 19701972, a higher value for the Malmberget iron miners were higher than those used
primarily during the 1940s and 1950s, and a linear extrapo- in the epidemiological study of Radford and Renard [R2].
lation back to 1890. Furthermore, Bergdahl et al. [B45] used However, to date, no epidemiological re-evaluation of this
substantially higher estimates of exposure for Koskullskulle group of miners using the updated exposure data has been
than did Radford and Renard [R2]. published. These updated exposure data represent a great
improvement in the quality of the data available on the expo- 263. In the cut and fill operation, ore was removed from
sure of Swedish miners and will provide an opportunity to the bottom, and mining advanced upward from one level to
update epidemiological analyses of Swedish iron miners. the next. The sand fraction of the mill tailings was used as
backfill in the mine, with miners working off the backfill to
remove the next lift. Simpson et al. [S30] investigated this
E. Canada: Beaverlodge, Saskatchewan, miners activity as a possible source of radon and concluded that no
positive evidence was found that backfill was a major source
1. Introduction of radon in the mine.
259. The uranium mineralization at Beaverlodge in north- 264. In addition to the Beaverlodge mine, Eldorado devel-
ern Saskatchewan, Canada, was discovered in 1946, and a oped and operated a number of satellite mines. In addition,
prospecting mine shaft (the Ace shaft) was started in 1949. according to Garbutt [G9], there were a number of other
By 1951, the company concerned, Eldorado, had identified uranium mines operating in the Beaverlodge Lake area of
ore reserves sufficient to proceed with uranium production. northern Saskatchewan. Eldorados policy was to recruit
By that time, ore bodies to the west of the Ace shaft had also experienced miners wherever possible. Consequently, as
been identified. In 1951, the Fay shaft was started as a pro- other local uranium mines closed and Eldorado remained in
duction shaft serving the western ore bodies. An underground production, there were opportunities for miners with non-
haulage way also provided access to the Ace ore body. By the Eldorado working experience to migrate to the Beaverlodge
1970s, the mine was over 1.6km deep and extended more operation.
than 5.6km horizontally. In addition, a number of satellite
mines, including two underground mines, were developed. 265. The other (non-Eldorado) uranium mines in the
Mining production in the area increased rapidly during the Beaverlodge area operated for only a few years, and all had
1950s, but fell off in the 1960s as the demand for uranium been shut down by the late 1960s. Most of these mines were
declined. Eldorado recruited experienced miners from the small operations without mechanical ventilation (the excep-
area to work at Beaverlodge. The Beaverlodge operations tion being the Gunnar mine) and hence there was a potential
were closed in June 1982. As the Beaverlodge mine devel- in these operations for high exposures even in a short time
oped, all three shafts were connected underground, and two period.
winzes (shafts that do not come to the surface) were also
constructed. 266. Estimation of individual employee exposures did
not begin at the Eldorado Beaverlodge uranium mine until
260. Mill construction started in 1952, and the first uranium 1967. While some measurements of the concentrations of
concentrate was produced in early 1953. By this time the radon and radon decay products were made between 1954
Verna ore body to the east of the Ace shaft was identified; and 1967, these were intended for monitoring ventilation
work started on the Verna shaft in 1953, with production rather than for personal dosimetry. Eldorado began routinely
commencing in 1956. recording individual exposures in 1968, but considered that
sufficient workplace data were available to assess individual
261. Twelve small satellite mines, most being small open exposures back to November 1966. The radon and radon
pits, were also developed during the 1960s and 1970s [G9]. decay product measurements from the earlier periods were
Two underground mines, Hab and Dubyna, were also devel- summarized and utilized to provide exposure rate estimates
oped, both located several kilometres north and east of the by occupational grouping and year [F7]. These were point
Verna shaft. estimates, primarily based on the median concentrations
recorded during the year, and were subsequently used in the
262. Bloy [B11] noted that the first mining method used original epidemiological analysis of Beaverlodge miners
was shrinkage stoping. This was changed to cut and fill, using [H19].
waste rock and surface sand as the fill material. In turn, this
method was replaced by hydraulic tailings fill. The initial 267. The employee exposures were estimated by merging
ventilation in working headings was mainly by compressed the annual exposure rates with information from the nominal
air from the drills, with some surface air being supplied roll. The nominal roll contained information on age, dura-
by a 16inch (~40cm) metal vent pipe located in the shaft. tion of employment and type of employment for Eldorado
Because of the lack of knowledge of the hazards of radon employees. The resultant exposure estimates were the basis
and radon decay products, the standards used to control the for many epidemiological studies, including the original
mine atmosphere conditions were the same as those used in cohort analysis [H19], a casecontrol study investigating the
gold mines at the time. This involved the measurement of air- effects of smoking and previous work experience [L17], the
borne dust by the konimeter dust sampling method as well as analysis of four underground mining cohorts performed by
radon measurements. An annual objective of the ventilation BEIR IV [C19], and the joint analysis of 11 underground
programme was to maintain a ventilation rate of 1025cubic miner cohorts in reference [L10] and BEIR VI [C20].
feet per minute (cfm) of air per square foot2 of working face.
268. On the basis of these exposure estimates, the appar-
2
1 cfm per square foot = 5.24 103 m3 s1 m2. ent lung cancer risk observed in the Eldorado Beaverlodge
cohort was substantially higher than the lung cancer risk because this method is complicated, most samples taken
observed in the Eldorado Port Radium cohort [H18], where were analysed for radon only.
the estimated exposure rates were typically much higher
than those ostensibly observed for employees who worked 273. According to Bloy [B11], a few measurements of
at the Beaverlodge mine. Given the substantially different RDP concentrations were made in the 1954 survey using
lung cancer risks observed between the two cohorts, and the Kusnetz method. Over time, an increasing proportion of
the importance of epidemiology for estimation of risk from the measurements were done in terms of RDPs. By the mid-
RDP exposure, the Atomic Energy Control Board (AECB) 1960s, the Beaverlodge ventilation department was rely-
of Canada commissioned re-evaluations of the exposure ing primarily on RDP measurements to assess ventilation
rates at both the Beaverlodge [S12, S14] and the Port conditions in the mine.
Radium uranium mine [S15].
274. During the period 1954 to mid-1962, mining engi-
269. Exposure conditions were re-evaluated for under- neers also began measuring radon gas concentrations in
ground work areas at Beaverlodge between 1949 and 1968, the Beaverlodge mine as a means to determine the ade-
when individual employee exposure estimates began. The quacy of mine ventilation, and not necessarily to deter-
re-evaluation of Eldorado Beaverlodge exposure rates sug- mine miner exposures to RDPs. Radon concentrations
gested that previous estimates were underestimated by were converted to RDP concentrations by use of equilib-
about 50% [S12]. The re-evaluation study noted that expo- rium factors determined in the years 1954, 1956, 1959 and
sure rates varied significantly (i.e. by more than a factor of 1961 from the simultaneous measurement of radon and
10) between different areas of the mine. As a result of this radon decay product concentrations. A large amount of
workplace variability, substantial uncertainty in individual data from the mine operating statements and radiation log-
employee exposures resulted when an average mine-wide books was captured in an electronic database by the 1991
estimate was assigned. SENES analysis [S12].
270. A detailed investigation of Eldorado Beaverlodge 275. Prior to mid-1962, most of the radiation measure-
records was conducted to further improve exposure estimates ments were for radon. In the years 1954, 1956, 1959 and
for a casecontrol group [S12]. Previous mining experience 1961, as mentioned above, paired measurements were taken
(including experience in gold and other uranium mines) was where radon decay product and radon concentrations were
noted for several of the underground employees; however, measured at the same time in the same workplace. The aver-
these records were largely incomplete, and exposure esti- age radon/radon decay product equilibrium factors were
mates for this experience were not calculated. Improvements calculated from these data. Equilibrium factors for the early
to the Eldorado Beaverlodge exposure estimates involved years (19541956) appear to be generally lower than for later
reviewing stope production records for the presence of years (19661968), and the equilibrium factors for the later
individuals from the casecontrol group. Exposure rates spe- years at high RDP concentrations (>2WL) approached and
cific to the area and the time where the individuals worked, sometimes exceeded the theoretical maximum value of 1.0.
rather than the mine-wide estimates, were then assigned to It was expected that the equilibrium factors for later years
the identified individuals. The individual exposures based on would be lower because of generally improved ventilation
specific mine areas were higher by a factor of 23 than those conditions. Radon concentrations without RDP measure-
based on mine-wide conditions. ments were multiplied by the equilibrium factor to estimate
the corresponding RDP concentrations [S12].
2. Radon and radon decay products 276. The total number of radon and radon decay product
measurements taken per workplace per year was gener-
271. The first measurements of RDP concentrations were ally less than 12 and frequently as low as one. The average
performed in 1954 at Beaverlodge; further measurements during the period 19541968 was about four measurements
were made in 1956 as part of surveys of radiation levels, per workplace per year.
dust levels and general ventilation conditions [F7]. These
initial surveys eventually led to a programme of radon and 277. The mine-wide underground estimates of exposure
radon decay product measurements. Data from the 1954 in units of WL produced in the 1991 SENES study [S12]
survey indicated that simply turning the compressed air are compared with the previous estimates in figure VI on
on or off gave rise to substantial changes in workplace the basis of various interpretations of exposure data, either
concentrations. Whether a miner worked within this enve- WL measurements or WL inferred from radon measure-
lope of fresh air or in the unventilated region outside ments. The estimates are somewhat higher than those cal-
it was thus a very important factor in estimating his true culated using the medians of available exposure (WL) data,
exposure. which included the estimates used by Howe et al. [H19],
which in turn were based on those determined by Frost [F7].
272. Early measurements were for the purpose of providing FigureVII shows that there is considerable variation in WL
data for ventilation control. Originally, only the Tsivoglou values throughout the year in winter, levels are higher
method was available for RDP measurements. However, than in summer and in different years.
Figure VI. Comparison of radon decay product concentration estimates with the previous estimates for the Eldorado
Beaverlodge mine [S12].
9
LEGEND:
Unpublished Eldorado estimates (based on means of WL data)
8
Unpublished Eldorado estimates
AVERAGE ANNUAL RDP CONCENTRATION (WL)
(based on WL means weighted by tonnage production)

7
1977 Eldorado back-calculation of WL
(based on medians of WL data)
6 Frost 1983 (based on medians of WL and radon-derived data)
Frost 1989 (based on means of WL and radon-derived data)

5
Frost 1991 (mine-wide average WL)
0
1949
1950
1951
1952
1953
1954
1955
1956
1957
1958
1959
1960
1961
1962
1963
1964
1965
1966
1967
1968
1969
1970
1971
1972
YEAR
Figure VII. Seasonal variation of radon decay product concentration in Beaverlodge area mines operated by Eldorado [S12].
The high concentration in 1967 coincided with a fan failure.
LEGEND:
2.5
1963
1964
1965
AVERAGE RDP CONCENTRATION IN MINE EXHAUST (WL)
1966
1967
2.0
1.5
1.0
0.5
J F M A M J J A S O N D
MONTHS
278. Several factors changed over time at the Eldorado Bea- 280. An attempt was made [S12] to correct for these effects
verlodge mine. The calendar years from the start of operation by excluding data for stopes and development headings
(1949) onward can be subdivided into five periods based on a where the mine operating statements did not identify any
combination of the production and ventilation characteristics. work activity. This did not mean that work was not going on
The period 19491953 covered the development of the mine in those areas. Therefore this procedure underestimated the
from early shaft sinking to the startup of the mill. The period exposures of radiation technicians and other workers who
19541957 was a period of rapid expansion of the Eldorado might, for various reasons, have been in those areas.
Beaverlodge mine as well as of many other uranium mines
in the Beaverlodge area; mine ventilation increased over the 281. To correct for this, SENES [S12] weighted the reported
period concurrent with substantial development work. The WL values by the recorded level of activity as measured in
period 19581962 was one of relatively little development man-shifts. However, there was oversampling in stopes rela-
at Eldorado, with most of the other area mines closing. The tive to other areas with respect to the number of man-shifts
period 19631967 saw the development of two areas in the worked. Other problems in assessing exposure were: the
Beaverlodge mine that were not ventilated by flow-through reporting, in early measurements, of radon concentrations
methods; during this time, all other mines in the area were rather than WL values; the uncertainty about the radon/radon
closed. The period from 1968 onward covers the remainder decay product equilibrium factor, which led to uncertainty in
of mine operation, during which the ventilation was increased the actual WL value; and the considerable variability in data
and individual personal exposure estimates were maintained. within and among workplaces and with time.
279. The 1991 SENES report [S12] discussed several 282. FigureVIII illustrates, using data for the Fay area of the
sources of uncertainty in the WL estimates, including the mine before 1963, the variability in the workplace data and the
lack of measurements in some of the early years (pre-1954). effects of agglomeration of the data. Moving from a mine-wide
For these years, the workplace WL values were assumed to stope average (left side of the figure) to individual work areas,
be the same as those estimated for 1954 [S12]. For the years a dramatic increase in the difference between the minimum
in which no data were recorded, a linear interpolation of the and maximum values (a factor of greater than 10) is evident.
data from the nearest years for which data were available Agglomeration of data reconstruction relied on work history
was assumed. Even when measurement data are available, files from Eldorado. It was possible that the work histories of
the measurements were focused on detecting deficiencies in the study cohort were deficient with regard to non-Eldorado
ventilation as opposed to evaluating worker exposure. employment. This observation is important, because miners
Figure VIII. Estimates of mean radon decay product concentration (WL) by level of aggregation of stoping workplaces, for
1963, Fay area of Beaverlodge mine in northern Saskatchewan [S12].
11
10
MEAN RADON DECAY PRODUCT CONCENTRATION (WL)
0455
8
STOPE
FAY WEST
5
UPPER STOPES
4
1 FAY EAST
LOWER STOPES 1009
STOPE
0
ALL STOPING MINIMUM MAXIMUM MINIMUM MAXIMUM
WORKPLACES MINE AREA MINE AREA WORKPLACE WORKPLACE
could have worked in other mines for which no radiation expo- which had been for radon only. Because of the paucity of
sure data were available. According to Howe et al. [H19], all pre-1964 data, Eldorado used an annual averaging process.
exposures prior to 1 November 1966 were recorded as single Owing to the known variability of workplace conditions,
lifetime totals rather than as separate annual exposures; this Eldorado decided to use the median, as opposed to arithme-
makes them less useful for epidemiological purposes. Howe tic mean, to describe the central tendency of the exposures.
et al. [H19] further indicated that the (annual) median value On the basis of a review of work histories for individuals
was used to describe (annual) average WLs. employed prior to November 1966, a system of 22 job cat-
egories was devised; classification into a particular category
was based on potential RDP exposure. Each person was
3. Exposure estimation assigned to a category for each job held throughout his or
her employment. An effective RDP concentration (WL) was
283. In 1967, Eldorado began maintaining personal records calculated for each job category for each year based on the
of RDP exposure for full-shift underground workers. Work- fraction of working time spent in each area (underground,
ers time cards indicated the hours spent in each workplace. office, etc.). These calculations [F7], recorded as single life-
These cards were consolidated into monthly printouts of time totals rather than separate annual totals, provided the
manpower in each working place. These printouts, together basis for the exposure estimates in Howe et al. [H18].
with measurements made in the workplaces and travelways,
were used to estimate monthly RDP exposures. 287. SENES [S12] used the raw radon and radon decay
product survey data from the Beaverlodge mine to assign
284. In 1970, the computer record system was expanded to WL values to individual stopes. Production data were then
include cumulative (i.e. lifetime total) exposure in the expo- used to retain only those measurements that were taken when
sure summary reports. At this time, records of the previous work was in progress in each area. The production data were
measurements made for ventilation purposes (as opposed used further to weight the data by the number of man-shifts
to the measurements made for the purpose of estimating worked in each area at the measured RDP concentration.
miners exposures) were used to back-calculate exposures to The effect of this re-evaluation is shown in figureIX, which
1 November 1966. illustrates, for the casecontrol sample of 195 miners, revised
exposure estimates plotted against the original exposure esti-
285. In September 1971, all maintenance, technical, super- mates. The 45 line corresponds to the situation when the two
visory and other personnel who had received some RDP estimates of exposure are equivalent. FigureIX shows clearly
exposure were added to the exposure roll. Their exposures that the majority of employees had revised exposure estimates
were calculated back to 1 November 1966 using mine aver- that are higher than the original estimates. Although a gen-
age working levels, hours worked per year, and a factor to eral correlation exists between the two methods of estimating
account for the portion of time spent underground. exposure, the revised estimates are substantially higher, up
to an order of magnitude for some employees. For example,
286. In the mid-1970s, work started on the estimation of two employees originally in the 549WLM category were
exposure prior to November 1966. Only RDP measurements reclassified to the 250+WLM category. Table15 shows the
were used in this estimate, thus excluding the early survey extent of movement from one exposure category to another
data and most of the measurements made during the 1950s, due to the revision of exposure estimates.
Table 15 Changes in exposure categories of Beaverlodge miners based on revised estimates of cumulative exposures [S12]
Original exposure Revised exposure (WLM) category Number of

(WLM) category employees
<5 549 5099 100149 150199 200250 250+
<5 61 16 1 0 0 0 0 78
(78) (21) (1) (0) (0) (0) (0)
549 7 36 7 2 0 0 2 54
(13) (67) (13) (4) (0) (0) (4)
5099 0 0 9 2 3 0 1 15
(0) (0) (60) (13) (20) (0) (7)
100149 0 0 1 0 5 5 1 12
(0) (0) (8) (0) (42) (42) (8)
150199 0 0 0 0 0 1 2 3
(0) (0) (0) (0) (0) (33) (67)
200250 0 0 0 0 0 4 1 5
(0) (0) (0) (0) (0) (80) (20)
Original exposure Revised exposure (WLM) category Number of

(WLM) category employees
<5 549 5099 100149 150199 200250 250+
250+ 0 0 0 0 0 0 5 5
(0) (0) (0) (0) (0) (0) (100)
Number of employees 68 52 18 4 8 10 12 172
Note: N
umber in brackets is the percentage of employees in the original exposure category that are also in the revised exposure category. Revised exposures were estimated
for 172 of the 195 employees in the casecontrol group. The remainder were not traceable in company records.
Figure IX. Comparison between revised and original suggested an association of higher equilibrium factors with
estimates of exposure for Beaverlodge uranium miners the higher dust levels in stopes with work activity; this seems
(note that both axes have logarithmic scales) [C17]. reasonable, because high dust levels and high equilibrium
factors both result from low ventilation rates. For the years
1000 where both RDP concentrations and dust levels were cap-
tured in the SENES database, the mean dust concentrations
by year and type of workplace were calculated. The data indi-
REVISED EXPOSURE ESTIMATE (WLM)
cated high dust concentrations in stopes in 1954 and 1956,

with mean concentrations of more than 500ppcc (particles
100 per cubic centimetre) in stopes. The mean dust concentration
was <100ppcc for the years 19631965, and was 133ppcc
in 1966. The highest mean dust concentrations were in the
raising workplaces; this is reasonable, because raises are
generally more difficult to ventilate during development.
10
290. SENES [S12] performed a detailed review of WLM
exposures for a casecontrol group defined by Howe. Sub-
sequently, Howe and Stager [H16] carried out an analysis
of the casecontrol group using the revised exposures and
1 observed that the inverse dose-rate effect was no longer
1 10 100 1000 present. The revised [S12] methodology for calculation of
RDP concentrations was based on estimating annual mean
ORIGINAL EXPOSURE ESTIMATE (WLM)
concentrations, taking account of the time spent by an indi-
vidual employee (employee duration) at specific workplaces.
Annual workplace mean RDP concentrations were weighted
288. The 1991 exposure estimates [S12] did not include averages of monthly RDP averages, and the weights were
non-Beaverlodge mining exposure. Because of the remote estimates of employee duration based on monthly produc-
location, the cost of recruiting at Beaverlodge was high; tion statistics.
consequently, Eldorados policy was to recruit experienced
miners wherever possible. Inclusion of non-Beaverlodge 291. Annual mean RDP concentrations for individual
exposure would probably result in further movement of the workplaces were agglomerated on the basis of the hier
miners into higher WLM categories. archy of workplace, mine area and mine-wide estimates.
Annual mean concentrations for mine areas were calculated
289. Beaverlodge miners were also exposed to airborne as weighted means of the annual workplace means, where
dust. Information on workplace dust levels (konimeter data) the weights were representative of the estimated employee
that had been recorded coincident with the WL measure- duration in each workplace. Similarly, the mine-wide annual
ments made at Beaverlodge was also entered into the new mean concentrations were weighted means of the mine-area
computer database [S12]. For active stopes, an analysis was annual mean RDP concentrations.
conducted to determine if a correlation existed between RDP
measurements and dust. The analysis revealed significant 292. This methodology provided estimated annual mean
correlations between the measured values of dust, the RDP RDP concentrations for individual workplaces and average
concentration and the calculated equilibrium factor. Dust mine-wide RDP concentrations. As previously noted, sub-
levels were significantly (99% confidence level) positively stantial differences in RDP concentration existed between
correlated with radon and radon decay product concentra- different areas of the mine; this was related both to worker
tions and with equilibrium factors. However, the association activity and the ventilation infrastructure development in
between the dust concentration and the equilibrium factor those areas. Even within these mine areas, substantial differ-
was the strongest of the associations. A correlation coeffi- ences in RDP concentrations existed. Although the method
cient of 0.31 was statistically significant at >99%level. This worked well for stoping workplaces, application of the
method to drifting, raising, travelways and shaft area work- average concentrations. When mine-area average concentra-
place categories was not as successful. tions were used instead of mine-wide average concentrations
only for months with bonus contract information, the esti-
293. Available bonus contract data were examined for the mated exposure to the group was 7,570WLM. A third esti-
casecontrol group of 195 miners. Bonus contracts were mate of exposure, using the ratio of mine-area to mine-wide
available for the periods 19551957, May 1960 and 1963 average RDP concentrations over all months with bonus
1965. These records were searched for information on the contract information, was 8,120WLM.
195 miners in the casecontrol group, of whom 129 had
underground work experience. For 61 of these employees, 294. Figure X shows the distribution for these 61 indi-
information was located on specific workplace, and expo- vidual employees of the ratios of exposures calculated by
sure durations were extracted from the bonus contracts. Total mine-area concentrations to those calculated by mine-wide
cumulative exposures were calculated for the 191 employees average concentrations [C17]. This distribution is indica-
with occupations and exposure durations described in the tive of the variability in exposure estimates due to RDP
personnel files. The total RDP exposure over 4,149 worker- concentration differences between the areas in the mine
months underground was 7,298WLM for the miners with for those underground employees with no bonus contract
bonus contract information, based on the use of mine-wide information.
Figure X. Distribution of ratios of exposures calculated by mine-area concentrations to those calculated by mine-wide
average concentrations for Beaverlodge employees for whom bonus contract information was available [C17].
40
Summary Statistics
35 Observations 61
Minimum 0.4
30 10th Percentile 0.6
Median 0.8
25 90th Percentile 1.9

PER CENT
Maximum 4.4
20 Arithmetic Mean 1.2

Standard Deviation 0.8
15
10
0
1.5
1.7
1.9
2.1
2.3
2.5
2.7
2.9
3.1
3.3
3.5
3.7
3.9
4.1
4.3
0.1
0.3
0.5
0.7
0.9
1.1
1.3
RATIO
295. An increase in average exposure for the casecontrol workplace concentrations and durations should equal the
group was seen when mine-area-specific concentrations mean exposure calculated using the total exposure dura-
rather than mine-wide average concentrations were used. tion multiplied by the duration-weighted mine-wide mean
This suggested the presence of a bias towards low individual concentration, irrespective of the variation or uncertainty
exposure estimates when mine-wide average RDP concen- in concentrations between workplaces. However, this is not
trations were used. necessarily so for nested casecontrol groups, where the pro-
portion of cases is higher than in the cohort group. This type
296. For a given cohort, the total exposure calculated of differential uncertainty is likely to be present in many of
by summing the individual exposures that are based on the other cohorts, since mine-wide average concentrations
were used for estimating the earlier (and generally higher) cancer rates based on the RDP exposure and the true refer-
exposures. ence (unexposed) lung cancer rate for the employee. The lung
cancer status was assessed for each year of the follow-up on
297. Substantial additional RDP exposures, both from non- the basis of the probability of lung cancer for that employee
Beaverlodge work and from other environmental sources during the year, conditional on that employee being alive at
(particularly radon in dwellings), along with exposure to the start of the year [C17].
other lung cancer risk factors such as arsenic and additional
radon exposure that might occur in gold mining, were con- 300. The exposure rates for an individual were probabil-
sidered as possible confounders. Of the 195 employees in istically drawn from log-normal distributions that reflected
the casecontrol study who joined the Eldorado company the variability in exposure rate for that occupation and time
with recorded previous mining experience, 9 had worked period of employment. The mean of this distribution was
in gold mines and 8 had worked in Beaverlodge area ura- equal to the mine-wide (or occupation) average conditions
nium mines. Kusiak et al. [K12] reported RDP levels of the and was retained as a nominal estimate. The true expo-
order of 0.3WL (or greater) in gold mines in Ontario during sure rate reflected the variation in exposure rates within
the 1960s, along with exposure to other risk factors, includ- the mine (or occupation). True reference lung cancer rates
ing exposure to silica and arsenic. The mean duration of were based on the nominal reference lung cancer rate but
recorded mining experience was 6.9 years. It is of interest included a modification based on individual employee vari-
to note that 5 of the employees selected from the nominal ations in this reference rate. These variations could reflect
roll, the restrictions on which were to have excluded persons interindividual variability in background rates or varying
with work experience at other Eldorado facilities, actually exposures to other lung cancer risk factors such as may
had recorded work experience at Eldorados Port Radium have existed in other types of mine, or variability in the
underground uranium mine. extent of smoking [C17].
298. Using the revised exposure estimates, Chambers 301. Employees were assigned to the exposure categories
etal. [C17] investigated how uncertainty in exposure might used in the 1986 cohort analysis, and the simulated number
affect the doseresponse relationship in the Beaverlodge of lung cancer deaths was determined. The expected number
miners. A file describing a cohort with characteristics sim- of lung cancer deaths was determined by summing the
ilar to that previously studied for determining the dose annual probabilities of lung cancer death during the follow-
response relationship was constructed on the basis of partial up. Relative risks (RRs) for the exposure category were
information from the nominal roll of Eldorado Beaver- determined by dividing the simulated number of lung can-
lodge employees. This information included an employee cers by the expected number. Relative risk coefficients were
identification code and the duration of each occupation for determined by dividing the excess relative risk (RR 1) by
each time period worked at Beaverlodge. Birth year or ages the average cumulative exposure in the exposure category.
were not available, nor was the vital status of individual The relative risk estimates and the relative risk coefficients
employees. Ages at the start of employment were assigned were then summarized by scenario to show the variability in
on the basis of random sampling from a uniform distribu- exposure response [C17].
tion of ages between 20 and 40 years. The cohort was simi-
lar in size and was assumed to be similar in characteristics 302. FigureXI represents a summary of the simulated dose
to the cohort studied in the epidemiological study [H19]. response based on the simple relative risk model with a risk
RDP exposures and doses were assigned to underground coefficient of 2 per 100WLM, no uncertainty in dose and
employment up to 1967 on the basis of the revised expo- no confounding factors. The three lines show the maximum,
sure estimates and the algorithm developed for estimating median and minimum simulated values of the relative risk
exposures. This provided estimates of nominal, or mine- coefficient, with the median relative risk coefficient follow-
wide average, annual exposures for each employee plus an ing the 2 per 100WLM value assumed to be true in the
estimate of the range of the exposures or variability due simulation. Any observed dose response falling within the
to differences in exposure rates between different areas of two outer lines would be consistent with the assumed model
the mine. Exposures were calculated by multiplying the for the scenario. The separation between the outer lines
exposure for a given year by the number of months that the reflects solely the statistical variation in the outcome of a
employee worked in that year. Exposures for other occu- random process, since for this scenario there is no uncer-
pational groups and for post-1967 time periods were based tainty in exposure and no confounding factors. For exam-
on previous estimates of exposure rates and an assumed ple, between 3 and 7 lung cancer deaths would typically be
variability between workplaces [C17]. realized if 5 lung cancer deaths were expected from the risk
model. The distance between the bounds is related to the sta-
299. Expected and simulated observed numbers of lung tistical power in that either a large effect or a large study
cancer deaths were calculated using a life table with refer- population is required for statistical significance. A mortality
ence age-specific total mortality and lung cancer mortality update, such as that reported in reference [H35], decreases
rates. The probability of lung cancer during each year of the distance between the upper and lower confidence bounds,
follow-up was calculated for every employee in the cohort since the predicted number of lung cancers deaths is higher
using both the reference lung cancer rates and the lung and the relative variability is reduced [C17].
Figure XI. Simulated exposure response for Beaverlodge miners [C17].

Shown are the maximum, median and minimum values of RR per unit exposure, based on a median RR of 2 per 100WLM.
10
Maximum
Median
6
Minimum
RR COEFFICIENT
x ? x indicates original (1986) estimate for

exposure category multiplied by 0.65
4
x
x
x
2
x
x
-2
0 100 200 300 400 500
MEAN CUMULATIVE EXPOSURE (WLM)
4. Epidemiological studies Howe et al. were not able to interview the Eldorado employ-
ees. The exposure reconstruction had to rely on work history
303. The Eldorado epidemiological cohort had 19,370 files from Eldorado. It was therefore possible that the work
work records for only 18,424 persons, meaning that up to histories of the study cohort were deficient with regard to
946 individuals worked at more than one Eldorado site [N6]. non-Eldorado employment. This observation is important,
Many of these miners worked at Port Radium, which was because miners could have worked in other mines for which
Eldorados first mine; therefore some miners in the Beaver- no radiation exposure data were available.
lodge study are likely also to have received exposure while
at Port Radium. 306. Howe [H35] reports an updated analysis of a cohort
of 17,660 individuals known to have worked for Eldo-
304. The mortality study of Ontario miners [M19] had also rado sometime in the period 19301999 [H35]. One of the
identified 1,430 former Eldorado employees from Saskatch- subcohorts of Eldorado employees includes underground
ewan who had worked in an Ontario mine; of this number, miners employed by Eldorado at the Beaverlodge ura-
726 had worked in Ontario uranium mines. Consequently, nium mine in northern Saskatchewan. The study design
Muller et al. excluded the Eldorado employees from their for the updated analysis was very similar to that used in
analysis of Ontario uranium miners because of the lack of the original study. The nominal roll was that used in the
exposure data for the time when they worked in the Eldorado original study [H16] with the addition of workers who had
mines. Conversely, the Beaverlodge study [H16] included joined the Beaverlodge operation between the cut-off of
many of these individuals but failed to take account of their the original study (31December 1980) and the final shut-
non-Eldorado (Ontario) exposure. down of the mine in 1982. A considerable effort was made
to improve the quality and quantity of the data that were
305. Howe and Stager [H16] reported on a study of extracted from the nominal roll. This resulted in some
Beaverlodge miners that was part of a larger study of some deletions and additions for the pre-1980 period [F19].
18,000 Eldorado employees. The Eldorado epidemiology Exposure estimates and estimates of gamma ray doses
project has been followed in a series of papers published by were accumulated for the cohort, partly from the origi-
Eldorado [A1]. Owing to the size of the study population, nal cohort records available at Eldorado supplemented
by records from the Canadian National Dose Registry. Newfoundland fluorspar mines), this exposure was added
Also, work histories and dose records for non-Eldorado to the miners total exposure. Exposures received up until
uranium mining employment were added. This included 1999, if a miner continued to work, were also included.
miners who worked in Ontario mines as well as a few from The updated study adds a further 19 years of mortality
Newfoundland. Thus, if a Beaverlodge miner had expo- data for the Eldorado cohort and also includes lung cancer
sure from RDPs from work at other locations (i.e. Port incidence results for 31 years, i.e. 19691999 [H35]. The
Radium mine, Port Hope uranium processing plant, non- basic characteristics of the updated cohort, including the
Eldorado mines around Uranium City, Ontario mines and Beaverlodge uranium miners, are summarized in table16.
Table 16 Basic characteristics of the updated Eldorado cohort [H35]
Characteristics Number Per cent
Sex Males 16236 91.9
Females 1424 8.1
Site Port Hope 3003 17.0
Port Radium 3300 18.7
Beaverlodge 10050 56.9
Other sites 1307 7.4
Birth year 1900 414 2.3
19011910 1028 5.8
19111920 1803 10.2
19211930 4030 22.8
19311940 3913 22.2
19411950 2790 15.8
19511960 3118 17.7
1960+ 564 3.2
Cohort/subcohort Mean RDP exposure (WLM) Standard deviation
Entire cohort 48.0 182.6
Port Hope 12.5 43.4
Port Radium 174.2 369.1
Beaverlodge 23.2 81.7
Other Eldorado sites 1.9 32.9
307. Two general types of comparison were used in the 308. The analysis of mortality rates showed that, while mor-
analysis of the Eldorado cohort data. Firstly, observed and tality from lung cancer was elevated, the cohort as a whole
expected values were used to estimate standardized mortal- and the various subcohorts had reduced risks relative to the
ity ratios (SMRs) and standardized incidence ratios (SIRs). Canadian population for most of the other causes of death.
Expected values were derived from Canadian national pop- The analysis of mortality from lung cancer among men in the
ulation rates for mortality between 1950 and 1999 and for cohort with respect to RDP exposure was based on 639lung
cancer incidence between 1969 and 1999. A second series of cancer deaths. (This compares with previous analyses of
comparisons were based upon internal comparisons between the Eldorado cohort where the total number of such deaths
subgroups within the cohort, i.e. with no reference to an was 122.) For the Beaverlodge underground miner subco-
external population. hort, there were 198 lung cancers observed compared with
120.7expected. The SMR for lung cancer was estimated at 1.6 exposure, exposure rate and age at risk, was also investi-
(95% CI: 1, 1.9) and was statistically significant (p<0.001). gated. Using the same approach as the BEIR VI Committee
[C20], Howe estimated parameters from the present study
309. Comparisons of the cancer incidence rates between for a full interaction model, which accounts for the influ-
1969 and 1999 for the cohort with those for the general ence of age at exposure, dose, dose rate and time since
Canadian population showed that the only cancer which is exposure (see table17). The BEIR VI Committees analysis
consistently elevated is lung cancer. For cancer as a whole was based on 11 studies of underground miners, including
and for specific cancers, incidence rates for the cohort were the previous analysis of the Port Radium and Beaverlodge
generally lower than those for the general population, which cohorts. In this study, Howe found that the addition of both
was considered to be a manifestation of the healthy worker the time since exposure terms and the six exposure catego-
effect. Howe also investigated mortality and cancer incidence ries resulted in a statistically significant improvement in
for diseases other than lung cancer and found no evidence of fit, but that the addition of age at risk terms did not. He
any causal relationship between exposure to RDPs or gamma suggested that these results may be regarded as essentially
exposure and an increased risk of any other diseases [H35]. independent of the data used by the BEIR VI Committee
[H35]. Howes 95% confidence limits on estimates of time
310. The application of the BEIR VI type of risk model, since exposure (WLM5, WLM15 and WLM25) parameters
which allows for effect modification with time since include the BEIR VI estimates.
Table 17 Parameter estimates for full interaction model and comparison with BEIR VI model estimates for males in the
Eldorado cohort (19501999) [H35]
Parameter Estimate 95% lower limit 95% upper limit Estimate for BEIR VI
WLM 5 5.23 1.33 14.52 7.68
WLM 15 2.5 0.63 7.05 5.99
WLM 25 1.37 0.36 3.99 3.92
Rate(1) 1 1
Rate(2) 1.02 0.39 2.67 0.49
Rate(3) 0.49 0.2 1.21 0.37
Rate(4) 0.35 0.12 1.01 0.32
Rate(5) 0.33 0.13 0.84 0.17
Rate(6) 0.16 0.06 0.44 0.11
Age(1) 1 1
Age(2) 1.94 0.77 4.89 0.57
Age(3) 1 0.37 2.72 0.29
Age(4) 0.05 0 6266.67 0.09
Parameters as specified below:

WLM = total WLM (per 100 WLM) lagged by 5 years
WLM 5 = WLM 514 years previously (per 100 WLM)
WLM 15 = WLM 1524 years previously (per 100 WLM)
WLM 25 = WLM 25 years+ previously (per 100 WLM)
Rate (2) = WL 0.51.0
Rate (3) = WL 1.03.0
Rate (4) = WL 3.05.0
Rate (5) = WL 5.015.0
Rate (6) = WL 15+
Age (2) = age at risk 5564
Age (3) = age at risk 6574
Age (4) = age at risk 75+
5. Evaluation K16, L3]. Enderle and Friedrich [E4] characterized the work-
place situation in the post-war years (to 1955) as compulsory
311. The Eldorado Beaverlodge cohort was updated with labour, use of prisoners of war (almost 50% in 1947) and a
the revised dosimetry [S12, S14] to add a further 19 years high rate of illness and accidents. In August 1953, a treaty
of mortality data and to include cancer incidence results for was signed to convert Wismut from a Soviet enterprise to a
31 years, i.e. 19691999 [H35]. The study design for the SovietGDR company, and this resulted in improvements in
updated analysis was very similar to that used in the original the working conditions [E4]. From 1946 to about 1955, the
study [H16]. The nominal roll was that used in the origi- underground mine conditions in the Erzgebirge of Saxony
nal study with the addition of workers who had joined the were characterized by dry drilling, no mechanical venti-
Beaverlodge operation between the cut-off of the original lation, very heavy manual work, the absence of industrial
study (31 December 1980) and the final shutdown of the health and safety standards, and very long working hours.
mine in 1982. The updated analysis found little evidence of
departure from a simple linear exposureresponse model. 316. According to Jacobi and Roth [J3, J4], three time
periods can be distinguished: the years 19461954, which
312. For the Beaverlodge cohort, an ERR of 0.96 (95% CI: were referred to as the wild years; 19551970, during
0.56, 1.563; p<0.001) per 100WLM was reported [H35]. which time, there was ongoing improvement in the condi-
This can be compared with the previous Beaverlodge esti- tions through the introduction of wet drilling and improved
mate of ERR of 3.25 per 100WLM [H16]. The estimate of ventilation; and the period after 1970, when individual expo-
ERR for the Beaverlodge cohort has decreased substantially sures were recorded and compared with ICRP limits. Some
in the new analysis. Howe suggests that this could in part 20,000 cases of silicosis and 7,000 cases of lung cancer are
be accounted for by the time-dependent effect modifiers on reported among the Wismut miners. Jacobi and Roth [J4]
the ageing Beaverlodge cohort [H35]. Extensive work was noted that radiation exposures in the years preceding 1970
undertaken in this update to add the exposures received in can only be roughly estimated. For 1955, on the basis of the
non-Beaverlodge mines to those received in the Beaver- assumptions of a mean radon concentration of 120 kBq/m3
lodge mines. Thus the decreased ERR could also be partly for drilling and ore exploration areas and 50kBq/m3 for other
explained by the addition of these non-Beaverlodge mine worksites, and the nominal time spent in workplaces, a nom-
exposures. inal workplace value of about 80kBq/m3 was estimated. On
the basis of a nominal equilibrium factor of 0.5, workplace
exposure was estimated at 160WLM/a. Prior to 1960, the
F. Germany: Wismut miners concentrations of long-lived alpha activity in the air could
have been higher by a factor of 100 to 1,000 than in post-
1. Introduction 1960 conditions. Finally, the mean external dose to miners in
the last 1020 years of mining were about 5mSv/a.
313. The Erzgebirge (Ore Mountains) of Saxony (Germany)
and Bohemia (Czech Republic) have a long history of
underground mining. As early as the 12th century, silver 2. Radon and radon decay products
mining was performed, while later other metals, such as
iron, bismuth, cobalt, nickel and tungsten, were mined. The 317. The first radon measurements in workplaces in the
mining of uranium started at the beginning of the 19thcen- Wismut mines were carried out in 1955 [J3]. The mean of
tury in the Schneeberg area. Miners often died of what was more than 2,000 measurements carried out in five mining
called Schneeberger lung disease, named after the town in operations was 110kBq/m3, which according to Jacobi [J3]
the Erzgebirge. By the end of the 19th century, this disease showed good agreement with measurements carried out in
was recognized as lung cancer. 1937 and 1938 in the Schneeberg mines. This author [J3],
on the basis of 1955 data, reported a mean annual miner
314. Shortly after the Second World War, the Wismut exposure of 150WLM, with a range of 30300WLM. (The
mining company carried out uranium mining in Saxony conversion from Bq/m3 to WLM depends on the equilibrium
and Thuringia in the former German Democratic Republic factor Feq. Assuming an Feq of approximately 0.4, exposure
(GDR). According to Jacobi and Roth [J3, J4], large-scale to a radon concentration of 110,000Bq/m3 for 2,000h corre-
uranium mining started in the Erzgebirge of Saxony in 1946 sponds, very roughly, to an annual exposure of 150WLM.)
and later was extended to the eastern parts of Thuringia.
The Wismut mines in Saxony were high in arsenic, while 318. As reported by Lehmann [L3], from 1946 to 1955
the Thuringia mines were low in arsenic. Overall, Wismut there was no dosimetric recording of radon by the Wismut
produced about 220,000 tons of uranium between 1946 and company. In 1955, radon gas monitoring commenced. Meas-
1990, making it the worlds third largest producer of uranium urement of radon and its decay products was introduced in
[K15]. Mining for uranium per se ended in 1990 following 1966 in Saxony and in 1975 in Thuringia. Formerly, for pur-
the reunification of Germany. poses of compensation, an average annual exposure to radon
decay products of 150WLM was assumed by the Wismut
315. Various papers discuss the potential exposure condi- company for underground workers for the period 19461954
tions in the uranium mines in the GDR [E3, E4, K5, K15, [B5]. This was used independently of conditions and led to
both over- and underestimation of individual exposures to since 1955, the annual exposures to radon, RDPs, long-lived
RDPs in the early years. A working group of experts was radionuclides and external gamma radiation were evaluated
convened in 1993 to develop a jobexposure matrix (JEM) for each year of employment between 1946 and 1989, each
in order to improve the estimation of exposure. The results mining facility and each place of work (underground, mill-
of their work were published in 1998 [L3]. Radon concen- ing or processing, open-pit mining or surface mining). This
trations for 19461954 were estimated retrospectively on evaluation (see figure XII) was performed for a reference
the basis of the first available radon measurements in 1955. job for each place of work (there were fewer reference jobs
These estimates took into account previous working condi- for underground than for above-ground workers), while the
tions in the mines, mine architecture, historical measure- exposures received in other types of job (of which there were
ments and data gathered by the Czech ore mining industry. more than 200) were derived using weighting factors for the
Based on these estimates and the measurements available specific reference job (ranging from 1.0 to 0.0).
Figure XII. Annual exposure to radon decay products as estimated using the jobexposure matrix for the job of hewer, in
five mining facilities typical for the Wismut cohort [K16].
400
350 Objekt 02 (Oberschlema)

ANNUAL RDP EXPOSURE (WLM)
300
Objekt 01 (Johanngeorgenstadt)
250
Objekt 03 (Schneeberg)
200
150 Objekt 09 (Aue)
100
Objekt 90 (Schmirchau)
50
0
46
49
52
55
58
61
64
67
70
73
76
79
82
85
88
19
19
19
19
19
19
19
19
19
19
19
19
19
19
19
CALENDAR YEAR
319. The improved estimates of the JEM showed that RDP relatively high. A JEM for arsenic, fine dust and quartz is
exposures in the early years depended strongly on the number being developed on the basis of estimates given in reference
of old shafts in a given mine and on mining activity. In newly [B22].
established mining facilities, such as Objekt 09 (Aue) and
Objekt 90 (Schmirchau), radon values in the very first years
of operation were rather low, while in old reopened min- 3. Epidemiological studies
ing facilities, such as Objekt 02 (Oberschlema), Objekt03
(Schneeberg) and Objekt 01 (Johanngeorgenstadt), radon 321. Several epidemiological studies of radiation exposures
concentrations were already high at the beginning of the among the Wismut miners are under way. These include a
operating period. Generally the levels of radon increased large cohort study [K5], a nested casecontrol study on lung
with uranium mining and the area of the worked vein to a cancer mortality [T11] and a cohort study among the off-
maximum in 19551956, and decreased later owing to the spring of miners [T11], among others [G17, K15, K16, K29,
introduction of different ventilation and sealing measures. K30, K31]. There is also an independent casecontrol study
on the incidence of lung cancer [B23, B24, B39]. About
320. The JEM [L3] provided estimates of exposures not 400,000people worked for Wismut between 1946 and 1990.
only to radon and its decay products but also to long-lived For about 130,000 of them, complete working histories,
radionuclides and gamma radiation. Owing to improved including start and end of work, job specification and places
working conditions, the exposure to radon and its decay of work (with dates) are available. From these, a stratified
products decreased, while gamma exposures still remained random sample of about 64,311 people was drawn [G17,
K15, K16, K30, K31]. In order to reflect the different mining evaluation of the occupational data, which were extracted
conditions in the Wismut company mines, the sample was from the original payrolls, a total of 5,150 individuals were
stratified by the date of first employment (19461954, 1955 excluded from the initial cohort, because they did not meet
1970, 19711989), place of work and area of mining. Criteria the criteria. The final cohort for the analysis thus consisted
for inclusion in the cohort study were as follows: (a)mini of 59,001 men [G17, K30, K31]. On the basis of year of
mum duration of employment of at least 6 months; (b) date first employment, three subcohorts were defined to reflect
of first employment between 1946 and 1989; (c) year of birth the different mining conditions: 19461954 (subcohort A),
after 1899; and (d) male. After collection and subsequent 19551970 (subcohort B) and 19711989 (subcohortC).
Table 18 Characteristics of the Wismut cohort study [G17, K30, K31]
Characteristics Number of cohort members Per cent
59001 100.0
Year of start of employment
19461954 23917 40.5
19551969 17950 30.5
19701989 17134 29.0
Year of end of employment
19461954 2720 4.6
19551974 19593 33.2
19751984 12963 21.9
1985+ 23725 40.2
Vital status as of 31 December 1998
Alive 39255 66.5
Deceased 16598 28.1
Cause of death available 14646 88.2
Cause of death not available 1952 11.8
Lost to follow-up 3148 5.3
Duration of follow-up in years
<10 3764 6.4
1019 11225 19.0
2029 12536 21.2
3039 12704 21.5
40+ 18772 31.8
Year of death
<1960 224 1.3
19601969 1255 7.6
19701979 3132 18.9
19801989 5368 32.3
19901998 6619 39.9

Characteristics Number of cohort members Per cent
Cause of deatha
Malignant cancers (C00C99) 4800 32.8
Circulatory diseases (I00I99) 5417 37.0
Respiratory diseases (J00J99) 1559 10.6
Digestive system (K00K99) 815 5.6
Injuries and poisoning (S00S99 and T00T99) 1284 8.8
Others 771 5.3
Exposed to radon
Never 8 244 14.0
Ever 50 707 86.0
Cumulative exposure to radon in WLM
Mean (maximum) 241 (3 244)
Median 18
a Codes from the International Classification of Diseases.
322. In the first mortality follow-up, the vital status for the of the study, which is in progress, was to identify the chil-
cohort was determined as at 31 December 1998. At that time, dren of miners to be included in the study and to investigate
66.5% were alive, 28.1% had died and follow-up was not their health status, life expectancy and causes of death. The
complete for 5.3%. The mean age of subjects alive at the most important outcome variables are genetic anomalies,
end of 1998 was 54 years for the total cohort and 71, 59 infant mortality and childhood cancers. The offspring cohort
and 40years in subcohorts A, B and C, respectively. A total consists of 7,855 children.
of 2,388 lung cancer deaths occurred in the first follow-up
period (19461998), which comprised 1,801,626 person- 326. Another casecontrol study on lung cancer incidence
years. The general characteristics of the Wismut cohort are among former Wismut employees was conducted between
summarized in table18 [K15, K16]. 1991 and 2001 [B23, B24, B39]. Patients with histologically
confirmed primary lung tumours were recruited from sev-
323. Data on smoking habits were available for about a eral study hospitals in Thuringia and Saxony. Controls were
third of the total cohort. This proportion was considerably randomly selected from the personnel files of the Wismut
lower for subcohorts A (20%) and B (33%) than for sub company and were frequency-matched to the cases accord-
cohort C (64%), reflecting the fact that smoking habits were ing to birth year in 5-year groups. Inclusion criteria for cases
recorded only after 1970. More than 50% of the miners and controls were: male workers; employed underground at
with known smoking habits were heavy smokers, while the the Wismut Company at some time between 1947 and 1990.
proportion of non-smokers was about 26% [K16]. Occupational exposure to radon, its decay products, gamma
radiation and long-lived alpha emitters was estimated by
324. Within the cohort study, a nested casecontrol study using the JEM described in reference [L3]. All subjects were
on lung cancer deaths was conducted that included individu- personally interviewed about occupational and smoking his-
als born after 1927. Two controls per case were matched tory. Lung cancer risk was calculated by using the ERR model
by date of birth. Controls could be either alive or deceased, and conditional logistic regression. A total of 505 cases and
Questionnaires were sent either to next of kin or, in the case 1,073 controls were included in the study. The cumulative
of the controls, to the miners themselves, if they were still exposure from RDPs ranged from 1 to 2,911WLM (an aver-
alive. Information was gathered on smoking habits and age of 552WLM for the cases and 420WLM for the con-
occupational exposures outside the Wismut facilities, which trols). The exposure rate ranged from 0.1 to 31.4WL (an
might be related to lung cancer. Next, data were abstracted average of 8.2WL for the cases and 7.2WL for the controls).
from the Wismut health archives in relation to smoking The odds ratios (OR; adjusted for smoking, year of birth and
habits, medical radiation exposures and jobs prior to Wismut asbestos exposure) in the two highest categories, compared
employment [G14, T11]. with the reference category of 50WLM, were significantly
increased: 8001,599 WLM, OR = 2.08 (95% CI: 1.40,
325. From the cohort, a subsample of 6,000 miners was 3.08); and 1,6002,911WLM, OR = 3.68 (95% CI: 1.92,
drawn as the basis for an offspring cohort study. The life- 7.03). More than half of the study subjects had been exposed
time exposure of the 6,000 miners to radon and radon decay more than 35 years earlier. Assuming a linear exposure
products varied between 0 and >3,000WLM. The first stage response relationship, there was a significant increase in the
relative risk of 0.10 (95% CI: 0.05, 0.17) per 100WLM after been shown for uranium workers of the Colorado Plateau
adjusting for smoking and asbestos exposure. After correct- in reference [T1].
ing, in a sensitivity analysis, for the fact that the controls of
this study had a higher average exposure than the popula- 328. Pathological findings on 243 Wismut uranium min-
tion of Wismut workers from which they had been recruited, ers with lung cancer, recruited between 1991 and 1995 into
the ERR increased to 0.24 per 100 WLM. For those still the casecontrol study on lung cancer incidence [B24], are
smoking, the increase in relative risk was lower (0.05 per reported elsewhere [K14]. The frequencies of all tumour cell
100 WLM), whereas it was higher (0.20 per 100 WLM) types were found to be associated with increasing RDP expo-
among non-smokers and long-time ex-smokers. Lung can- sure, but high radiation exposures tended to increase the rela-
cer risk declined with time since exposure, except for those tive proportion of small cell lung cancers and squamous cell
miners who had been exposed 45 or more years in the past. carcinomas [K14]. This effect was more pronounced among
No inverse dose-rate effect was observed. those who had stopped smoking or had never smoked, and
it seemed to be masked among those still smoking [K14].
327. More recently, the autopsy data in the archives of the The first evaluation of the pathology archive of the Wismut
Central Institute of Pathology of the Wismut Company were company showed a shift from small cell lung carcinomas
analysed for 19,271 persons; these included 12,926 uranium as the predominant cell type in the first follow-up years to
miners (WLM > 0, group 3), 1987 control cases of non- squamous cell carcinomas in the later years [W4]. At present,
exposed Wismut workers (WLM = 0, group2) and 4,358 con- 5,215 lung carcinoma cases have been identified among
trol cases most likely never employed by Wismut (group1) former Wismut employees, showing extremely high propor-
[W17]. The mean age at the start of exposure was 33.5years, tions of small cell lung carcinomas (69%) in the early years
mean duration of exposure 11.8years and mean age at death (19571965), which declined to 34% up to 1990 [W4].
62.7years. The autopsy data investigated comprised about
152,300 person-years of uranium mining work with radon
exposure. Mean RDP exposure was about 725WLM, with a 4. Evaluation
maximum of more than 3,000WLM. Mean exposure to long-
lived radionuclides (LRN) was about 7.3kBqhm3 (238U), 329. A number of reports have presented information on the
with a maximum of more than 50kBqhm3. On the basis of predicted numbers of lung cancers in former Wismut miners
the main cause of death or concurrent diseases, 8,882 cases [B5, J3, J4]. On the basis of a sample of 3,654 persons drawn
of malignant tumours were found (6,403 for group3,889 for from the Wismut database, which resulted in a final data set
group2 and 1,581 for group1). For primary malignant lung consisting of 2,282 men, and using 1985 death tables for the
tumours, a higher incidence was found for exposed Wismut German Democratic Republic and various risk projection
workers (4,526 (35%) in group 3, 377 (19%) in group 2 models, one analysis [B5] predicted a further 1,700 to 4,800
and 2,472 (11%) in group 1). For primary malignant lung additional lung cancer cases from 1995 onward. The peak
tumours, a significant correlation between OR and WLM incidence was predicted to occur between 1985 and 1991.
category was shown. Depending on the chosen category, Another study on pathological findings among Wismut
the OR for groups with high exposure increased to 10. In uranium miners was published in 2006 [T50].
categories of high LRN exposure, the OR increased to 8.4
(95% CI: 6.19, 11.56). Below the 400599WLM category, 330. The main strengths of the Wismut cohort study are
no significant difference of OR related to the leading histo- its size, a wide range of exposure levels, a long duration of
morphological tumour types could be determined. In higher exposure and a large number of cases of lung cancer and
WLM categories, small cell carcinomas and squamous cell other diseases, as well as the availability of information
carcinomas showed an OR nearly twice as high as that of on dust and arsenic exposure. A joint analysis of 11 miner
adenocarcinomas. For non-exposed Wismut workers, 6% cohort studies [L10] was based on a total of 60,606 exposed
of non-smokers and about 19% of smokers showed lung miners, including 2,674 with lung cancer, and a mean radon
tumours, and for exposed workers, 18% of non-smokers and exposure of 164 WLM. Data were combined from differ-
34% of smokers had developed lung tumours. The relative ent cohorts of miners around the world. Heterogeneity with
share of small cell carcinomas and squamous cell carcino- respect to the quality of exposure assessment, the presence
mas was higher for smokers than for non-smokers. In turn, of relevant covariates such as arsenic, dust and tobacco
the relative share of adenocarcinoma was lower in smokers smoke, as well as lifestyle and genetic factors, was likely
than in non-smokers. According to autopsy diagnosis, the to be present in this combination of cohorts. The Wismuth
relative share of silicosis cases increased with the WLM cohort provides a data set for analysis that is similar in size
category. This mirrored, at least for the mining sites in Sax- (59,001 miners and 2,388 lung cancer cases) to the data set
ony, the parallel exposures to quartz-containing dust and used in the combined analysis, yet it is more homogeneous
ionizing radiation. The available data gave no indication with respect to data collection and estimation of exposure.
of a causal connection between silicosis as the cause of Therefore it represents a unique opportunity to verify the
death and primary malignant lung tumours for the W ismut results of the combined analysis in an independent data set.
workers. Molecular biological investigations revealed no The potential limitations of the Wismut cohort are the lim-
evidence for repeated mutations of codon 249 of the p53 ited information on smoking and the limited validity of the
tumour suppressor gene in the Wismut workers, as had exposure assessment, particularly in the years before 1955.
331. A number of reports have already presented data on plant for heating air going into the mine were installed in
the feasibility of epidemiological studies of Wismut miners 1946 and were in operation by early 1947.
and have provided some early results [K5, K15, K16, T11].
Recent observations suggest a linear smoking-adjusted ERR 335. By 1956, ore zones at the Port Radium mine had
of about 0.10 (95% CI: 0.05, 0.17) per 100 WLM [B24, reached a stage where it was necessary to relocate the mine
B39]. As noted in reference [T11], the results of future epi- surface ventilation unit and steam heating unit to accom-
demiological studies will depend greatly on the quality of modate active workings. Owing to the apparent short life
the exposure assessment and the information on vital status expectancy of the mine, driving a complex ventilation raise
and causes of death. system was deemed impractical. As an alternative, old man-
ways and workings were used to bring the air to active areas.
Air was forced into the mine down 136 Raise into 136 Stope
G. Canada: Port Radium miner study
and down to the first level through the stope raises. From
1. Introduction there, the air was channelled to the lower levels through a
series of old raises. The air on the levels was controlled by a
332. The Eldorado Port Radium mine has a long history series of vent doors [B14]; there were, however, substantial
extending back to 1930, when a prospector by the name of air losses between the first and fifth levels as a result of air
Gilbert LaBine identified pitchblende on the north shore escaping through old stopes filled with broken material. For
of the Great Bear Lake in Canadas Northwest Territories. instance, at the first level, a loss of 7,000 cfm was noted.
Open-pit mining started shortly thereafter, and the first pitch- Bloy [B14] concluded that it was virtually impossible to
blende was shipped in 1931. Underground operations were adequately ventilate the winze section with the existing set-
at a high level of activity by 1932. Mining continued until up, since air volumes were substantially reduced and any air
1940, when a decreasing demand for uranium ore led to the reaching the area was highly contaminated.
mine being shut down. In 1942, the Port Radium mine was
reopened at the governments request, and it continued in 336. In 1956 and 1957, the main fan on the surface was
production until 1960, when it was shut down. Annual aver- stepped up from 22,000 cfm to 35,000 cfm. Heating facili-
age ore grades in the 1940s were 0.51.2%, with occasional ties were increased to handle the extra airflow in winter. By
pockets of high-grade pitchblende being encountered. then, a definite air route was established underground. How-
ever, when the installation was completed and the air volume
333. Bloy [B11] noted that ventilation in the Port Radium checked, only 6,000cfm of the approximately 35,000cfm of
mine was somewhat unusual. At the start of underground air put into the mine actually reached the active workings, and
work, the mine had only natural ventilation; this was greatly this was contaminated with radon and dust. The rest of the air
reduced in winter, as all openings to the surface were kept escaped through leaking doors, bulkheads and coarse backfill.
closed because of the extremely cold temperatures. Open- To solve this problem, the airways were lined with two types
ings to the surface other than the shaft, such as raises from of plastic: polyethylene plastic sheeting of about 4mil thick-
stopes through the surface pillar, were covered and tightly ness (0.1mm) and a liquid spray plastic called cocoon [B12].
sealed in the winter. The only air entering the mine, in winter
was compressed air used to power the drills [T3]. Thomp- 337. The plastic sheeting lined the raises from the first level
kins conducted a ventilation survey at the Port Radium mine to the surface fan inlet. Although the sheeting worked very
in 1945 [T4]. There was only a relatively small amount of air well, it was difficult to handle and tore easily. By the time
circulating through the mine. This condition, together with these raises were completed, the liquid spray plastic method
there being no definite routing of the air currents and the (cocoon) was being tried, and the results were so encouraging
lack of dust-reducing features on mine machinery, resulted that the system was used for all remaining airways [B12].
in generally high dust concentrations in the mine. As part of
the 1945 ventilation survey, Thompkins [T4] estimated the 338. An auxiliary fan delivering approximately 11,000cfm
balance of the air entering and leaving the Port Radium mine was located on the 11th level to ventilate the winze area,
by natural means. Airflow from the surface entering through thus supplying this area with much better ventilation than
the 921 Raise and the 722 Raise was estimated at 455 and had been found in the 1956 survey. A raise system was also
1,500cfm,3 respectively. Compressed air entering the mine completed in the winze area, which greatly improved the
was estimated to be 1,400cfm. Therefore the total volume ventilation [B13]. In addition to the cocoon method, three
of air entering the mine was approximately 3,350cfm. The additional auxiliary fans were added in the winter of 1957
volumes of air leaving through the shaft and the manway/ 1958, resulting in a significant lowering of radon concentra-
pipe raise were estimated as 2,350 and 850cfm, respectively, tions by the spring of 1958 [F5]. No ventilation data for the
for a total of 3,200cfm. Only 150cfm of the air that entered periods after 1958 were found in the records of Cameco, the
the mine remained unaccounted for [T4]. later owner, or the literature review.
334. By 1944, the need for heated ventilation at the Port 339. Kupsch [K6] provided a detailed history of the Eldo-
Radium mine was recognized. A ventilation unit and steam rado company, including its Port Radium mine. Additional
interesting information on the history of the Port Radium
3
1 cfm = 4.72 104 m3 s1. mine was provided by McNiven [M6]. He reviewed the
operations at Port Radium from the reopening of the mine in 345. In a 1996 re-evaluation [S15] of RDP concentrations,
1942 to its final shutdown in September 1960. radiation measurements recorded by Eldorado staff were
compared with the duration of employee exposure for each
2. Radon and radon decay products radiation measurement. All but a few of the radiation meas-
urements were solely for radon concentrations, as the three
340. Port Radium was the first mine in Canada where radon paired measurements of radon and radon decay product con-
and radon decay product sampling was performed. According centrations in 1957 did not provide enough information to
to Bloy [B11], the first radon samples at this mine were taken estimate equilibrium factors. Thus a modelled equilibrium
in February 1945. The reason for the study was to investigate factor based on the ventilation rate was used to convert radon
the suffocating gas noticed by the miners. (The suffocating levels to WL RDP concentrations.
gas turned out to be simply oxygen deficiency.) Radon levels
were found to range from 13,000 to 47,000pCi/L. 346. WL estimates for individual workplaces were aggre-
gated as a function of the workplace classifications to which
341. Representatives from the Chalk River Nuclear Labo- the 171 employees selected for this study were assigned by
ratories visited the Beaverlodge and Port Radium operations Howe [S15]. At each level of aggregation, efforts were made
and carried out preliminary surveys for radon in 1951 and to provide a consistent estimator of WL. Since there were no
1952 [S15, S30]. The surveys established that both Beaver individual measurements of RDP concentrations, individual
lodge and Port Radium had serious radon problems. By WLM exposures could not be calculated directly. An esti-
1954, Chalk River Nuclear Laboratories had designed and mate of the exposures of individual employees was based on
built new radon sampling equipment which they used in the mine-wide average.
another survey of the Port Radium mine [B11].
347. The duration-weighted arithmetic mean was cho-
342. It was the practice in those years to perform konime- sen in this analysis as the estimator to characterize RDP
ter dust sampling from time to time in parallel with the radon concentrations. This statistic facilitated the calculation of
and radon decay product sampling. In addition, an external a mine-wide average for a variety of employee classifica-
gamma radiation survey of the Port Radium mine in 1952 tions. This mine-wide average (mine index) provided a WL
showed gamma exposure levels in a few areas of 95 mR value that would be the expected WL concentration over
(approximately 0.95mSv) per shift [B11]. all the individuals in the classification. From a preliminary
review of the data for Port Radium provided by Cameco,
343. The radon and radon decay product data were dis- the amount of downcast ventilation into the mine varied
cussed by Frost [F6]. Initially, only radon was measured. By substantially (by about a factor of 2) by season of the year,
the mid-1950s, both radon and radon decay product concen- especially from 19471957. This was because air needed
trations were measured (the Kusnetz method was used for the to be heated in the winter to prevent the upper portion of
latter). The equilibrium factor between radon and its decay the shafts from freezing. The limited capacity of the heating
products was found to be approximately 30% in 1957. Frost plant required the ventilation volume to be reduced during
[F5, F6] concluded that the equilibrium factor was likely to the colder winter months (mid-December to mid-March) to
have been higher in the early years of mining when there was avoid freezing the workings.
no forced ventilation.
348. On the basis of the ventilation characteristics, the
344. Average RDP concentrations were estimated by Frost entire operational period of the mine was divided into three
[F5] to be of the order of 77WL in 1945, 38WL in 1952, subperiods: pre-1947, 19471955 and post-1955. Table19
10WL in 1956 and 8WL in 1957, on the basis of the avail- summarizes the available radon data for shaft stations.
able measurements and assuming an equilibrium factor of Similar data are available for active stopes and other under-
30%. Unfortunately, these data and the corresponding esti- ground workplaces. A large winter/summer difference is
mates of miner exposure have not been published. evident.
Table 19 Radon concentration in shaft stations of the Port Radium mine [S15]
Period Season Radon concentration (pCi/L)a
Pre-1947 Summer 8318 (6)
Winter 8318b
19471955 Summer 2084 (10)
Winter 4760 (6)
Post-1955 Summer 3434 (16)
Winter 593 (4)

a Arithmetic mean of measured radon levels with number of observations given in b Indicates an estimated value, since measurements were not available.
round brackets; 1 pCi/L = 37 Bq/m3
3. Exposure estimation higher values. Working time was based on a 40-hour week
and 48 weeks per year. Howe et al. [H19] acknowledged that
349. Information provided by Howe allowed a comparison there were many potential sources of error in the procedure
of exposure duration and exposure (WLM) for a 171-member for estimating RDP exposure.
casecontrol group. There were significant differences in the
estimates of months worked between the 1996 re-evaluation 354. The average exposure of the 2,103 miners was
and the original epidemiological study [H15]. Estimates of 183.3WLM. About 42% of the person-years at risk were in
total WLM for the casecontrol group as a whole are not sig- the <5WLM exposure category. The ERR was estimated to
nificantly different between the two approaches. However, be 0.27 per 100WLM and the excess absolute risk was esti-
as for exposure duration, individual differences in exposure mated to be 3.1 cases per 106 person-years per working level
(WLM) could be very large. To assess the implications of month [H18].
this re-evaluation for the epidemiological study, it would be
necessary to look at the differences in the individual miner 355. The ERR per 100 WLM for Port Radium from the
exposures between the two studies. It is not known from the updated study [H35] is essentially unchanged from the pre-
evaluation whether the cases follow the general pattern or if vious assessment [H18], whereas the ERR for Beaverlodge
a difference exists between the cases and the controls (which has decreased substantially. Howe suggests that this could be
was the expectation of the authors). accounted for in part by the early exposures of Port Radium
workers, for whom the time-dependent effect modifiers (time
since exposure and age at risk) may be of less importance
4. Epidemiological studies than for the younger Beaverlodge subcohort [H35].
350. Since early miners had a potential excess risk of lung 356. More recently, the Eldorado cohort was updated to
cancer, Eldorado sponsored a pilot epidemiological study of add a further 19 years of mortality data (19501999) and
Port Radium workers. This study [G5] found an excess of to include cancer incidence results for 31 years (i.e. 1969
lung cancers in miners who had 5 years or more of under- 1999) [H35]. The study design for the updated analysis was
ground experience. very similar to that of the original study [H18]. The updated
estimate of the ERR for Port Radium miners was 0.37 (95%
351. Consequently, Eldorado initiated a more detailed epi- CI: 0.23, 0.56; p<0.0001) per 100WLM, which may be
demiological study [A1] that included the radiation exposure compared with the ERR of 0.27 per 100 WLM from the
data, and that involved Statistics Canada and the National 1980 mortality analysis [H18]. As noted previously, the cur-
Cancer Institute of Canada, which performed the actual rent estimate of ERR for Beaverlodge is 0.96 per 100WLM
epidemiological analyses. [H35], compared with the previous estimate of 3.25 per
100WLM [H16].
352. This study by Howe et al. [H18] investigated some
2,103 miners employed between 1942 and 1960. In this
group, 57 lung cancer deaths were observed compared 5. Evaluation
with 24.73 expected. Employment records were not avail-
able before 1940 and hence exposures before that date were 357. During the early years of mining (pre-1947), WL val-
not estimated. As a consequence, the exposures of the Port ues in the Port Radium mine were of the order of 60, and
Radium miners may well have been underestimated. Risk annual exposures of miners were likely to have been of the
coefficients estimated from the Port Radium analysis should order of 6001,000 WLM. By the end of mining (around
therefore be regarded as upper limits [H18]. 1959), the calculated WL values declined to 23, and hence
annual exposures were likely to have been of the order of
353. Radon gas samples were collected for seven of the 2040 WLM. The estimates have large uncertainties, per-
years between 1945 and 1958, with between 9 and 71sam- haps a factor of 10, for both pre-mechanical-ventilation and
ples per year and a total of 251 samples. The range of post-mechanical-ventilation periods [M5]. Few data are
concentrations was reported as 50300,000 pCi/L. Howe available for their estimation, and the quality of the sparse
etal. [H18] cite Frost [F5] as the source of their RDP expo- data available is suspect.
sure data. The Port Radium study, unlike the Beaverlodge
study by the same investigators, in at least some circum- 358. Exposure estimates were particularly uncertain for a
stances, used the annual average rather than the median as number of work types where the proportion of time spent
representative of workplace RDP levels. While radon gas underground was unknown. This included mechanics and
samples were made as early as 1945, early data are sparse electricians who may have worked underground for extended
and the uncertainties in the exposures are likely to have periods. The uncertainty in risk estimates if these employees
been very large. Howe et al. [H18] indicated that weighted are included in an epidemiological analysis could be substan-
average equilibrium factors were calculated on the basis of tial, and exclusion of these workers should be considered.
the known labour distribution and type of workplace. The
highest factor used for many work groups was 0.5, although 359. In addition to the sparsity and limitations of radia-
it was discovered that there could have been substantially tion and ventilation data for the early years, there exist other
recognized sources of uncertainty. Based on the sample of 10010,000 pCi/L in mine air (based on 40 samples).
of 171 miners provided by Howe, many pre-Port-Radium Groundwater from mineralized zones was an important
employment histories are incomplete. Many Port Radium source of radon. The paper noted that, in one mine, a cross-
miners are likely to have worked in other mining environ- cut was driven into barren rock and air was blown through
ments (notably gold mining), which provided a further pos- the cross-cut. The air came into contact with radon-rich
sible risk factor. Epidemiology for Port Radium miners only water, and within a distance of 300m exceeded the work-
included miners work after 1941, as work records prior to place concentration limit for radon, referred to as the toler-
that time were not available. Prior, unrecorded experience at ance level (50pCi/L of air in French mines at that time). The
Port Radium may be a risk factor in some instances. The Port paper also noted high levels of radon in the smoke generated
Radium ores contained significant concentrations of other by blasting (levels of as high as 50,000pCi/L).
elements, including arsenic, nickel and cobalt. The degree
of confounding arising from these elements in workplace 364. The 1974 paper by Pradel and Zettwoog [P9] showed
dust is not known. Overall, the Port Radium cohort provided that RDP measurements started in 1955 with about 65 sam-
evidence of the risk of exposure to RDPs. The 1996 expo- ples being taken per mine per year. Beginning in 1955, min-
sure re-evaluation [S15] represents the best available data ers were required to wear an individual dosimeter to record
for epidemiological assessment of the Port Radium cohort. their exposure to gamma radiation. Monthly exposures to
However, the exposure uncertainties are very large, and RDPs and long-lived radioactive dust were calculated, and
quantitative estimates of doseresponse relationships must all results of exposure were reported on personal cards.
be viewed as having substantial uncertainty. Annual and lifetime exposures for all three components of
radiation dose RDPs, gamma radiation and long-lived
360. Notwithstanding the re-evaluation of miners expo- radioactive dust were obtained by summing monthly expo-
sures, the Port Radium data set provides a much weaker sures over time. From Tirmarche et al. [T9, figure6], about
basis for doseresponse investigation than, for example, the 2,500person-years of exposure in the 19471956 period had
Beaverlodge cohort, and is of lower reliability for use in a to be reconstructed, about 11% of the total person-years.
quantitative assessment of risk.
365. Pradel and Zettwoog [P8] commented that, prior to
1953, only 40 measurements of radon had been made. Large
H. French uranium miners numbers of radon measurements were made later, and this
enabled a close approximation to be made of the inhaled
1. Introduction quantities of radon. The authors also discussed the possi-
bility of relatively elevated exposures for short periods of
361. Uranium prospecting began in 1947 in France, and time when mining was taking place in high-grade-ore areas.
the production of the first tonne of uranium occurred in Data from Duport [D9] showed that, in the period 1956
1949. Extraction was located in four main mining divisions: 1982, there were typically more than 30 radon measure-
Crouzille (Limousin) and Forez from 1947, Vende from ments per person-year. This is very high compared with the
1953 and Hrault from 1977. It continued up to 1999, when number available for the other miner cohorts used for risk
the last mine closed. assessment.
362. The first radon measurements were taken in 1953. In 366. After 1983, the system of exposure monitoring based
1956, forced ventilation was introduced in the mines, leading on area measurements was replaced by personal alpha and
to a sharp decrease in exposure levels, and systematic con- gamma dosimeters. The portable device is described by
trol of individual exposures began to be applied in the mines. Zettwoog [Z10]. It comprises an active dosimeter with a
Individual exposure was assessed for each miner on the basis spectrographic head for the measurement of alpha radiation
of ambient measurements. Monthly individual records of (ionograph track detection) and a thermoluminescent dosim-
RDP and gamma exposures were kept in the mining divi- eter for the measurement of external gamma radiation. It
sions. By 1958, a regulation decreed limits for internal and allows the measurement of the number of 222Rn atoms inhaled,
external exposures. From 1959 onward, systematic records the energy of the alpha particles emitted by the three short-
of uranium ore dust exposure were kept for each miner. After lived decay products of radon and thoron (218Po, 214Po, 212Bi),
1983, the system of assessment of exposure was replaced the alpha activity of the five long-lived alpha emitters (238U,
by the use of personal alpha and gamma dosimeters [Z10]. 234
U, 230Th, 226Ra, 210Po) contained in ore dust (after decay of
Pradel and Zettwoog [P8] and Bernhard et al. [B46] describe the short-lived products) and the gamma radiation dose.
the radiation protection practices in French uranium mines.
3. Exposure estimation
2. Radon and radon decay products
367. Information about RDP exposure in the initial cohort
363. A 1955 paper by Jammet and Pradel [J7] pro- of French uranium miners is found in references [L10, T5, T6,
vided insight into the early conditions in the French ura- T7, T9]. This group includes 1,785 miners who began under-
nium mines. This paper reported radon concentrations ground work between 1946 and 1972 and who were exposed
for at least 2 years. The mean cumulative RDP exposure was 4. Epidemiological studies
relatively low (70WLM). The reports describe the reassess-
ment of the RDP exposure of miners by an expert group, nota- 369. The initial cohort included 1,785 uranium miners
bly for the period 19471956, for which retrospective estima- who began underground work between 1946 and 1972 and
tion was necessary. Working conditions changed dramatically were exposed to RDPs for at least 2 years. Tirmarche et al.
in 1956, with a large reduction in the exposure of miners [T8]. gave a status report on the epidemiological follow-up of
Tirmarche et al. [T7, T8] provided a distribution of individ- these uranium miners in a 1985 paper [T9]. A first analy-
ual annual exposure (WLM). Prior to 1956, median annual sis of this cohort, based on follow-up to December 1985,
exposures were estimated to be of the order of 1011WLM. was published in 1993 [T6]. Compared with national rates,
After 1956, annual exposures were in the range 13WLM significant excesses of deaths from lung cancer (observed =
until 1980 and were <1WLM thereafter, as illustrated in fig- 45, expected = 21) and cancer of the larynx (observed = 17,
ureXIII. The figure also shows that exposures prior to 1956 expected = 7) were observed.
had a 5-fold range of interindividual variability.
370. For lung cancer only, a linear doseresponse rela-
368. Rogel et al. [R10] and Tirmarche et al. [T30, T31] tionship was described with respect to the cumulative expo-
provided an update of the exposures of the enlarged cohort sure to RDPs [T6]. The ERR coefficient was relatively low
of French uranium miners. This group included 5,098 (0.35WLM1) in comparison with those found in other miner
males, employed as miners by CEA-COGEMA for at least studies, but as the number of lung cancer deaths was also
1 year between 1946 and 1990. Among the 4,134 miners low (n = 45), the CIs of this coefficient included most of the
who were exposed to RDPs, the mean cumulative expo- values of the other studies, as well as estimates from inter-
sure was 36.5WLM (with a range of individual exposures national committees [L10]. The authors cautioned that, since
of 0.1960.1 WLM) over a mean duration of 11.5 years the mean age of the cohort was only 56 years, the cohort was
(with a range of 137 years). The mean annual exposure too young for full expression of the lung cancer risk.
was 23.9WLM before 1956, whereas after 1956 it was only
1.5WLM [R10]. 371. Laurier et al. described the results obtained from the
initial cohort after extension of the follow-up to 1994 [L44].
Figure XIII. Distribution of annual exposures to radon The mean age at study exit was then 63 years. Causes of death
decay products by calendar year in the initial cohort of were obtained from the National Mortality Database, which
French uranium miners [T7]. collects information from all death certificates in France.
Compared with previous analyses, the use of the National
56 Mortality Database as the principal source of information on
55 the causes of death allowed a reduction in the potential bias
54
53 in the calculation of standardized mortality ratios (SMRs).
32 The analysis showed, however, that this had little impact
31
30 on the relationship between RDP exposure and lung cancer
29 risk. Compared with the earlier study [T6], the number of
28
27 person-years was increased by 25% (n = 56,372) and the
26 number of deaths by 74% (n = 612). The analysis confirmed
25 the existence of an excess risk of death from lung cancer
24
among French uranium miners (85 observed deaths, SMR
ANNUAL RDP EXPOSURE (WLM)
23
22 = 1.9; 95% CI: 1.5, 2.3), and an increase of this risk with
21
20 cumulative RDP exposure (ERR = 0.6 (95% CI: 0.1, 1.2) per
19 100WLM). An excess risk of laryngeal cancer, noted in the
18 Upper quartile 1993 paper by Tirmarche et al. [T6], was not confirmed in
17
16 Median the later study (12 observed deaths, SMR = 1.1; 95% CI: 0.6,
15 Lower quartile 1.9) [L44, T5].
14
13
12 372. The French cohort of uranium miners was enlarged
11 by the inclusion of additional miners with lower radon
10
9 exposures, and the follow-up was extended to December
8 1994. The enlarged cohort is described in references [L40,
7
6 R10, T30, T31]. The study was limited to males who had
5 been employed as miners by CEA-COGEMA for at least
4 1 year between 1946 and 1990. The main characteristics
3
2 of the enlarged French cohort of miners are summarized in
1 table 20. This cohort comprised 5,098 miners followed-up
0
from 1946 to 1994, with a total of 133,521 person-years.
The percentage of miners lost in the follow-up was 2.3%.
46
48
50
52
54
56
58
60
62
64
66
68
70
72
74
76
78
80
82
84
19
YEARS The average age at the end of the study was 55 years. A total
of 1,162 deaths were observed. The cohort included a group miners). Among the exposed miners, the mean cumulative
of 964 non-exposed individuals (but who had the status of a exposure was 36.5WLM, accumulated over a mean duration
miner and were working in the same mining divisions as the of exposure of 11.5years.
Table 20 Characteristics of the enlarged French cohort of uranium miners [R10]
Period of follow-up: 19461994
Number of workers 5 098
Non-exposed miners 964
Number of person-years 133521
Average cumulative exposure (WLM)a 36.5
Average annual exposure (WLM)
Before 1956 23.9
1956 and later 1.5
Average duration of exposure (years)a 11.5
Person-years by lagged cumulative exposure (WLM)
0 49408
010 35817
1050 27778
50100 11358
100200 6213
>200 2947
a Among 4,134 exposed miners.
373. The total number of lung cancer deaths observed in 1956 and thereafter. This could be explained by a better
between 1946 and 1994 among the enlarged cohort of quality of exposure assessment after 1956. The ERR for
French uranium miners was 125. On the basis of the ref- exposures after 1956 was 2.4 (95% CI: 1.1, 4.6, p<0.0001)
erence rates for the general French male population, the per 100WLM [R10, T30].
number of lung cancer deaths expected was 83.1. The analy
sis confirmed a significant excess of lung cancer deaths
(SMR = 1.51; 95% CI: 1.25, 1.79). A significant excess 5. Evaluation
was also observed for all cancer mortality (SMR = 1.14;
95% CI: 1.03, 1.25), but this disappeared after exclusion of 375. The assessment of RDP exposure among French ura-
the lung cancer deaths (SMR = 1.02; 95% CI: 0.90, 1.10). nium miners is of good quality. Beginning in 1956, monthly
Thus no significant excess of deaths from any other cancer records of individual exposure were systematically kept in
was observed [T30]. the mining division. Furthermore, compared with the ini-
tial cohort involved in the international joint study in 1994
374. Rogel et al. [R10] reported on how factors such as [L10], the size of the cohort was increased almost 3-fold,
time since exposure and exposure rate modified the lung and the follow-up was extended by 10 years. Also, it is worth
cancer risk in the enlarged cohort of French uranium min- noting that, after 1956, the exposures of the French miners to
ers. The statistical analyses were based on a linear rela- RDPs were of the same order of magnitude as those received
tive risk model using Poisson regression to fit the models, in some homes. Therefore the potential contribution of the
maximum-likelihood methods to estimate parameters and French uranium miner cohort data to the estimation of the
likelihood ratio tests for nested models. A linear exposure risk coefficient for lung cancer could be especially relevant
response relationship with an ERR of 0.8 (95% CI: 0.3, 1.4; to the estimation of the risk for populations exposed to RDPs
p<0.001) per 100WLM was found. No inverse exposure- in their homes. A European project that includes the French,
rate effect was observed in the extended French cohort. Czech and German cohort studies is in progress [T27, T30].
The strongest modifier was the period of exposure. Analy- The combined data, which are of good quality and relate to
sis showed an ERR that was 10 times higher per WLM for miners with low levels of exposure, will allow an analysis to
exposures received before 1956 than for exposures received be undertaken with a large statistical power.
376. The quantification of the relationship between cumula- stage, pumps could not cope with the amount of water in the
tive RDP exposure and risk of lung cancer mortality required open cut, and it was necessary to sink a shaft, which even-
elaborate statistical methods. Different models were applied, tually went to a depth of 250feet [A14]. This mine ceased
and modelling was performed independently by different operations in 1942. In 1937, the St. Lawrence Corporation
researchers [L10, R10, T6, T27]. All analyses confirmed an started work on a vein called Iron Springs. Originally, min-
increase of lung cancer mortality with cumulative exposure. ing there was also by the open-cut method, but by 1938, the
In the framework of a European programme, data from the work had moved underground, with the mine eventually
French and Czech miner cohorts were made available to descending to a depth of 970feet. This mine was closed in
researchers involved in biologically based modelling, with December 1956.
the aim of comparing the approaches and results of the dif-
ferent models [T30]. The different biologically based solu- 381. Standard underground mining procedures were
tions gave a reasonably good fit of the data and confirmed a adopted with the first underground mine in 1936. Wet drill-
linear increase of risk with cumulative exposure [B27, H32]. ing (which resulted in reduced dust levels) was generally
The comparison of the different approaches provided very adopted in 1942. Shrinkage stoping and cut-and-fill methods
interesting discussions regarding the biological validity of were not practised until after 1964. The underground mines
the models, the means for testing various hypotheses about were in general very wet. Ventilation was mostly provided by
the processes of radiation carcinogenesis, the selection of the natural means. Except in one case, supplementary blowers
best fitting model, and the comparison of these biologically were not used until 1946 [D5].
based models with the empirical approach that uses a statis-
tical model for describing the data [B37, H33, L42]. 382. The report of the Royal Commission [A14] noted
that the St. Lawrence Corporation had 16 veins of fluorspar
377. Data on yearly gamma and long-lived radioactive ore on its mining properties, and at one time or another most
dust exposure are also available since 1956 and 1959, respec- of these were mined by the company. Practically all min-
tively, for each miner of the enlarged cohort. The informa- ers employed by the St. Lawrence Corporation who worked
tion will allow all three components of radiation exposure underground prior to 1960 had at some point also spent time
RDPs, gamma radiation and long-lived radioactive dust to working in the Iron Springs mine. According to the report of
be considered in an analysis of the doseresponse relation- the Royal Commission [A14], the working conditions in the
ship. In addition, a nested casecontrol study investigating Black Duck mine were unpleasant. The Commission noted,
the joint effect of RDP exposure and smoking on lung cancer that prior to 1942, drilling was done with a dry hammer, and
risk among French uranium miners was published [L44]. It that dust and smoke were always such that the driller could
confirms the existence of a significant effect of RDP expo- only be seen at close quarters. He was always like a snow-
sure when smoking information is taken into account. man and also had to shut off his machine to clear out his eyes
and nostrils. Clearly, the mines were poorly ventilated, and
any radon brought into the mines with mine water would
I. Canada: Newfoundland fluorspar miners likely remain in the mine for a long period of time, resulting
in high radon/radon decay product equilibrium conditions.
1. Introduction
383. Until 1942, there were three shifts working under-
378. The 1969 report of the Royal Commission Respecting ground at the Iron Springs mine. Late in 1942, the mine
Radiation, Compensation, and Safety at the Fluorspar Mines, was put on two shifts. This change was most beneficial: the
St. Lawrence, Newfoundland [A14] provided a wealth of four hours between shifts could be used for blowing out
interesting historical data, and is the source of much of the the smoke with compressed air. There was practically no
following information. forced ventilation in any of the mines before 1960, natural
ventilation having been the only source of ventilation until
379. For many years, St. Lawrence, Newfoundland, was that time.
an isolated fishing community. Shortly after the First World
War, the community was devastated by the drop in price of 384. Mines were inspected annually by inspectors brought
salt-cured fish (the main source of income) and, in 1929, all in by the Newfoundland government; however, it was not
of the fishing equipment was destroyed by a tidal wave. Min- until 1951 that mining regulations were in place. Conse-
ing eventually took over as the principal occupation [D4]. quently, prior to this date, the inspectors had to rely solely
Fluorspar, which is used in the production of steel, alumin- on persuasion to achieve improvements in the conditions in
ium and high-octane gasoline, is the only mineral resource the mines.
known to be of economic quality in the St. Lawrence area.
385. Morrison et al. [M16, M17] noted that, although more
380. The earliest mine to start operation at St. Lawrence than 40 fluorspar veins were located in the St. Lawrence
was the Black Duck mine, which belonged to the St. Law- area, most of the ore produced came from only two mines,
rence Corporation. This mine opened in March 1933. Origi- namely the Iron Springs and the Director mine, mined by
nally, mining was by open-cut methods. By 1937, however, the St. Lawrence Corporation and the Newfoundland Fluor-
the open cut had reached a depth of about 90 feet. At this spar Corporation, respectively. According to Morrison et al.
[M16, M17], the Iron Springs mine was believed to have had Radon levels in neighbouring communities close to St. Law-
the worst ventilation of any mine in the St. Lawrence area. rence were found to range from 1 to 1,140pCi/L.
In contrast, the Director mine, from 1955 onward, employed
some forced ventilation. Both mines were extremely wet. 390. Morrison et al. [M17] noted that in 1960, because
of the high levels of radon identified, mechanical ventila-
386. Morrison et al. [M16, M17] postulated that, since tion was introduced into all levels of the mine that were still
operations were converted to underground mining procedures operating, and the RDP levels subsequently fell below the
in the mid-1930s, in the middle of the Depression, work was then current limit of 1WL. In 1978, mining operations in
done with antiquated equipment, and it was possible that St.Lawrence ceased, and the last fluorspar mine was closed.
the health and safety conditions were poor as a result of the By this time, 78 cases of lung cancer had already been
financial situation at that time. From the mid-1950s, it was identified [C12].
clear that miners in St. Lawrence were suffering from various
respiratory troubles, some of which had been diagnosed as 391. Surveys conducted by Windish and Little in 1959 and
silicosis. For this reason, the Newfoundland Department of 1960 collected 17 radon and 80 RDP readings (the Kusnetz
Mines requested the federal Department of National Health method was used for measuring the RDP concentrations)
and Welfare to carry out a survey of dust conditions in the and several gamma radiation readings (reported in reference
St. Lawrence mines. Subsequently, the Industrial Hygiene [A14]).
Division of the Department of National Health and Welfare
(now Health Canada) conducted a dust survey in the period 392. A retrospective study of early mining conditions and
19561957. By the end of 1957, it was clear that the miners working level exposures to RDPs was carried out by Corkill
of St. Lawrence were suffering from a respiratory ailment and Dory of the Atomic Energy Control Board (AECB)
that was not caused by the excessive quantities of siliceous of Canada [C12]. On the basis of a detailed study of each
dust. The dust survey was therefore expanded into a broader mine, including measurement data, mining records, ventila-
epidemiological study. By the end of 1959, Windish and tion data, interviews and simulation studies, every mine was
Sanderson had completed two brief radiation surveys in the assigned a high, medium or low RDP exposure level for each
mine [W6, W7]. The results of these surveys established that operating year (19331960). No RDP measurement data
airborne radioactivity in the form of radon and radon decay were available prior to 1959. Before 1960, when additional
products was present in the two mines surveyed in excess ventilation and control measures were introduced, miners
of the maximum permissible concentration (indicated in the were likely to have been exposed to average RDP concentra-
Royal Commission report to be 1WL). One of the sugges- tions of 2.510WL, depending upon the type and place of
tions made by Windish [W5] was that radon was carried into work. From 1960 onward, estimates of RDP exposures were
the mine by mine water and then released to mine air. available for miners by calendar year [M14].
387. As described in Aylward et al. [A14], the Occu-

pational Health Division of the Department of National 3. Exposure estimation
Health and Welfare began a detailed clinical investigation
of the St. Lawrence miners in August 1960, under the direc- 393. Sources of RDP exposure data include: values esti-
tion of Dr. A.J. deVilliers. Current epidemiological studies mated and assigned to each mine and each calendar year for
have evolved from this foundation. It should be noted that, 19331960 in the retrospective study by Corkill and Dory
prior to 1959, there were no measurements of radon or [C12]; survey data by Windish and Little in 1959 and 1960
radon decay product concentrations in the Newfoundland (as reported in reference [A14]); and personal exposure data
fluorspar mines. starting in 1960. The data (80 samples collected at 50 differ-
ent locations) in Windish and Littles survey formed the basis
of de Villiers epidemiological studies in 1964 and 1971 [D4,
2. Radon and radon decay products D5]. In the 1964 study, mortality among fluorspar miners
was compared with normal mortality in the same geographi-
388. On the basis of work done described in the report of cal region and with that of uranium miners.
the Royal Commission [A14], the source of radon was even-
tually identified as the water that poured into the mines [D5], 394. The WLM method of exposure measurement for indi-
the radon itself apparently originating from the host granite. viduals was not used until de Villiers 1971 paper [D5]. In
The report of the Royal Commission ([A14], tableII) reported the 1971 study, analyses were performed on miners, drillers
levels of radon of 30013,000pCi/L in mine water. and muckers. Pre-1960 exposures were included, since the
mortality analysis started in 1933; however, no explanation
389. Interestingly, high radon levels in water were not of how they were accounted for is given. The only exposure
limited to the mine. According to data of the Royal Com- data mentioned were those given in the Windish survey.
mission [A14], measurements of municipal water supplies
in the St.Lawrence area revealed radon levels ranging from 395. The retrospective study of Corkill and Dory [C12]
1,800 to 14,370pCi/L. Radon levels in other water supplies and the study of Morrison et al. [M14] provided more com-
in the St. Lawrence area ranged from 6,000 to 12,000pCi/L. prehensive data for miners employed during the period
19331978, including mortality data from 1933 to 1981. In miners working in an established area near an air circuit the
the analysis by Morrison et al. [M16, M17], the cohort con- low average concentrations. The high and low averages often
sisted of 1,772 miners employed either by the St. Lawrence differed considerably (by a factor of from 2.5 to 10). To use
Fluorspar Company or Newfoundland Fluorspar Limited. these averages, good knowledge of each workers duties was
Morrison et al. [M16, M17] described the databases, per- developed.
sonal identifying information and occupational histories.
The exposure estimates in WLM used in this analysis were 401. No mention of the effect of job mobility was made in
calculated on the basis of year, mine and occupation for the Corkill and Dorys study. This might have been taken into
period 19331960, based on data provided by the AECB account, at least to a certain degree, since the payroll records
[C12]. used to construct the occupational history were recorded
every two weeks.
396. According to Dory and Corkill [D6], from 1961
onward, estimates of RDP concentrations in WL and/or RDP 402. No mention was made of whether previous hard rock
exposures in WLM were available from the miners individ- mining experience had been taken into account. However,
ual files. The environmental conditions in the early years of since St. Lawrence was an isolated fishing community, espe-
mining were reviewed. Exposure re-evaluations were carried cially in the early years, miners were most likely to have
out on the basis of an assessment of the environmental con- been fishermen before they started work in the St Lawrence
ditions determined by a review of mine maps, inspectors mines.
reports, Royal Commission hearings, anecdotal informa-
tion from former workers and the authors own experience. 403. A working month was considered to be 167 hours by
Comparison was also made with the conditions in the mines de Villiers and Windish [D4] and 170 hours by Morrison et
in later years for which radiation measurements were avail- al. [M16, M17] in the WLM calculations. Accumulations of
able. Dory and Corkill [D6] also used computer modelling working hours were likely to have been reasonable, since
to simulate expected work environment conditions for each they were compiled from payroll records (on the basis that
mine for each year of its operation. Most importantly, the miners were paid on an hourly basis).
authors recognized the uncertainty in the estimation proce-
dure and presented a range of RDP concentrations for vari-
ous workplaces taking into account the degree of wetness 4. Epidemiological studies
and the degree of ventilation assumed to be present. Corkill
and Dory [C12] noted that the ranges they presented do not 404. Early studies of the St. Lawrence fluorspar miners
represent extreme concentrations but are average workplace included those of de Villiers and Windish [D4], Parsons
concentrations for high, medium and low areas. etal. [P1] and Wright and Couves [W10]. However, the first
attempt to examine the RDP exposureresponse relation-
397. Corkill and Dory [C12] considered it possible to place ship was given in a paper published in 1971 by de Villiers
job types within certain average concentration ranges. Their et al. [D5]. The number of hours worked underground was
exposure re-assessment substantially improved the estima- used as a surrogate for actual exposure to RDPs. A plot of
tion of RDP concentration (WL) and RDP exposure (WLM) lung cancer deaths versus number of hours worked revealed
for the Newfoundland fluorspar miners. Nevertheless, as in an exponential relationship. To adjust for the variable
all attempts at reconstruction, there are large (and probably radiation exposure of differing occupations, hours worked
irreducible) uncertainties in the actual conditions that existed were weighted according to occupation. Drifters and stope
in the workplaces for the period 19331960. workers were assigned an RDP concentration of 8 WL,
muckers, trammers, and chute operators were assigned a
398. Detailed occupational histories were obtained from level of 4WL and shaftmen were assigned a level of 2WL.
company records. The records for the 19331936 period With the assignment of these weights, the exposureresponse
were reconstructed from census data, interviews with com- relationship became linear. This procedure was followed by
pany officials and company report reviews [D4]. Morrison et al. [M18], who extended the mortality follow-
up first to 1978 [M18] and then to 1981 [M14]. In the latter
399. Workers occupational histories, by accumulated study (published in 1985), the expected number of deaths
hours of exposure and type and place of work, were pre- was calculated from data for an internal control group of
pared for all men on the employee list [D5]. Occupational unexposed surface workers, with an attempt to account for
history was particularly important for fluorspar miners, since cigarette smoking and latency period. These analyses, like
epidemiological studies included surface workers as well as previous ones, used a modified person-years approach.
underground miners.
405. In 1988, Morrison et al. [M16, M17] modelled the
400. Corkill and Dory [C12] assumed that the type of job exposureresponse relationship using an external control
dictated where a man worked, and thus the concentration of group, and estimated the attributable and additive relative
RDPs to which a worker was exposed. For example, devel- risk coefficients. The radon exposure estimates developed by
opment miners were assigned the high average concentra- Corkill and Dory [C12] were used. Attributable and relative
tions, stope miners the medium average concentrations, and risk coefficients were examined by attained age, age when
first exposed and smoking status. In addition, lifetime risk of bias, then it follows that the ERR would have been an
of lung cancer mortality was assessed using both the rela- underestimate, since the significant random exposure mis-
tive and the attributable risk model. The cohort consisted of classification that constituted the basis for the bias should
1,772miners employed by either the St. Lawrence Fluorspar also bias the overall ERR towards lower values at higher
Company or Newfoundland Fluorspar Limited. Morrison exposure rates.
et al. [M16, M17] described the databases, personal iden-
tifying information and occupational histories. Estimates 410. The 1995 analysis [M20] found an ERR for lung can-
of exposure in WLM were calculated on the basis of year, cer of 0.66 per 100WLM, slightly lower than that observed
mine and occupation for the period 19331960, and the by Lubin et al. [L10] in their analysis of the fluorspar cohort.
calculations provided by the AECB [D6]. The difference with the more recent analysis was that it was
based on a later follow-up time (1990 versus 1984 for ref-
406. A 1995 cohort study of the Newfoundland fluorspar erence [L10]). However, the ERR of 0.66 per 100 WLM
miners by Morrison and Villeneuve [M20] and Morrison was similar to that noted by Lubin for all 11 mining cohort
et al. [M27] examined the mortality experience (1950 studies combined (0.49 per 100 WLM). Although statisti-
1990) of 1,744 underground miners and 321 millers or sur- cally significant differences in ERR were detected between
face workers. As in the 1988 study, exposure estimates in smokers, non-smokers and former smokers, the joint effects
WLM by year, mine and occupation for 19331960 were of exposure to RDPs and smoking could not be assessed.
provided by the AECB [C12]. RDP exposure during the
5 years preceding lung cancer was assumed to be unre- 411. A more recent report described an 11-year updated
lated to lung cancer risk. Overall, 60,000 person-years of analysis of the mortality experience (19502001) of the
follow-up were noted, with a mean cumulative exposure Newfoundland fluorspar miners [V4]. The new study reports
for underground workers of 382.8WLM over an average of on an analysis of 328 miners who worked exclusively on
5.7years of exposure. Smoking information was available the surface and 1,742 individuals exposed to RDPs from
for 65% of the exposed cohort. working underground. When compared with Newfoundland
males, the fluorspar miners had significantly increased num-
407. Values of relative risk (for exposures estimated on the bers of deaths for lung cancer, silicosis, and accidents, poi-
basis of the category of work), adjusted for attained age and soning and violence. In total, 206 lung cancer deaths were
period since exposure, increased with cumulative exposure identified, 191 of which occurred among individuals who
and were statistically significant for cumulative exposures had at some stage worked underground, the other 15 occur-
exceeding 200WLM. On the basis of Poisson regression of ring among miners who had worked only on the surface.
the ERRs and the exposure estimates, and through the use
of a constrained intercept, the ERR was estimated to be 0.66 412. Villeneuve et al. [V4] found a strong association
per 100WLM, with a standard error of 0.17%. The effect of between cumulative exposure to RDPs (WLM) and lung
cell killing at high WLM was not statistically significant at cancer risk. Workers with estimated cumulative exposures
the p=0.05 level. The attributable risk coefficient for con- exceeding 2,100WLM had relative risks more than 20-fold
tinuous exposure was estimated to be 6.3 deaths (standard higher than unexposed miners. After adjusting for age and
error of 0.74) per working level month per 106 person-years, calendar period, the linear ERR among underground and sur-
with a multiplicative correction estimated from the cohort. face miners (combined) was estimated to be 0.47 (95% CI:
0.28, 0.65) per 100WLM. The relationship between cumula-
408. The ERR per unit exposure increased with duration of tive exposure in WLM and lung cancer risk was modified by
exposure, suggesting that those exposed over longer periods time since last exposure, duration of exposure and exposure
of time had a greater risk than those exposed over a shorter rate. In contrast, age at first exposure was not a statistically
period at the same exposure level. significant determinant of lung cancer risk. After 35 years
since the time of last exposure, lung cancer mortality rates
409. The ERR per unit exposure decreased with increased among exposed miners dropped to levels experienced by
duration of exposure in a previous 11-cohort study by Lubin those who worked exclusively on the surface. Morphology
et al. [L10]. While this is biologically plausible, these was available for 88 of the 191 lung cancer deaths among
authors presented an alternative explanation for the inverse those who worked underground. The histology included
dose-rate effect, namely that the finding is an artefact result- squamous cell carcinomas (28), adenocarcinomas (8), small
ing from a greater non-differential exposure misclassifica- cell carcinomas (7) and other carcinomas (45). Owing to the
tion at higher exposure rates than at lower exposure rates. small number of cases, it was not possible to determine the
Because exposure rates were extrapolated for the period ERR per unit exposure by histological type.
prior to 1960, when they were high, these authors suggested
that there may be a much higher degree of miscalculation of 413. Twenty-eight lung cancer deaths occurred among men
these exposures than of exposures from 1960 onward. The who started working after 1960 (when ventilation was intro-
effect of non-differential misclassification would be to bias duced). There was no significant variation in the ERR per
the risk estimates towards lower values, resulting in a greater unit exposure between those who started work before and
reduction in risk estimates at high dose rates than at low dose after 1960. However, the evaluation of cancer risk among
rates. If the inverse exposure-rate effect is indeed the result those who started mining after 1960 is based on younger
men. Thus few cancer deaths were identified, so the statis- follow-up period 19711985. Over this period, the average
tical power to detect an association in these workers was RDP concentrations were 0.3WL for the prospecting teams
limited [V4]. and 1.0WL for the miners, resulting in average cumulative
exposures of about 80WLM for each group. In total, there
414. Some data on smoking were available for 1,107 of were 28 lung cancers. ERRs of 1.19 per 100WLM and 1.09
the 2,070 miners (53%). There was no statistically signifi- per 100WLM were estimated for the prospecting teams and
cant difference in the ERR per unit exposure between those the miners, respectively [S52].
who had smoked and those who had never smoked. How-
ever, strong associations between cumulative radon expo- 417. There are some English language papers (e.g. [L11,
sure and lung cancer risk were noted among individuals who L27, S26, S27, S50, S51, S52, S53, S54, S58, T32, Z6])
had smoked different numbers of cigarettes daily (p<0.05). and many Chinese papers that discuss the lung cancer expe-
Specifically, the ERR was 0.31, 0.46 and 0.94 per 100 WLM riences of miners who worked in the Yunnan tin mines in
among individuals who reported smoking <15, 15<30 and China. Qiao et al. [Q1] reported on an investigation of risk
30 or more cigarettes per day, respectively. An evaluation of factors and the early detection of lung cancer in a cohort
the joint effect of exposure to RDPs and smoking (as meas- of Chinese tin miners. They described a dynamic cohort
ured by the number of cigarettes smoked daily) could not using an ongoing lung cancer screening programme among
adequately discriminate between additive and multiplicative tin miners exposed to arsenic and RDPs. The investigation
models. However, the data were suggestive of an intermedi- noted that about 6,000 tin miners are screened per year with
ate relationship (between additive and multiplicative). The sputum cytology, chest X-rays and personal interviews. The
evaluation of the joint effects of smoking status and radon authors calculated SMRs and 95% CIs. They also calculated
was severely limited by the small number of lung can- relative risk and 95% CIs for lung cancer risk factors from a
cer deaths that occurred among miners who never smoked proportional hazards model. Exposures to RDPs and arsenic
(n = 8) [V4]. were the predominant risk factors, but silicon and smoking
were also lung cancer risk factors in their cohort.
5. Evaluation 418. Chen and Chen [C36] reported a nested casecontrol

study of 130 male lung cancer cases and 627 controls from a
415. One possible advantage of the Newfoundland fluor cohort of 7,855 miners employed for at least 1 year between
spar cohort over most other studies of radiation-exposed 1972 and 1974 in any of four tin mines in China. The
mining populations is that the source of RDP in the fluor- Maentel-Haenzel OR was used to measure the association
spar mines was from groundwater and not from radioactive between lung cancer and various risk factors. Unlike Qiao et
ore. Thus it was possible to exclude the effects of gamma al. [Q1], these authors did not find that silica exposure was
radiation, thoron and radioactive dust. The cohort was, how- related to the risk of lung cancer. However, the authors did
ever, exposed to silica. Another advantage is that fluorspar find a strong association between risk of lung cancer and
miners were almost without exception local men with no cumulative exposure to dust, cumulative exposure to arsenic
previous mining experience. Upon ceasing to mine fluorspar, and duration of dust exposure. The most recent English lan-
the people went back to non-mining professions. Unfortu- guage summary of this cohort was provided in a paper by
nately, all the exposures in the period of high exposure rates Shiquan et al. [S54], which indicated that the high incidence
(19331960) were estimates only and are subject to large of lung cancer in miners of the Yunnan Tin Corporation
uncertainty. While the exposure data are weak, the avail- (YTC) in Gejiu, South China, had attracted attention since
ability of smoking histories and the ability to investigate the the early 1970s. Underground monitoring of dust started in
effect of changes in individual smoking histories over time 1955 and of RDPs in 1972. Data collection from medical
are strengths of the cohort. The study of Villeneuve et al. examinations, chemical analysis of pulmonary tissues and
[V4] confirms the strong association between cumulative animal experiments started in 1975. The database for epide-
exposure in WLM and lung cancer incidence. miological studies was established in 1976, and reports from
cooperative studies with the National Cancer Institute (NCI)
in the United States began in 1998. Some of these epidemio-
J. Chinese miners logical studies and the database provided by YTC were used
by the National Institutes of Health [L10] and BEIR VI [C20]
416. Uranium prospecting and uranium mining started as the basis of data for the Chinese miners in the joint analy-
between 1955 and 1958 in China, and routine monitoring of sis of 11 underground miner cohorts. Lung cancer cases from
radon was carried out after 1959. The first uranium mine was the YTC, one of the largest of the 11 cohorts, made up 36% of
established in Hunan province in August 1958; very high the total cases in the NIH and BEIR VI combined analyses.
levels of radon were measured because of poor ventilation.
Radon levels decreased rapidly after 1960. Comprehensive 419. About 90% of the lung cancer cases at YTC had a
studies of radon exposure were completed in 1993 for 11ura- history of working underground [S54]. Prior to 1950, the
nium prospecting teams and four uranium mines. A total of principal work involved men carrying ore on their backs
27,172 and 108,744 person-years were accumulated for the in small tunnels. That working style was gradually abol-
prospecting teams and the miners, respectively, during the ished after 1953 as mechanization started to be introduced.
YTC miners represented a stable population without sig- combination of tobacco smoke and arsenic, 15.8% to arsenic
nificant loss of follow-up. Mose miners started work before alone, 11% to a combination of arsenic and RDPs, 9.2% to a
1950, some before 1920. Most miners with lung cancer began combination of tobacco smoke and RDPs, 8.7% to a combi-
mining as children under the age of 14, but this groups age nation of arsenic, tobacco smoke and RDPs, 5.5% to RDPs
of death and risk of lung cancer showed no prominent dif- alone and 8.7% to background gamma radiation.
ferences from those of miners who started mining after the
age of 15 or 20.
K. Australia: Radium Hill uranium miners
420. The first systematic monitoring for radon was done in
four YTC mines in 1972. The highest level was at the Lmine, 424. In addition to the studies discussed earlier in this sec-
at 28.6Bq/L on the average. Radon concentrations decreased tion, other miner groups exposed to radon have been dis-
after the improvement of underground ventilation in 1974 cussed in the literature. For example, the BEIR VI report
[S54]. To estimate RDP exposure before 1950, 13existing [C20] also discussed lung cancer in workers in the Radium
small tunnels were measured in around 1980, and showed Hill uranium mine in Australia [W15]. Exposures in this mine
an average RDP concentration of 2.3 WL. Measurements were estimated on the basis of 721 measurements of radon
of 210Pb in rib bones obtained after operations on miners concentrations; however, no data on RDP concentrations
with lung cancer provided additional data for retrospective were reported. Ventilation data were used to estimate mean
dose assessment [L27]. Estimates of cumulative exposure to residence time in the mine and subsequently the exposure of
RDPs could be divided into three stages: 19501953, when miners in WLM. Overall exposures of this cohort were very
the miners carried ore on their backs; 19531972, a period low, with a mean exposure of 7WLM. The authors reported
of modern mining but lacking radon monitoring; and after an excess of lung cancer (4 lung cancer deaths) in miners
1972, with radon monitoring. whose estimated cumulative exposures exceeded 40WLM.
Thirty-six per cent of the cohort could not be traced beyond
421. Before 1965, airborne dust concentrations under- employment at the mine. Overall, while supporting the find-
ground were very high at about 2760 mg/m3, because of ings of an association between RDP exposure and increased
dry drilling. In 1965, the dust levels decreased to 6mg/m3 lung cancer, this study provides no useable information for
after the introduction of wet drilling, [L27, S58]. Arsenic the evaluation of an exposureresponse relationship.
and iron were present as relatively insoluble compounds in
YTC mines; the arsenic concentration in the rock was about
0.51%. Airborne arsenic concentrations measured in the L. Overall evaluation of miner studies
1970s were about 0.01mg/m3 and were thought to have been
more than 10times higher in earlier years. 425. All of the miner studies reviewed in this section
involve retrospective evaluation of exposures to RDPs. In
422. A combined effect of exposure to RDPs and arsenic some cases, such as the Newfoundland fluorspar miners and
on the aetiology of lung cancer among the YTC miners was the Port Radium miners, almost all of the exposures were
reported previously [S51, X1, Y1]. The data for arsenic estimated, whereas for the Czech and Wismut cohorts (start-
(dust containing arsenic) and RDPs, the only occupational ing after about 1971), relatively less speculation was needed.
carcinogens underground, were compared to identify their Studies of miners also differ by type of mine (e.g. uranium,
relative contribution in the aetiology of lung cancer. Since iron, tin, fluorspar), exposure rate (i.e. WL in the workplace),
cumulative exposures to RDPs and arsenic were highly cor- size of study (e.g. number of subjects, number of lung can-
related, both being related to the duration of underground cers) and other factors. All of the miner studies described
work, comparison of the relative contributions to risk from in previous sections confirm the risk of lung cancer from
RDPs and arsenic had to be approached from differences in exposure to RDPs. However, not all of the studies are of the
lung cancer risks in miners working at different jobs (min- same quality. It is evident that the studies summarized in
ing, tunnelling, auxiliary) and different mines (L, M and S, table 21 vary widely with respect to factors that affect the
the three largest YTC mines). determination of the exposureresponse relationship and
factors that modify that relationship, including, for example,
423. Sun et al. [S53] suggested that the arsenic adjustment the number of excess lung cancers, the quality of the expo-
used by the NIH [L4] was unsuitable for use in risk projec- sure data (both the range of exposures and the uncertainty in
tion. BEIR VI [C20] noted that adjustment for arsenic expo- exposures) and confounders such as smoking and exposure
sure was difficult because of the strong correlation between to arsenic. A qualitative overall evaluation of such considera-
RDP and arsenic exposures. Hazelton et al. [H7] noted a tions is provided in table21.
high risk from arsenic exposure and an interaction of arsenic
with other sources of exposure in the study of the YTC min- 426. Table 2l is a summary of some of the key features of
ers. These authors analysed the arsenic, radon, cigarette the various miner studies discussed in this section. The table
smoke and pipe smoke exposures using the biologically also provides the average ERR per unit exposure estimated
based two-stage clonal expansion model. They concluded for a simple linear ERR model for each of the studies. The
that, of 842lung cancer deaths among YTC miners in Gejiu, ERR per unit exposure ranges over approximately a factor
21.4% were attributable to tobacco smoke alone, 19.7% to a of 5. On the basis of an analysis of 11 miner cohorts, Lubin
et al. [L10] reported an ERR of 0.49 (95% CI: 0.2, 1.0) using a generic inverse variance method and assuming that
per 100WLM. random effects were present between studies. The results are
illustrated in figureXIV, which shows a combined ERR of
427. In a manner similar to that adopted by Lubin et al. 0.59 (95% CI: 0.35, 1.0) per 100WLM, comparable to that
[L10], the estimated ERRs reported in table21 were combined reported by Lubin et al. [L10].
Figure XIV. Estimates of ERR per unit exposure from studies of miners.
Combined ERR of 0.59 (95% Cl: 0.35, 1.0) per 100WLM; 95% CI developed with random effects model.
Chinese tin [L10]
Port Radium [H35]
Colorado [H17, L10]
Newfoundland fluorspar [V4]
Ontario [K12, K13, L10]
French [R10, F30]
Swedish [R2, L10]
Beaverlodge [H35]
Czech [B9]
Combined
0.1 0.2 0.5 1 2 5 10

EXCESS RELATIVE RISK (100 WLM) -1
428. It is of interest to compare the risks based on miner compares remarkably well with values from pooled resi-
studies with those from the more recent pooled residential dential radon studies, as discussed in the next section. The
radon studies. Assuming for purposes of illustration a nomi- miner studies show that the ERR decreases with increasing
nal indoor equilibrium factor of 0.4, 35 years of exposure time since exposure. This is an important consideration in
to indoor radon at 100 Bq/m3 for 7,000 h/a, an exposure evaluating potential risks from lifetime exposure. Finally, as
of about 19.5 WLM can be estimated. If an ERR of 0.59 evidenced by the updates of the Port Radium and Beaver-
(95% CI: 0.35, 1.0) per 100WLM based on miner studies lodge cohorts [H35], continued follow-up of miner studies
is assumed (see para. 427), an ERR of about 0.12 (95% CI: is important, because the ERR and other outcomes of the
0.04, 0.2) per 100 Bq/m3 can be estimated, a value which epidemiological analyses may change as the cohort ages.
Table 21 Excess relative risk of lung cancer for exposure to radon in mines
Study Observed cases Expected cases Mean cumulative Mean follow-up time Person-years Main potential Average ERR per unit Overall evaluation
exposure (years) confounders exposure (subjective)
(WLM) (per 100 WLM)
(95% CI in brackets)
Colorado Plateau 327 74 807.2 24.6 75 032 Exposure uncertainty; 0.42 (0.3, 0.7) Medium
uranium miners other hard rock mining;
[H17, L10] smoking
Ontario uranium 282 221 30.8 17.8 319 701 Other hard rock mining; 0.89 (0.5, 1.5) High
minersc smoking
[K12, K13, L10]
Czech uranium miners 915 240.8 70 23.2 261 428 Exposure uncertainty in 1.6 (1.2, 2.2) High
[T39] early years; smoking
Swedish iron miners 79 44.7 80.6 25.7 32 452 Exposure uncertaintyb; 0.95 (0.1, 4.1) Lowa
[L10, R2]a smoking
Beaverlodge uranium 279 217.8 23.2 33 285 964 Exposure uncertaintyb; 0.96 (0.56, 1.56) High
miners [H35] smoking
Wismut uranium 2 328 Not available 242 30.5 1 801 626 Exposure uncertainty 0.21 (0.18, 0.24) Potentially high
miners [K27, K28, K29] (especially prior to
1966); smoking;
arsenic; asbestos
Port Radium uranium 230 142.7 174.2 >44 111 222 Exposure uncertaintyb; 0.37 (0.23, 0.59) Low
miners [H35] smoking
French miners 125 83.1 36.5 26 133 521 Exposure uncertainty 0.8 (0.3, 1.4) High
[R10, T30] prior to 1956; smoking
Newfoundland 206 378 >35 70 894 Exposure uncertainty; 0.47(0.28, 0.65) Low to medium
fluorspar miners [V4]] smoking; high dust
levels
Chinese tin miners 936 649 277.4 10 135 357 Exposure uncertainty; 0.16 (0.1, 0.2) Low to medium
[L10] smoking; arsenic; age
at exposure
ANNEX E: SOURCES-TO-EFFECTS ASSESSMENT FOR RADON IN HOMES AND WORKPLACES
a Exposures in the Malmberget iron ore miner study have been updated, and miner doses have increased by about 50% from those used in reference [R2]; however, at this time the epidemiological study has not been updated.
b Uncertainty remaining after dose re-evaluation.
c The Ontario miner study is being updated and will more than double the number of person-years.
279
V. EPIDEMIOLOGICAL STUDIES OF RESIDENTIAL EXPOSURES
A. Introduction therefore a matter that requires careful consideration, ideally

on a subject-by-subject basis. The pooled studies [D17, D21,
429. Over the past twenty years or so, there has been a K1, K26, L26], based on individual data, are more informa-
great deal of interest in the risks arising from exposure to tive than the previous meta-analyses.
radon and its decay products. It is clear from studies of min-
ers that exposure to radon and radon decay products causes 431. Several ways to address the problems resulting from
lung cancer, as described in section IV (e.g. [C20, D14, such exposure assessment errors are discussed in the litera-
D16, I2, I5, L10, N11, U2, U5]). Data from animal experi- ture, including the use of special films placed on glass arte-
ments such as described in sectionIII also demonstrate that facts to measure the long-lived RDPs directly [L31]. One of
exposure to radon and its decay products causes lung cancer. the primary motivations for the glass-based measurements
Until recently, data from studies of underground miners, in was to take account of systematic increases in residential
uranium mines and other mines, formed the basis for esti- radon concentration due, for example, to efforts to increase
mating risks from exposure to RDPs and for investigating the energy efficiency of homes by providing better insula-
the exposureresponse relationship, as, for example, was tion and decreasing air leakage. However, United Kingdom
carried out by BEIR VI in their pooled analysis of 11miner data [L45] suggest that, in the United Kingdom at least, any
cohorts [C20]. Risks from residential RDP exposure were increase has not been substantial. Another motivation for the
estimated by extrapolation from miner studies. Now, how- glass-based measurements was to eliminate the difficulties
ever, there are more than 20 casecontrol studies of resi- caused by missing measurements in the residential studies,
dential radon exposure and lung cancer. While individual for example in cases where a house was demolished. Much
studies have limited power, pooled analyses of European work in improving the retrospective assessment of radon
[D17, D21], North American [K1, K26] and Chinese [L26] exposure was conducted using glass-based detectors and
residential radon exposure studies provide a clear demon- other approaches (e.g. [F9, L31, M33, P15]). Bochicchio
stration of the risks of lung cancer from residential radon reviewed the use of nuclear track detectors in the context of
exposure and a direct basis for estimating risk in dwellings residential radon epidemiology and also discussed the vari-
from such exposure. This section provides an overview of ous sources of uncertainty in the retrospective estimation of
the casecontrol residential radon exposure studies and, in residential exposures. Bochicchio suggests that 210Po alpha
addition, a short commentary on the relevance of geograph- activity on the surfaces of glass objects might be a better
ical correlation (ecological) studies. Further information surrogate for past exposures than contemporary radon meas-
on the epidemiology of radon exposure and on ecological urements. However, he noted that such data are confounded
studies is provided in annex A, Epidemiological studies of by aerosols from cigarettes, which reduce the ratio of 210Po
radiation and cancer. surface activity to radon concentration [B42].
432. An early casecontrol study of domestic exposure to

B. Casecontrol studies of residential radon RDPs and lung cancer in Port Hope, Ontario, was carried
out to determine if there was an excess of lung cancer in Port
430. Many casecontrol studies published prior to about Hope residents attributable to exposure to elevated RDP lev-
2000 are well described by Lubin and Boice [L4], BEIR els [L41]. Since smoking is the major cause of lung cancer,
VI [C20], NCRP SC65 [N11] and the UNSCEAR 2000 the study controlled for smoking. Cases were defined as
Report [U2]. Lubin et al. [L8] discussed how errors in any person who developed or died from lung cancer in the
exposure assessment can affect the interpretation of results. period 19691979 and who had lived at least 7years in Port
These authors showed that information from seven case Hope. The 7-year residence period was selected because
control residential radon studies supported a wide range this was the shortest possible time between exposure and
of risks, ranging from no excess risk to excess risks larger the occurrence of lung cancer. Twenty-seven cases met the
than those predicted using data from miner studies. These criteria. There were two controls for each case. Estimates of
authors discussed various sources of error in the estimation exposure were developed by adding the cumulative expo-
of residential exposure, including various potential sources sures estimated for each house occupied by a case or control
of measurement error. In addition, a number of authors (e.g. since 1933. The statistical analysis failed to demonstrate an
[L4, P17]) have reported meta-analyses that are based on increased risk of lung cancer from elevated domestic radon
published relative risks. However, such studies are not able exposure, but did identify a very strong risk of lung cancer
to correct for smoking, a key determinant of lung cancer and from cigarette smoking.
281
433. High concentrations of indoor thoron were observed mobility with exposure to radon indoors and outdoors. Out-
in the Loess Plateau region of China (e.g. [S67, T35, W13, doors, radon concentrations varied from 7.4 to 56 Bq/m3,
W20, Y8]). The assessment of the risk from RDPs is known the latter being comparable to the United States national
to be affected by the presence of thoron and its decay prod- average indoor radon level of 48 Bq/m3 (see figure I). An
ucts [P19, T17]. It was thought that the detectors used in average of four radon detectors were placed in each home.
the study by Wang et al. [W13] might have been affected by The measurements exhibited approximately a log-normal
the presence of thoron [S10, T17] and thus that the meas- distribution. The majority of basement measurements and a
ured radon concentrations might have been overestimated. significant fraction of the measurements on the ground level
A re-assessment of the exposures from radon and thoron and the upper level exceeded 148Bq/m3 (the United States
decay products is currently under way. Moreover, the screen- Environmental Protection Agency action level of 4pCi/L).
type diffusion battery (SDB) measurements in underground The authors calculated cumulative exposures to RDPs
dwellings indicated the presence of ultrafine particles of that occurred 519 years prior to diagnosis for the cases,
around 10nm [Y8]. Current evaluations are based on expo- or prior to time of interview for the controls, as 8.6WLM
sures; however, since the dose conversion factor for these and 7.9WLM, respectively. The odds ratios (ORs) for lung
small particles is high, a modified contribution to dose might cancer in women who had smoked at least 100 cigarettes
need to be considered in the future. or for at least 6 months in their lifetime relative to women
who had never smoked was 13.2 (95% CI: 9.5, 18.3). The
434. Several studies investigated residential radon exposure authors also found a significant positive trend between lung
and lung cancer in China. A study carried out by Blot etal. cancer and RDP exposure. The authors estimated risks for
[B25] in Shenyang City, during 1988 and 1989, included a cumulative 15-year radon exposure of 11WLM (taken by
308 females with lung cancer and 356 female controls. The the authors as equivalent to an average radon concentration
median radon level measured in the homes of both cases and of 4 pCi/L) for all cases. After adjustment for age, active
controls was 2.3pCi/L (85.2Bq/m3). The median duration smoking and education, the authors estimated an EOR of
of residence was 24 years. No link between radon exposure 0.24 (95% CI: 0.05, 0.50) or (95% CI: 0.004, 1.81), when
and an excess risk of lung cancer was found, irrespective of radon exposure was treated as a continuous or a categori-
smoking status (other than a non-significant trend in heavy cal variable, respectively. A subsequent paper by Fieldetal.
smokers). A study by Wang et al. [W13] included 1,659 cases [F11] reported a slightly different CI for the EOR of 0.24;
and 768 controls who lived in an area of Gansu province. this was 95% CI: 0.05, 0.92, calculated treating radon
Prior to 1976, many of the subjects had lived in underground exposure as a continuous variable. Field et al. observed a
dwellings (99%), although many had since moved to above- statistically significant trend for large cell carcinoma and
ground houses. The mean radon levels were quite high for a suggestive trend for squamous cell carcinoma (categori-
both cases and controls, at 230.4 Bq/m3 and 222.2 Bq/m3, cal p for the trend of 0.06). However, the linear excess odds
respectively. Using a linear model, the authors estimated an between different histological types were not significant.
excess odds ratio (EOR) of 0.19 (95% CI: 0.05, 0.47) at an
exposure of 100Bq/m3. If adjustments were made for uncer- 437. Tomasek et al. [T10] reported a residential radon
tainty in exposure, the EOR increased by about 50%. study of 12,000 people living in central Bohemia with
a total of 173 lung cancers and a follow-up period of
435. Tokonami et al. [T35] and Sun et al. [S63] carried out 19611995. This follow-up period was later extended to
a radon and thoron survey in the Loess Plateau region of 1999 [T29]. A total of 210 lung cancers were observed.
China. Their study area was located near Gansu province. The study area in central Bohemia is mostly granitoid and
Since the geological features seemed to be almost the same has radon levels considerably higher than other areas of
as in Gansu province, the characteristics of radon and thoron the Czech Republic. Exposure estimates were based on
concentrations were also likely to be similar. The radon con- measurements of the equilibrium-equivalent concentra-
centration was lower than that in the study by Wang et al. tions (EECs) of radon (i.e. the RDP concentrations) made
[W13], but the thoron concentration was higher. Because in most (80%) of the homes in the study area. Typically,
thoron was underestimated in the past, reassessment of risks two detectors were installed for 1 year in the two most
due to radon exposure may need to take the presence of occupied rooms. To compare their results with those of
thoron into account. other studies, the authors established a conversion factor
on the basis of 652 simultaneous measurements of EEC
436. Field et al. described a residential radon study of and radon. Where necessary, mean values for a community
females in Iowa, United States [F10]. The Iowa radon were used to replace missing data. The mean radon concen-
study included 413 cases and 614 controls. The median tration was estimated at 509Bq/m3, with 10% of the homes
residency was 33 years for cases and 31 years for controls. having indoor radon levels in excess of 1,000 Bq/m3. The
Some 357 cases and 200 controls were ever smokers authors used a linear relative risk model, taking into account
(i.e. people who had at some time smoked); an additional the exposures received between 534years previously and
104cases and 200 controls were former smokers. The radon estimating expected cases from national mortality data. The
exposure assessment involved a number of components, authors estimated an ERR of 0.087 (90% CI: 0.017, 0.208)
including 1 year of on-site radon measurements, regional per 100Bq/m3. The ERR did not change substantially after
outdoor radon measurements and linkage of the subjects adjustment for smoking.
438. Barros-Dios et al. [B26] described a population- radon exposure over the 20 years of the study. None of the
based casecontrol study in an area of north-west Spain ORs calculated using regression was statistically significant.
considered to be radon-prone. The study covered 163 cases The authors attributed this in part to the small sample size.
(151 men and 12 women) and 241 controls (219 men and
22 women). Radon concentrations were measured using 441. The risks of lung cancer from residential exposure to
alpha track detectors placed in the homes for a minimum radon in Devon and Cornwall in the south-west of the United
of 90 days and a median of 150 days. The mean radon Kingdom were reported by Darby et al. [D15]. The study
levels were 141.4Bq/m3 for the cases and 114.0Bq/m3 for looked at 982 cases of lung cancer and 3,185 controls, all
the controls. Overall, 22% of the homes had radon levels under 75 years of age. Detailed information on the demo-
of above 148 Bq/m3. A multiple logistic regression analy- graphics of the study population, smoking characteristics and
sis assessed the risk of lung cancer, taking into account a residency was provided. The investigators attempted to meas-
number of possible confounding factors, including smoking, ure radon levels at all of the addresses where the subjects had
family history of lung cancer, type of dwelling construction lived in the preceding 30 years. Two alpha track radon detec-
and hours per day spent at home. A total of 145 (91.8%) of tors produced by the United Kingdom National Radiological
the cases and 129 (54.7%) of the controls were smokers. The Protection Board were installed (one was placed in the living
authors reported ORs by quartiles of the radon distribution, area and the other in the bedroom) for a period of 6 months.
and observed a greater than 2-fold increase in the risk of For residences in which radon had been measured, the inves-
lung cancer for exposures to radon of above 37Bq/m3. The tigators calculated a weighted average radon concentration
authors noted that the risk of lung cancer in smokers was assuming that residents spent 45% of their time in the living
46times higher than in non-smokers exposed to radon levels area and 55% of their time in the bedroom. A time-weighted
of below 37Bq/m3. average radon concentration was estimated for the 30-year
period of interest using the times spent at each address as
439. Lagarde et al. [L31, L32] reported on a Swedish resi- the weights. Estimates of the lung cancer ERRper unit con-
dential radon study based on an existing database of per- centration in air were obtained using linear logistic regres-
sons who had never smoked that had been developed to sion on the assumption that the subjects radon exposure was a
study environmental and occupational exposures to agents continuous variable. The regressions also included interactions
other than radon. The database was augmented with meas- with the factors noted earlier and other variables. The mean
urements of radon concentrations made with alpha track seasonally adjusted radon level in the 9,448 residences was
detectors that had been placed in the bedrooms and living 58Bq/m3, with a maximum of 3,549Bq/m3. The ERR for lung
rooms of residences for 3 months. The database was also cancer risk was 0.08 (95% CI: 0.03, 0.20) per 100Bq/m3 after
supplemented with data from a nationwide Swedish case adjustments for age, sex, smoking status, county of residence
control study for which the radon measurements were simi- and social class. After further adjustment for the uncertainty
lar. On average, about 25 years of the 32-year residential in estimates of exposure, the authors reported an ERR of 0.12
history of subjects was covered by measurements. Covari- (95% CI: 0.05, 0.33) per 100Bq/m3. The observed variations
ates included environmental tobacco smoke and history in among different tumour types were no larger than would be
occupations with a risk of lung cancer. A total of 436 cases expected by chance.
and 1,649 controls (all of whom had never smoked) were
included in the risk assessment. The excess relative risk per 442. A casecontrol study for the period 19901996 in
unit of time-weighted residential radon concentration was western Germany was carried out by Kreienbrock et al.
estimated using conditional logistic regression and a linear [K18]. Detailed demographics and information on potential
relative risk model. The authors found a trend in relative risk confounding factors (smoking and occupational asbestos
with increasing radon exposure, comparable to that found in exposure) were collected, as was detailed information on res-
the nationwide Swedish study. The trend of increased risk idences occupied in the previous 35 years. Radon measure-
with increasing radon levels was limited to subjects exposed ments were made over 1 year using nuclear track detectors
to environmental tobacco smoke at home. For those who had exposed in the living rooms and bedrooms of participants
never smoked, a relative risk of 1.10 (95% CI: 0.96, 1.38) current and previous homes. (Radon exposure was quanti-
was estimated, and for those exposed to passive smoking, the fied in two ways: a time-weighted average of the living room
relative risk was estimated at 1.29 (95% CI: 0.97, 2.24). and bedroom radon concentrations in the last residence;
and an estimation of the time-weighted average cumulative
440. Sobue et al. [S34] reported a casecontrol study of radon exposure in the 515 years prior to the interview date.)
residential radon levels and risk of lung cancer in Misasa, An attempt was made to correct for home alterations and
Japan. The case series consisted of 28 lung cancer deaths changes to home ventilation. There were 1,449 cases and
(26males and 2 females) between 1976 and 1996, and 36 2,297 controls for the entire study area, with a subgroup in a
(33 males and 3 females) controls chosen randomly from radon-prone area consisting of 365 cases and 595 controls.
residents. Radon levels were measured using alpha track In the overall study area, women constituted 235 of the cases
detectors in the most frequented areas of the subjects homes and 432 of the controls. Among the men, 2% of the cases and
for a period of 1 year. The average radon level in the study 23% of the controls had never smoked. Among the women,
area was about 50Bq/m3. The residential radon value meas- 31% of the cases and 60% of the controls had never smoked.
ured over the year was used as a surrogate for cumulative Occupational exposure to asbestos was identified for men
only (30.6% of the cases and 19.8% of the controls). Rate 72cases and 288 controls. About 78% of cases and 94% of
ratios and 95% CIs were calculated using logistic regression. controls were non-smokers. Radon measurements were made
All ORs were adjusted for age, sex, smoking and occupa- using alpha track detectors. For 24 houses in Schneeberg, the
tional asbestos exposure. The authors noted two results. In authors compared the radon data with measurements of 210Po
the entire study area, no rate ratios were significantly dif- in glass samples, which were used for backward extrapola-
ferent from unity, while in the radon-prone areas, for an tion of the radon concentrations, and concluded that indoor
increase in radon concentration of 100 Bq/m3, an ERR of exposure conditions had been stable over the study period.
0.13 (95% CI: 0.12, 0.46) was obtained for the exposure They also noted a large variation in indoor radon levels by
assessment based on the last residence only, and an ERR of week and by season, and cautioned that, while 1-year meas-
0.09 (95% CI: 0.14, 0.38) was obtained for the assessment urements will yield quite constant values, shorter-term
based on cumulative exposure in the 515 years prior to the measurements could be misleading. The authors reported
interview date. After conducting sensitivity analyses, the radon levels of 730 Bq/m3 in case homes in Schneeberg,
authors attributed the absence of an observable risk in the about 540Bq/m3 in register controls and about 290Bq/m3
radon-prone areas to inaccuracy of radon exposure assess- in hospital controls. Logistic regression was used in the
ment. The inaccuracy increases if the variation in exposure risk analysis. Elevated odds ratios (OR = 4.35; 95% CI: 1.47,
within the study population is low, which was the case in the 12.90 and OR = 1.94; 95% CI: 0.59, 6.33) were observed
entire study area. in the two highest exposure categories (radon concentra-
tions of 1,0001,500 Bq/m3 and >1,500 Bq/m3) compared
443. Kreuzer et al. [K17] reported on a study of residen- with the reference category of 50 Bq/m3. No elevation in
tial radon concentrations and lung cancer in Saxony and risk was evident in the lower exposure categories, but this
Thuringia, which are areas in eastern Germany with natu- might be attributed to the low statistical power. When data
rally elevated radon levels. The study included 1,192 cases were restricted to non-smokers and lung cancer cases with
and 1,640 controls. Alpha track radon detectors were placed histological confirmation (38 cases, 172 controls), the risk
for 1 year in the living room and bedrooms of the sub- remained elevated in the highest exposure category, with a
jects homes. Radon exposure was calculated as the time- radon concentration of >1500Bq/m3, showing a borderline
weighted average of radon concentrations in each room. significant trend only among small cell lung cancers.
The authors also calculated a time-weighted average radon
concentration for the whole of the study period, which was 445. Pisa et al. [P6] carried out a residential radon study
535 years prior to the interview date. Mean radon concen- in an alpine valley in Italy where residential radon levels
trations were 76Bq/m3 among cases and 74Bq/m3 among averaged 132 Bq/m3, compared with the Italian national
controls. Detailed information on demographics and poten- average of 77 Bq/m3. Ecological evidence suggested
tial confounding factors was obtained using a standardized the possibility of a weak association between lung cancer
questionnaire similar to the one used in the study by Kreien- and residential radon. Measurements of residential radon
brock et al. [K18]. Approximately 12% of cases and 14% levels were carried out over the course of 1 year using alpha
of controls were women. Among the men, only 2% of the track detectors in the bedrooms of the most recent residence
cases and 26% of the controls had never smoked. Among for each subject. Between 1January 1987 and 31 Decem-
the women, 51% of the cases and 77% of the controls had ber 1993, 224 residents in the study area died from lung
never smoked. ORs and 95% CIs were calculated using con- cancer. Of these, interviews were completed for 138 cases
ditional logistic regression (for example, smoking and work (122 men and 16women) and 291 controls matched for sex
history with asbestos exposure were quantified). The OR for and year of birth. Lifetime smoking, dietary variables and
smokers compared with those who had never smoked was 18 occupational history were all considered in the statistical
(95% CI: 12, 29) for men and 2.8 (95% CI: 1.70, 4.8) among analysis, in which multiple unconditional logistic regres-
women. For men, about 30% of cases and 28% of controls sion, with radon treated as a continuous variable, was used
had occupational asbestos exposure. Asbestos exposure in to estimate the OR and its 95% CI. The OR showed a strong
women was negligible. ORs adjusted for age, sex, smoking association with smoking in both males and females. No
and occupational asbestos exposure, as well as 95% CIs were association was observed between lung cancer and expo-
calculated using conditional logistic regression. Overall, an sure to potential occupational carcinogens. An association
ERR of 0.08 (95% CI: 0.03, 0.20) per 100Bq/m3 and 0.09 between radon and lung cancer was seen in men only. Men
(95% CI: 0.06, 0.27) per 100 Bq/m3 was found for sub- who lived in homes with radon levels of 40199 Bq/m3
jects with complete measurements for all 30 years. Smoking (mean 80.4Bq/m3) showed an OR, adjusted for age, sex and
acted as a negative confounder, and there was a moderate smoking, that was approximately a factor of 2 greater than
increase in lung cancer, which for small cell cancers was that of men who lived in homes with radon levels of below
pronounced. 40Bq/m3. The authors reported an OR of 1.4 (95% CI: 0.3,
6.6) per 100Bq/m3 for the group as a whole.
444. Conrady et al. [C9, C32] conducted a residential radon
study among females living in the Schneeberg and Schlema 446. Oberaigner et al. [O2, S59] carried out a residential
areas of Saxony in eastern Germany. This study looked at all radon study in the highly radon-prone district of Imst in Tyrol,
female lung cancer cases in the study area between 1 Janu- Austria. Lung cancer deaths and a sample of deaths with
ary 1952 and 31 December 1989. The final group included causes other than lung cancer during the years 19701992
(causes of death highly related to smoking were excluded) cases and the controls, respectively, were concluded to have
were matched by age, sex and year of death. The next of kin good radon exposure data. The adjusted ORs were 1.30 (1.03,
of the cases and the controls were interviewed for residential 1.64), 1.48 (1.08, 2.02), 1.49 (0.82, 2.71) and 2.89 (0.45,
history, smoking and other risk factors. Radon concentra- 18.6) for radon concentrations in the range 5099, 100
tions were measured in the last residence for approximately 199, 200399 and above 400Bq/m3, respectively, compared
1 year by means of alpha track detectors placed in the bed- with the reference category with radon concentrations of
rooms and the living rooms. The study included 194 cases 049Bq/m3 (OR=1; 0.56, 1.79). The adjusted odds ratio risk
and 198 controls. The percentage of men was 88% among for 100Bq/m3 was 0.14 (0.11, 0.46) for all subjects, 0.24
both cases and controls. Measurements covered 68% (cases) (0.09, 0.70) for subjects with complete radon measurements
and 75% (controls) for the period 535 years before death. and 0.30 (0.08, 0.82) for subjects who had lived in no more
The mean radon concentrations were 266Bq/m3 among the than one or two dwellings. There was a tendency towards
cases and 123 Bq/m3 among the controls. ORs were esti- higher risk among subjects with low to medium consumption
mated using conditional regression models adjusted for of dietary antioxidants (EOR = 0.32; 0.19, 1.16). In conclu-
smoking and occupation. The ERR at an increased radon sion, both categorical and continuous analyses clearly sup-
exposure of 100Bq/m3 was 0.25 (95% CI: 0.08, 0.43). port an association between residential radon concentration
and lung cancer. Moreover, subjects with a presumed lower
447. Wichmann et al. [S61, W19] reported the results of a uncertainty in the concentration assessment showed a higher
pooled analysis of the two German radon studies. These two risk. Finally, this is the first study indicating that dietary
casecontrol studies were performed during 19901997 in antioxidants may act as an effect modifier for radon.
eastern and in western Germany [K17, K18], with identical
study design. The original data were extended and pooled, 449. Baysson et al. reported on indoor radon concentration
and included a total of 2,963 incidences of lung cancer and and lung cancer in France [B33]. The study took place from
4,232 population controls. Radon measurements were carried 1992 to 1998 in French districts with elevated concentrations
out over the course of 1 year in houses occupied during the of radon. The study included 486 lung cancers cases recruited
535 years prior to the interview date. Conditional logistic from university hospitals, and 984 controls. Subjects were
and linear relative risk regression was used for the analysis. eligible if they had lived in the study area for at least 25
Measurements showed an average radon exposure of 61Bq/ of the previous 35 years. Full residential histories covering
m3. The smoking- and asbestos-adjusted ORs were 0.97 (95% the previous 30 years were obtained, with specific infor-
CI: 0.85, 1.11) for radon concentrations of 5080 Bq/m3, mation collected for the dwellings that had been occupied
1.06 (95% CI: 0.87, 1.30) for radon concentrations of for more than 1 year. Radon concentrations were measured
80140Bq/m3 and 1.40 (95% CI: 1.03, 1.89) for radon con- using track etch detectors placed for a 6-month period in the
centrations of above 140Bq/m3, compared with the reference current and the former residences. The authors estimated a
category with radon concentrations of <50 Bq/m3. The lin- time-weighted average radon concentration for each subject
ear increase in the OR was 0.10 (95% CI: 0.02, 0.30) per for the period of 530 years prior to the interviews. Finally,
100Bq/m3 for all subjects and 0.14 (95% CI: 0.03, 0.55) the authors considered the effect of smoking and occupa-
per 100Bq/m3 for less mobile subjects who had lived in only tional exposure to carcinogens. The ORs and 95% CIs were
one home in the previous 535 years. The risk coefficients calculated using logistic regression with adjustments for sex,
generally were higher when measurement error in the radon age, region, smoking and occupational exposure. Adjusted
concentrations was reduced by restricting the population to odds ratio risks for 100Bq/m3 were estimated for all subjects
those for whom good measurements had been made. With as OR = 1.04 (95% CI: 0.99, 1.11) and for subjects with
respect to histopathology, the risk for small cell carcinoma complete measurements (850 subjects) as OR = 1.07 (95%
was much higher than for other subtypes. CI: 1.0, 1.14). The French study supports a small excess risk
of lung cancer arising from exposure to residential radon.
448. Bochicchio et al. [B43] reported on a casecontrol
study of lung cancer and residential radon in Lazio, central
Italy, characterized by high levels of indoor radon and by C. Ecological studies of residential radon
Mediterranean climate and diet. All subjects 384 cases
and 404 controls, aged 3590 years were recruited in the 450. The limitations of ecological epidemiological analy-
hospital. Detailed information regarding smoking, diet and ses are well discussed in references [C20, L8, L28, U2, U5],
other risk factors were collected by direct interview. Residen- as well as in annex A, Epidemiological studies of radia-
tial history during the 30-year period ending 5 years before tion and cancer. Nonetheless, a few short comments on
enrolment was ascertained. In each dwelling, radon detectors ecological versus casecontrol studies are appropriate here.
were placed in both the main bedroom and the living room Radon studies that rely on averages over geographical areas
for two consecutive 6-month periods. A quality assurance are especially vulnerable to biases that are not present in
programme was set up for radon measurements [B41]. ORs results based on individual-level data such as those used in
and 95% CIs for time-weighted radon concentrations were casecontrol or cohort studies. This is because radon levels
computed using both categorical and continuous uncondi- are highly variable even within limited geographical areas.
tional logistic regression analysis and adjusting for smoking, In addition, smoking is the major cause of lung cancer, and
diet and other variables. Approximately 89% and 91% of the risk is highly dependent on individual smoking habits. The
distribution of smoking habits across the population in a at whether (county average) lung cancer rates in United
particular geographical area is an important confounding States counties decreased with increasing (county aver-
factor. age) radon concentration. Cohens work, involving 275,000
measurements in all 50 states [C23, C24, C25, C26, C27,
451. Stidley and Samet [S49] reviewed 15 ecological stud- C28], generated a great deal of discussion, including refer-
ies of residential radon exposure from a number of countries. ences [A21, F8, F12, G15, G16, L24, L28, L29, L30, S48].
A positive association between radon concentration and lung The focus of the discussion was the use of ecological rather
cancer was observed in 7 of the studies, no association was than analytical studies to investigate the potential risks
observed in 6 and statistically significant inverse relation- from residential radon. Puskin [P10] provided a plausible
ships were observed in 2. The authors discussed methodo- explanation of Cohens observation of a negative associa-
logical issues associated with the ecological studies and sug- tion (see figure XV) between lung cancer and residential
gested that ecological studies should be given little weight in radon concentration. However, Cohen points out that, while
assessing the potential risks of residential radon. In a subse- an ecological study such as that given in reference [C24]
quent paper [S3], the authors showed by simulation that even cannot determine a risk versus exposure relationship, it can
modest levels of error in exposure or misspecification of the test the LNT theory. Puskin [P10] found that the inverse
risk model could introduce significant biases into the results association between lung cancer and residential radon was
of ecological studies. As discussed in sectionB, the pooled also seen in other smoking-related cancers not related to
analysis of casecontrol studies in Europe [D17] and North radon exposure. The result suggested that Cohens observa-
America [K1] have gone to considerable effort to correct for tions could largely be explained by a negative correlation
uncertainty in radon concentrations. Further discussion of between smoking and radon exposure [P10]. On the other
this limitation of ecological studies is provided in annex A. hand, Cohen [C37] argued that Puskins observation of
similar dependence on radon exposure for lung cancer and
452. Cohen used ecological epidemiological studies to for other smoking-related cancers is not affected by data on
investigate the linear no-threshold theory (LNT) by looking smoking prevalences.
Figure XV. Risk estimates of lung cancer from exposure to radon (adapted from reference [L4]).
Shown are the summary relative risks from meta-analysis of eight indoor radon studies and from the pooled analysis of underground miner
studies, restricted to RDP exposures of less than 50WLM [L19], together with the estimated linear relative risk from the correlation study by
Cohen [C24]. Note that references [L4] and [C20] both show Cohens data extrapolated to beyond where they were actually analysed, about
200Bq/m3. The figure has been adjusted to reflect this.
Relative risks from:

Indoor studies (case-control)
Miner studies (cohort)
5
Ecological study by Cohen
Log-linear fit to indoor

data with 95% CI
RELATIVE RISK
Relative risk = 1
0.3
0 100 200 300 400
RADON CONCENTRATION (Bq/m)

453. Heath et al. [H29] discussed exposure to residential this led the authors to suggest that confounding by smoking
radon and lung cancer risk, as well as providing commen- is particularly important at low levels of radon. Cohen argued
tary on Cohens county-based studies [C24, C25, C35]. To that figureXVI is meaningless because the effects of smoking
understand Cohens work, the authors obtained the data sets prevalences were fully taken into account in his analyses, and
on which his study was based and carried out an independent these smoking prevalences were derived from three independ-
analysis of lung cancer mortality on a subset of the data (lung ent sources, all giving the same results. He also argued that no
cancer mortality for 19701979). FigureXVI (adapted from remotely plausible correlations between radon concentrations
reference [H29]) shows the results of the analysis of lung can- and smoking prevalences or intensities of smoking could sub-
cer mortality in relation to (ecological) radon levels but uncor- stantially change his results. Nonetheless, Heath et al. [H29]
rected for smoking (solid circles). The same figure shows the suggested that Cohens ecological studies are of limited value
pattern of smoking frequencies superimposed (solid squares). in assessing the risk from residential radon exposure because
The smoking frequencies shown in figureXVI paralleled the of their reliance on grouped data, coupled with confounding
pattern of lung cancer except at the lowest radon levels, and by cigarette smoking.
Figure XVI. Average annual lung cancer mortality per 100,000 males, 19701979 (), and average percentage of cigarette
smokers among males () within counties, grouped by average county radon level.
Confidence intervals are expressed as the standard deviation of the distribution for each county group (adapted from [H29]).
100 100
90 90
MORTALITY RATE IN MALES DUE TO LUNG CANCER (10-5 a-1)
80 80
70 70
SMOKING PREVALENCE (%)

60 60
50 50
40 40
30 30
20 20
10 10
0 0
0 50 100 150 200 250
AVERAGE RADON CONCENTRATION (Bq/m3)
454. Large ecological studies such as Cohens [C24, C25], and provide a methodologically sound basis for estimating
which show an inverse relationship between county aver- the risks from residential radon.
ages of radon exposure and lung cancer mortality, continue
to generate controversy, despite the results of the numerous
analytical (casecontrol) studies such as those discussed in D. Overall evaluation of residential radon studies
the preceding section. As discussed in references [S3, S49]
and in annex A, ecological studies have a number of meth- 455. Baysson and Tirmarche [B29] provided an overview
odological challenges, notably their inability to adjust for of the casecontrol studies of residential radon concentration
mobility and smoking habits. The pooled studies involved and lung cancer carried out since 1990. They suggested that
control of both individual exposures and smoking habits, the results of these studies indicated a positive association
between lung cancer risk and residential radon concentration the house ventilation system and residents habits, all of
with, an EOR of 0.060.09 per 100Bq/m3. Table 22 and fig- which can affect both the levels of radon and the levels of
ureXVII summarize much of the currently available data on RDP exposure. Further discussion of the effects of measure-
the risks per unit concentration in air from residential case ment error in assessing radon exposure is provided in ref-
control studies. In considering the residential casecontrol erences [H37, H41]. As noted previously, the pooled stud-
studies summarized above, it is important to understand ies in Europe [D17, D21], North America [K1, K26] and
that some studies have greater statistical power than others, China [L26] have attempted to account for measurement
owing to factors such as study size and data quality. The key error uncertainty (uncertainty in the measurement of radon
residential casecontrol studies were included in the pooled concentration and exposure) by restricting the assessment
analyses of Darby et al. [D17, D21] and Krewski et al. [K1, to individuals who had lived in only one or two homes. In
K26], as previously discussed. Uncertainty in exposure addition, as noted earlier, Darby et al. attempted a statistical
assessment is a factor in residential radon studies, as are the correction for measurement uncertainty [D21].
effects of smoking (both active and passive). However, when
the results of individual studies are pooled and analysed in a 457. Bochicchio et al. also provided a convenient summary
consistent format, there is a coherent trend of increasing risk of residential casecontrol studies [B44]. The OR per unit
of lung cancer with increased radon exposure. concentration in air and 95% CIs for each study are shown
in figureXVII. Also shown in figureXVII are the results of
456. Bochicchio [B42] reviewed the application of solid- several meta-analyses and three pooled analyses in Europe,
state nuclear detectors in residential radon studies. He argued North America and China. These include the Lubin and Boice
that exposure uncertainty is generally non-differential and meta-analysis of the residential studies [L4], Lubins analysis
therefore not only adds to the uncertainty in estimated of North American and Chinese residential studies [L36], the
risks but also introduces a bias towards underestimation meta-analysis of 17 casecontrol studies by Pavia et al. [P17],
of risks. Among the factors discussed by Bochicchio are: the Wichmann et al. pooled study of residential exposure in
seasonal variability, which can vary from house to house Germany [W19], two pooled studies of 13 casecontrol stud-
depending on the source of the radon; the characteristics ies in Europe by Darby et al. [D17, D21], and the pooled study
of the house and of peoples living habits; and the difficul- by Krewski et al. [K1, K26] of 47 casecontrol studies in North
ties in retrospective dosimetry. Most of the radon studies America. All of the studies included in the meta-analyses by
reviewed by Bochicchio covered periods of up to 35 years, Wichmann et al. [W19] and Lubin and Boice [L4] are also
during which there may have been changes to the house, included in the pooled analyses [D17, K1].
Table 22 Indoor radon casecontrol studies (adapted from reference [B29])
Reference Region Population Number of cases Radon ORa 95% CI

(controls) measurements
Year Author
1990 Schoenberg et al. [S42] New Jersey, Women 480 (442) 1 year 1.49 0.89, 1.89
United States
1990 Blot et al. [B25] Shenyang, China Women 308 (356) 1 year 0.95 Undefined 1.08g
1992 Pershagen et al. [P16] Stockholm, Women 201 (378) 1 year 1.16 0.89, 1.92
Sweden
1994 Pershagen et al. [P11] Sweden Both sexes 1281 (2576) 3 months 1.10 1.01, 1.22
1994 Letourneau et al. [L25] Winnipeg, Canada Both sexes 738 (738) 1 year 0.98 0.87, 1.27
1994 Alavanja et al. [A19] Missouri, Women, 538 (1183) 1 year 1.08 0.95, 1.24
United States non-smokers
1996 Auvinen et al. [A5] Finland Both sexes 517 (517) 1 year 1.11 0.94, 1.31
1996 Ruosteenoja et al. [R3] Southern Finland Men 164 (331) 2 months 1.80 0.90, 3.50
1997 Lagarde et al. [L1] Sweden Both sexes 1281 (2576) 1.17b 1.03, 1.37
1998 Darby et al. [D15] South-west Both sexes 982 (3185) 6 months 1.08 0.97, 1.20
United Kingdom 1.12b 0.95, 1.33
1999 Alavanja et al. [A18] Missouri, Women 247 (299) 1 year 0.85c 0.73, 1.00
United States 372 (471) 1.63d 1.07, 2.93
Reference Region Population Number of cases Radon ORa 95% CI

(controls) measurements
Year Author
2000 Field et al. [F11] Iowa, Women 413 (614) 1 year 1.24 0.95, 1.92
United States
2001 Kreienbrock et al. [K18] Western Germany Both sexes 1449 (2297) 1 year 0.97e 0.82, 1.14
1.09f 0.86, 1.38
2001 Pisa et al. [P6] Trentino, Italy 138 (291) 1 year 1.40 0.3, 6.6
2001 Lagarde et al. [L32] Sweden Non-smokers 436 (1649) 3 months 1.10 0.96, 1.38
2001 Tomasek et al. [T10, Pluton, 210 1 year 1.087 1.017, 1.208
T29] Czech Republic
2002 Wang et al. [W13] Gansu, China Both sexes 768 (1659) 1 year 1.19 1.05, 1.47
2002 Barros-Dios et al. [B26] Spain 163 (241) 150 days 2.48 1.29, 6.79
2002 Lagarde et al. [L31] Sweden Non-smokers 110 (231) 3 months 1.33c 0.88, 3.0
1.75d 0.96, 5.30
2002 Oberaigner et al. [O2]; Tyrol, Austria Both sexes 194 (198) 1 year 1.25 1.08, 1.43
Schaffrath et al. [S59]
2003 Kreuzer et al. [K17] Eastern Germany Both sexes 1192 (1640) 1 year 1.08 0.97, 1.20
2004 Wichmann et al. [S61, Eastern and Both sexes 2963 (4232) 1 year 1.1 0.98, 1.3
W19] western Germany
2004 Baysson et al. [B33] France Both sexes 486 (984) 6 months 1.04 0.99, 1.11
2005 Bochiccio et al. [B43] Lazio, Italy Both sexes 384 (404) 6 + 6 months 1.14 0.89, 1.46
a OR at 100Bq/m3 (calculated). e Entire study period, 515 years.

b Analysis including measurement error. f Radon-prone areas.
c Analysis based on air monitors. g As reported in reference [B29], Blot et al. [B25] found no association between
d Analysis based on surface monitors. lung cancer and radon.
458. FigureXVII is a graphical presentation of the data United States. The meta-analysis included those studies
for the individual studies shown in table 22. In addition, with 200 or more cases and long-term measurements of
the results of pooled analyses are also shown in the fig- indoor radon concentrations. The pooled study contained
ure along with an estimate of the ERR from the combined in total 4,263 lung cancer cases and 6,612 controls. Using
pooled studies (see table22 and previous paragraph). As published data from each of the eight studies, the authors
discussed earlier, corrections for measurement uncer- carried out regression analyses. The risks (OR) and 95%
tainty increase the predicted ERR somewhat, as shown in CIs for each of the studies are also shown in figureXVII.
table22. As was shown also in figureXIV, such results are generally
consistent with extrapolations from miner studies based on
459. Lubin [L36] discussed several casecontrol studies of the results of BEIR IV and BEIR VI [C19, C20]. As noted
residential radon in North America and two in China. He by Lubin and Boice, the CIs for the individual studies are
acknowledged the inherent difficulties in establishing an large and include a relative risk of unity, which is consistent
association between lung cancer risks and residential radon with the possibility that there is no effect from exposure to
concentration as a consequence of the overall expected risk residential radon. Overall, however, the authors found that
from radon and the large uncertainties. He noted the latest the excess risk from the combined data was significantly
studies in dosimetry, and suggested that pooling may permit different from zero. For residential exposure to 150Bq/m3,
more detailed assessment of the risk. This has been demon- the authors estimated a combined OR of 1.1% (95% CI: 1.0,
strated, for example, in the pooled residential casecontrol 1.3). Overall, Lubin and Boice concluded that the risk from
studies in Europe [D17, D21], North America [K1, K26] and residential radon is unlikely to be larger than that predicted
China [L26]. on the basis of the miner data, that the negative exposure
response seen in some studies is likely to have been due to
460. Lubin and Boice [L4] undertook a meta-analysis exposure misclassification or uncontrolled confounding fac-
of eight casecontrol residential radon studies carried out tors, and that their results are consistent with a small effect
in China, Finland, Sweden, the United Kingdom and the on lung cancer from residential radon [L4].
Figure XVII. Risk estimates from residential radon studies [B29].

Shown are the summary relative risks for exposure at a radon concentration of 100Bq/m3 (except for references [L4, P17] at 150Bq/m3) and
the corresponding 95% confidence intervals.
INDIVIDUAL STUDIES
Alavanja et al. (1999) [A18]
Blot et al. (1990) [B25]
Kreienbrock et al. (2001) [K18]
Letourneau et al. (1994) [L25]
Baysson et al. (2004) [B33]
Darby et al. (1998) [D15]
Alavanja et al. (1994) [A19] Non-smokers
Kreuzer et al. (2003) [K17]
Tomasek et al. (2001) [T10]
Wichmann et al. (2005) [W19]
Lagarde et al. (2001) [L32]
Pershagen et al. (1992) [P16]
Auvinen et al. (1996) [A5]
Pershagen et al. (1994) [P11]
Lagarde et al. (1997) [L1] Non-smokers
Wang et al. (2002) [W13]
Field et al. (2000) [F11]
Oberaigner et al. (2002) [O2]
Lagarde et al. (2002) [L31] Non-smokers
Pisa et al. (2001) [P6]
Schoenberg et al. (1990) [S42]
Ruosteenoja et al. (1996) [R3]
POOLED ANALYSES
Lubin & Boice (1997) [L4]
Pavia et al. [P17]
German [W19]
Chinese [L26]
North American [K1, K26]
European [D21]
0.1 0.2 0.5 1 2 5 10

RELATIVE RISK (at 100 Bq/m)
Includes [B25, W13]

Includes [A18, A19, F11, L25, S42, S76]
Includes [A5, B26, B33, B43, L32, O2, P11, P16, R3, T29, W19]
461. Pavia et al. [P17] reported the results of a meta- risk of lung cancer according to the time-weighted average
analysis of residential exposures to radon gas and lung can- observed residential radon concentration, after stratification
cer from 17 casecontrol studies. Their analysis suggested by study, age, region of residence and smoking habits. The
an association between residential radon concentration and relative risks and 95% CIs for categories of radon concentra-
lung cancer. A weighted log-linear regression analysis was tion are shown in table23. When the analysis was repeated
used to develop estimates of pooled ORs for exposure to a with only those exposed below a radon concentration of
radon concentration of 100 Bq/m3, reported as OR = 1.15 200Bq/m3, the doseresponse relationship remained statisti-
(95% CI: 1.07, 1.24). The authors indicated that not all stud- cally significant (p = 0.04).
ies were adjusted for smoking and that their results cannot
exclude the possibility that their inability to fully adjust Figure XVIII. Relative risk of lung cancer versus observed
for smoking (or other confounders) could account for the residential radon concentration.
increased risk seen in their study. The estimated linear relationship RR = 1 + 0.00084 (solid line),
with 95%confidence limits (dashed lines). The relative risk is equal to
462. Darby et al. [D17] reported a pooled analysis of 1 at 0Bq/m3 (adapted from figure2 of reference [D21]).
13 European casecontrol studies of the risk of lung can-
cer from residential radon. This analysis is of great interest,
especially since heterogeneity among the results of the vari-
ous individual studies disappeared once the data from the 3.00
13 studies were put into a common format and analysed in
a consistent manner. The study included 7,148 lung cancer
cases and 14,208 controls. The mean radon level measured
using long-term alpha track-etch detection in the houses of
the control group was 97Bq/m3, and in the houses of lung
cancer cases was 104 Bq/m3. Radon exposures during the 2.00
RELATIVE RISK
previous 534 years were considered in the analysis. The

authors investigated the association between radon concen-
tration and lung cancer using two models. In one model the
risk of lung cancer was proportional to (1 + ), where is
the measured radon level and is the proportional risk fac- 1.00
tor per unit increase in radon. The second model subdivided
cases and controls by categories of radon exposure. The
authors noted that the doseresponse relationship appeared
to be linear with no threshold and did not depend on smok-
ing status. Before correcting for random uncertainties in 0.00
measuring radon concentrations, the authors reported an 0 200 400 600 800 1 000 1 200 1 400
increased excess odds ratio (EOR) of about 0.08 (95% CI:
0.03, 0.16) per 100Bq/m3. FigureXVIII shows the relative OBSERVED RADON CONCENTRATION (Bq/m)
Table 23 Relative risk of lung cancer according to time-weighted average observed residential radon concentration
(adapted from table 16 of reference [D21])
Observed radon concetrationa Number of cases Number of controls Mean observed radon Relative risk
(Bq/m3) concentration (95% CI)
<25 566 1474 17 1.00 (0.87, 1.15)
2549 1999 3905 39 1.06 (0.98, 1.15)
5099 2618 5033 71 1.03 (0.96, 1.10)
100199 1296 2247 136 1.20 (1.08, 1.32)
200299 434 936 273 1.18 (0.99, 1.42)
400799 169 498 542 1.43 (1.06, 1.92)
800 66 115 1204 2.02 (1.24, 3.31)
Total 7148 14208
a Observed radon concentration for each address in the 30-year period ending 5 years prior to the index date weighted according to the length of time that the person lived at
that address.
463. When the analysis was restricted to people who had the information collected on smoking habits gives estimates
lived in at most two residences during the previous 30 years, of the risks of lung cancer that are very much in line with
the excess (EOR) increased to 0.094 (95% CI: 0.034, 0.175) those of other studies of lung cancer and smoking [C20,
per 100 Bq/m3. Finally, after correction for random uncer- C39, P20].
tainties in the assessment of radon concentrations, the dose
response relationship remained linear, but the relative risk 466. Becker [B34] reviewed the radon experience of min-
doubled to 0.16 (95% CI: 0.05, 0.31) at 100 Bq/m3. Darby ers, residential radon exposure and the therapeutic use of
etal. also discussed the combined effect of smoking and res- radon. Becker noted that BEIR VI [C20] indicated that smok-
idential radon exposure on the absolute risk of lung cancer, ing has a much greater risk of lung cancer than does expo-
and indicated, using the same relative risk factor of 0.16 for sure to radon. He then argued that the correction of the miner
lifetime exposure (taken as 75 years) to a radon concentra- data for smoking is complicated by the under-reporting of
tion of 100Bq/m3, that the risks of lung cancer in lifelong actual smoking, and hence that the uncertainties associated
non-smokers and cigarette smokers would be about 0.47% with retrospective analysis of smoking greatly confound the
and 11.6%, respectively. Expressed differently, almost all of analysis of radon risk in miners. Similar arguments were
the risk accrues to the population of smokers. made about the residential radon studies, noting that uncer-
tainties in smoking by far dominate the uncertainties asso-
464. Krewski et al. [K1, K26] reported a pooled analysis ciated with the retrospective analysis of exposure to radon.
of residential radon exposure and lung cancer risk in seven
casecontrol studies in North America. The combined study 467. Conclusion. The main studies of residential radon are
included some 3,662 cases and 4,966 controls. Residen- the pooled analyses of European [D17, D21], North Ameri-
tial radon levels were determined using long-term alpha can [K1, K26] and Chinese [L26] residential casecontrol
track detection spanning 12 months. The analysis focused studies. These studies indicate a significant association
on exposures 530 years prior to the interview date. Data between the risk of lung cancer and exposure to residential
were analysed using conditional likelihood regression and radon. The studies also examined the effect of restricting
the linear model OR () = 1 + , where is the cumula- analyses to those who had lived in at most two residences. In
tive radon exposure in the previous 530 years. The authors addition, Darby et al. [D17, D21] also carried out analyses
stated that the EORs for individual studies ranged from 0.01 that adjusted for exposure uncertainty. Both the European
(95% CI: <0.00, 0.42) per 100 Bq/m3 in a Missouri study and the North American studies have looked at the estimated
[A18] to 0.56 (95% CI: 0.22, 2.97) per 100Bq/m3 in a New relative risk from radon for individuals with different smok-
Jersey study [S42]. The authors also investigated potential ing habits and demonstrated not only that there is no signifi-
modifying effects of smoking and demographic factors, and cant heterogeneity, but that the risk estimates on the relative
noted that, while there was no apparent heterogeneity in scale are very similar for individuals in different smoking
EOR by sex or education level, there was some suggestion categories.
of a decreasing radon-associated risk with increasing age.
The authors also indicated that they had found no significant 468. Table 24 shows the ERR per unit residential radon
differences in EOR with measures of smoking status. Over- concentration from three pooled analyses of casecontrol
all, an EOR = 0.11 (95% CI: 0.00, 0.28) per 100Bq/m3 was studies. The pooled analyses also reported the ERR for
estimated. The authors also indicated that analyses restricted analyses restricted to individuals who had lived in only one
to subsets of the data with presumed more accurate radon or two residences and hence, whose radon exposures are
dosimetry resulted in increased estimates of the EOR, of presumed to be more precisely known than those of indi-
0.18 (95% CI: 0.02, 0.43) per 100Bq/m3. viduals who changed residences many times. The ERR
estimates from the restricted analyses were higher than the
465. Smoking is a potential confounding factor in both ERR estimates from the primary analyses. The analysis by
the residential and the miner studies. However, there is far Darby et al. used a regression model correction for expo-
more information about smoking histories available in the sure uncertainty, which approximately doubled the ERR
residential studies. Furthermore, several analyses show that obtained from analysis of the primary data [D21].
Table 24 ERR per unit radon concentration in air (per 100Bq/m3) and 95% confidence intervals from combined residential
radon studies
Study Primary analysis Restricted analysis Exposures adjusted
for uncertainty
European [D17, D21] 0.084 (0.03, 0.158) 0.094a (0.034, 0.175) 0.16c (0.05, 0.31)
North American [K1, K26] 0.11 (0.00, 0.28) 0.18a (0.02, 0.43)
Chinese [L26] 0.133 (0.01, 0.36) 0.319b (0.07, 0.91)
Combined 0.093 (0.04, 0.15) 0.11 (0.05, 0.19)

a Only one or two residences and at least 20 years of coverage. c Correction for measurement uncertainty.
b Only one residence with complete coverage.
469. An analysis was conducted to (approximately) com- error correction of Darby et al. [D21] requires a number of
bine the risk estimates from these three pooled analyses assumptions concerning the distribution describing the long-
using weighting by the inverse of the variance in the ERR term average residential radon levels within a geographical
estimate. The ERR estimate for the combined primary analy- area and the variability associated with repeated measure-
ses was 0.093 per 100Bq/m3, and for the restricted analyses, ments of radon concentrations in the same dwelling. How-
the combined ERR estimate was 0.11 per 100 Bq/m3. The ever, as discussed by Darby et al. [D21], there is also infor-
European study [D21] provided 72% of the weight (of information to support many of the assumptions concerning, for
mation) from the primary analyses and 82% of the weight example, the magnitude of year-to-year variability. Nonethe-
(of information) from the restricted analyses. less, at this time it seems reasonable to adopt the estimate
corrected for random uncertainties in the assessment of radon
470. The European study provided an ERR estimate of 0.16 concentrations from Darby et al. [D21], namely an ERR of
per 100Bq/m3 of residential radon, based on a correction for 0.16 (95% CI: 0.05, 0.31) per 100Bq/m3, as an appropriate,
measurement uncertainty that was about twice as high as the if possibly conservative, estimate of the (lifetime) risk from
ERR from the primary analyses [D21]. The measurement residential radon.
VI. EFFECTS OF RADON ON organs and tissues other than THE lung
A. Dosimetric considerations much higher dose than any other organ. Of the other organs
and tissues, those with a high fat content receive somewhat
471. It is generally recognized that the main hazard from higher doses from radon gas. Red bone marrow, thought to
inhaled RDPs is from irradiation of the lung. However, in be the tissue in which childhood leukaemias originate, does
some circumstances, irradiation of the stomach from inges- not receive doses that are large compared with those to other
tion of water containing dissolved radon gas may need to be tissues. Nevertheless, the calculated doses are high enough to
considered. One important factor is the length of time that suggest that radon may be responsible for a small proportion of
ingested radon remains in the stomach [I14]. Various esti- childhood leukaemias [H38]. It is possible that alpha particles
mates of dose to the stomach are within a factor of about 10 from RDPs irradiate the cells in which skin cancers originate
[N9], which is quite a small variation considering the uncer- and thus induce skin cancer. However, the location of these
tainties associated with such estimates. Calculations also sensitive cells is not known with certainty, and it is possible
suggest that decay products deposited on the skin may be that they are too deep to receive a significant dose. If they are
capable of irradiating the sensitive basal cells [S4]. irradiated, it is likely that the doses would be larger in the case
of children than in adults. However, the evidence so far avail-
472. In addition to the dose to the lung, Jacobi and Eisfeld able is inconclusive.
[J2] and Harley and Robbins [H38] calculated the dose to
organs other than the lung, such as kidney, bone marrow and 475. Robbins and Harley [R5] suggested that maternal
skin. Kendall and Smith [K21] applied ICRP dose models to ingestion of radon in water can deliver a dose to the foetus.
estimate effective doses to organs and tissues from radon and Radon is transported by the blood and diffuses throughout the
its decay products, including doses arising via inhalation, body, including the placenta. Radon and its short-lived decay
external exposure of the skin and ingestion. The aim was to products can thus reach an embryo/foetus. There is an inter-
provide a self-consistent summary that would allow the vari- val during pregnancy when the foetus is at the highest risk of
ous hazards to be compared and put into context. The largest severe effects from radiation exposure. For the early embryo,
dose overall from inhaled radon and its decay products was there are two important factors to consider: the very small size
to the respiratory tract; doses to other organs were usually of the embryo yields a small target for alpha particle hits, but
at least an order of magnitude smaller (see table25, adapted conversely, alpha particle damage to DNA may have major
from reference [K21, table2]). In particular, doses to tissues consequences. The dosimetric calculations for the developing
with a relatively high fat content (such as red bone marrow), embryo and foetus used the maternal and the foetal placental
while somewhat higher than those to most other tissues, did blood supply at different points in time [R5]. These calcula-
not appear to be high enough to present a particular problem. tions relied on available published data for these, and for foetal
The conclusion was that the conventional focus on risk of weights. The accumulation of radon in various compartments
lung cancer from inhaled RDPs was appropriate following the ingestion of 100Bq of radon dissolved in water
was estimated, and the dose determined as a function of time,
473. Kendall and Smith [K21] also considered the dose to on the basis of the pharmacokinetic model developed. The ratio
the foetus. For RDPs, they adopted the foetal discrimination of the weight of blood in the embryo/newborn infant to its total
factors of the ICRP. The ICRP makes no recommendation weight was assumed to be a constant, as was blood flow to the
for radon gas. Kendall and Smith noted that, for many radio- placenta at 115mLkg1min1. These parameters need verifica-
nuclides, the dose to the foetus is similar to that to maternal tion, as they are critical not only for such calculations but for
muscle. Arguing that the fat content of the foetus is low, they other basic toxicological calculations. The clearance half-times
assumed that maternal muscle provides a reasonable surro- of radon for the various tissues in the mother were based on
gate. An alternative approach is discussed below. published human data [H24, H25]. For an average intake of
0.6L of raw tap water per day, containing a radon concentra-
474. According to Kendall and Smith [K19], the general tion of 100 Bq/L, the calculated total equivalent dose to the
pattern of doses to different tissues for inhalation and inges- foetus over the term of pregnancy was 250Sv. The highest
tion of radon and its decay products by children is similar to calculated equivalent dose of 3Sv/week occurred between
that in adults. Both for inhalation and for ingestion, the organ weeks 6 and 16 [R5]. The foetal doses estimated in reference
of intake receives much higher doses than any other organ. In [R5] are considerably higher than those reported by Kendall
the case of inhalation, the largest doses are to the lung and the and Smith [K19], who have noted that the foetus has little fat
extrathoracic part of the respiratory tract (the nose, pharynx until late in gestation. The difference between these estimates
and larynx). In the case of ingestion, the stomach receives a originated from the assumptions made in the models.
295
Table 25 Summary of dose coefficients from inhaled radon decay products together with annual doses from decay products and radon at 200Bq/m3 (see reference [K21] 296
for discussion)
222
Type F Type M Rn
Dose per unit intake (Sv/Bq) Dose per unit intake (Sv/Bq)
218 214 214 218 214 214
Po Pb Bi Mixture Annual dose (mSv) Po Pb Bi Mixture Annual dose (mSv) at Annual dose (mSv)
at 200Bq/m3 200Bq/m3 at 200Bq/m3
Lung 1.1 10-8 1.4 10-8 3.9 10-8 2.5 10-8 35.8 2.7 10-8 1.3 10-7 1.1 10-7 1.1 10-7 159 1.2
Ext.thor. 4.4 10-9 2.7 10-8 6.3 10-8 3.0 10-8 44.5 6.7 10-9 4.8 10-8 9.3 10-8 4.9 10-8 70.9
Stomach 3.3 10-11 1.7 10-10 9.4 10-11 1.3 10-10 0.19 1.2 10-11 7.7 10-11 4.9 10-11 5.6 10-11 0.08 0.06
Small intestine 3.0 10-11 1.7 10-10 7.5 10-11 1.2 10-10 0.17 6.9 10-12 4.9 10-11 1.8 10-11 3.2 10-11 0.05 0.06
Colon 2.8 10-11 1.5 10-10 8.2 10-11 1.1 10-10 0.16 3.9 10-12 2.4 10-11 9.9 10-12 1.7 10-11 0.02 0.05
RBM 3.9 10-11 3.2 10-10 6.8 10-11 1.9 10-10 0.28 4.2 10-12 3.7 10-11 7.4 10-12 2.2 10-11 0.03 0.65
Bone surface 3.4 10-11 2.1 10-9 6.8 10-11 1.0 10-9 1.48 3.6 10-12 2.5 10-10 7.3 10-12 1.2 10-10 0.17 0.03
Liver 5.8 10-11 5.0 10-10 6.8 10-11 2.9 10-10 0.43 6.3 10-12 5.6 10-11 7.6 10-12 3.2 10-11 0.05 0.09
Breast 2.8 10-11 1.4 10-10 6.8 10-11 1.0 10-10 0.15 3.0 10-12 1.6 10-11 7.8 10-12 1.2 10-11 0.02 0.42
Kidney 8.7 10-11 4.8 10-9 5.8 10-9 3.6 10-9 5.20 9.5 10-12 5.0 10-10 5.9 10-10 3.7 10-10 0.54 0.05
Gonads 2.8 10-11 1.4 10-10 6.8 10-11 1.0 10-10 0.15 2.9 10-12 1.5 10-11 7.1 10-12 1.1 10-11 0.02 0.05
Brain 2.7 10-11 1.5 10-10 6.8 10-11 1.1 10-10 0.15 2.9 10-12 1.5 10-11 7.1 10-12 1.1 10-12 0.02 0.06
UNSCEAR 2006 REPORT: VOLUME II
Bladder 2.8 10-11 2.1 10-10 1.0 10-10 1.4 10-10 0.21 2.9 10-12 2.2 10-11 1.0 10-11 1.5 10-11 0.02 0.05
-11 -10 -11 -10 -12 -11 -12 -11
Muscle 2.8 10 1.4 10 6.8 10 1.0 10 0.15 3.0 10 1.6 10 7.4 10 1.1 10 0.02 0.05
CED 1.4 10-9 2.5 10-9 5.6 10-9 3.6 10-9 5.30 3.3 10-9 1.6 10-8 1.4 10-8 1.3 10-8 19.7 0.28
-11 -11 -11 -11 -12 -12 -12 -12
Foetus 1.3 10 5.3 10 2.6 10 4.1 10 0.06 1.6 10 6.2 10 2.9 10 4.9 10 0.01 0.04
Skin 25 25
Note: The activity of decay products in comparison with radon is taken to be 218Po:214Pb:214Bi in the ratio 0.9:0.45:0.225; F = 0.41. 90% of decay products are taken to be attached to aerosols, 10% unattached. Annual volume breathed taken to be
7,300m3. Ext.thor. is the extrathoracic part of the respiratory tract. RBM is red bone marrow. CED is committed effective dose. Kidney is shown as the organ receiving the next highest dose after the respiratory tract. The dose to the foetus from
radon gas taken to be that to muscle over 9 months. Dose to skin is taken from reference [N9]. It does not depend on type.
476. Kendall and Smith [K19] also investigated differ- similar across all radon categories. Except for non-melanoma
ences between doses to adults and those to children aged 1 skin cancer, the authors found no significant positive corre-
and 10years. They calculated both dose coefficients, i.e. the lation with radon. Overall, the authors found no significant
equivalent dose resulting from an intake of unit activity of difference in the corrected survival rates for any cancer site
the material in question, and also annual equivalent doses. between the low- and high-radon areas.
The former tend to be higher in children than in adults. The
differences between the annual doses to children and adults 481. A research letter by Law et al. [L20] commented
are smaller than the differences in the dose coefficients, on residential radon exposure and leukaemia, referring
because children breathe less air and ingest less water than to an earlier study [K24] of acute leukaemia in the south-
adults. west, north and north-west of England of residents aged
1669 years. Radon measurements (of about 6 months
duration) were made in the living rooms and bedrooms of
B. Epidemiology of cancers other than lung 1,881 houses (about 78% of the homes of the subjects, 76%
for the cases and 80% for the controls). No association was
477. Annex A, Epidemiological studies of radiation found between acute leukaemia and radon concentration; the
and cancer, provides a discussion of the epidemiological authors concluded that their study did not support exposure
methods as well as information complementary to that to residential radon as a causal factor in leukaemia in the
provided in this annex. United Kingdom.
478. The currently available epidemiological evidence 482. Thorne et al. [T24] investigated possible associations
indicates that risks other than lung cancer from exposure to between residential radon exposure and paediatric cancers in
radon and its decay products are likely to be small. A number Devon and Cornwall, United Kingdom. This study compared
of studies of residential radon and non-lung cancer are avail- the incidence of childhood cancers in postal sectors with low
able. Laurier et al. [L18] reviewed 19 ecological studies, radon concentrations (<100Bq/m3, average 57Bq/m3), and
8residential casecontrol studies and 6 miner cohort stud- high radon concentrations (>100Bq/m3, average 183Bq/m3)
ies published between 1997 and 2000 in order to examine a in a total of 238 postal sectors. The authors found no sig-
possible association between radon exposure and leukaemia. nificant difference in cancer incidence rate between low- and
While the ecological studies suggested a possible positive high-exposure sectors.
association, the casecontrol studies and the miner cohort
studies did not. Overall, the authors concluded that the avail- 483. Steinbuch et al. [S46] reported an investigation of res-
able data (i.e. to 2000) did not provide any evidence of an idential radon exposure and risk of childhood acute myeloid
association between radon exposure and leukaemia [L18]. leukaemia (AML). Alpha track detectors were placed in the
houses of 173 cases and 254 controls for 1 year. Overall,
479. A series of papers [E6, L38, T28] followed the review there was no association between residential radon concen-
by Laurier et al. [L18]. Eatough [E6] noted that potential tration and the risk of AML. Lubin et al. [L12] reported an
leukaemia risk to miners was investigated by looking for age-matched study of childhood acute lymphocytic leukae-
trends in relative risks with increasing exposure to RDPs. mia (ALL) and residential radon exposures of children in the
However, studies of the dosimetry for radon gas and RDPs United States. Radon levels for the 505 cases and 443con-
suggest that the doses to the red bone marrow are not appre- trols were estimated for 97% of the exposure period. The
ciable [H38]. Tomasek [T28] reported a study of Czech min- mean radon level was lower for cases (65.4Bq/m3) than for
ers in which an excess of leukaemia related to duration of controls (79.1 Bq/m3). No association between ALL and
exposure was observed, and went on to suggest that duration radon exposure was found.
of exposure in the mine environment is likely to be a surro-
gate for exposure to uranium dust, which he considered to be 484. Evrard et al. evaluated the ecological association
the predominant dose contributor. Laurier et al. [L38] com- between indoor radon concentrations and acute leukaemia
mented that results published since their review [L18] did incidence among children under 15 years of age in France
not modify the conclusions that available epidemiological [E7]. The study considered the whole country, divided into
data do not demonstrate an association between leukaemia 348 geographical units. Incidence data included 4,015 cases
and exposure to radon. They also noted that if such a rela- of acute leukaemia registered by the French National Regis-
tionship exists, the association would be slight and of little try of Childhood Leukaemia and Lymphoma between 1990
significance for residential exposure. and 1998. Exposure was based on a national campaign of
13,240 indoor radon measurements. A positive ecological
480. An ecological study of cancer incidence and radon association was observed between indoor radon concentra-
levels in the south-west of the United Kingdom looked at tion and childhood leukaemia incidence, on the borderline
14major cancer sites, using data for the South-Western Can- of statistical significance (p = 0.053). A significant associ-
cer registry [E5]. Average radon levels for residences were ation was observed for AML (p = 0.004) but not for ALL
sorted into 10 categories, from low (<40Bq/m3) to very high (p = 0.49). Consideration of exposure to terrestrial and
(>230Bq/m3), and age standardized cancer rates were calcu- cosmic radiation did not modify the observed association
lated for each category. Incidence rates for lung cancer were between radon exposure and incidence of AML [E8].
485. In a 1993 paper, Tomasek et al. [T51] reported on observed, which was close to the expected number (O/E =
a study of RDP exposure and cancers other than lung can- 1.01; 95% CI: 0.95, 1.07). Among the 28 individual cancer
cer in a cohort of uranium miners in western Bohemia. types studied, the only sites of statistically significant excess
These authors investigated site-specific cancer mortality in cancers were the stomach and the liver; however, mortality
4,320miners who had been followed-up for an average of from these cancers was not related to cumulative RDP expo-
25years. An average exposure of 219WLM was reported. sure in WLM and was thus unlikely to have been caused by
Data on smoking habits and alcohol consumption were not radon. Among the leukaemias, the O/E ratio for acute mye-
available. An analysis of rates of observed to expected num- loid leukaemia was larger than for other leukaemias, but was
bers of deaths (O/E) showed that overall, the risk of death not statistically significant. Overall, the authors concluded
from non-lung cancers was slightly greater than the natural that exposure to high concentrations of radon in the air is
rates but not significantly so. A significant excess of non-lung unlikely to result in an increased risk of cancer mortality
cancer mortality in men who started to mine when they were other than from lung cancer [D12].
younger than 25 years of age was found, but the increase was
not related to cumulative RDP exposure. Overall, the authors 489. Mhner et al. [M44] reported on a study of leukae-
concluded that there is no significant risk of any cancer other mia in German miners. This casecontrol study included
than lung cancer, although further investigation is needed of 377cases and 980 individually matched controls. Exposures
the effect of RDP exposure on cancers of the gall bladder were based on a jobexposure matrix that included expo-
and extrahepatic bile duct and on multiple myeloma. sure to radon and its decay products as well as exposure
to external gamma radiation and to long-lived radioactive
486. Rericha et al. [R13] reported an investigation of the dust. Using logistic regression methods and taking study
incidence of leukaemia, lymphoma and multiple myeloma, power into account, the authors concluded that a casual
a total of 177 cases, in Czech uranium miners, using a retro relationship between radon progeny and risk of leukaemia
spective casecohort design in a study of 23,043 uranium can largely be excluded. The study did, however, suggest
miners. The authors found no apparent association between an elevated risk of leukaemia for cumulative exposures of
RDP exposure and either non-Hodgkins lymphoma or mul- >400WLM.
tiple myeloma, but did find an association between RDP
exposure and an increased risk of leukaemia (chronic lym- 490. Kreuzer et al. [K29] reported on a study of the risk of
phocytic leukaemia, CLL), which was not previously thought lung cancer and other cancers in the German uranium miner
to be radiogenic. The association is based on a comparison cohort. The study, based on external comparisons, showed
of the relative risk (RR) of CLL in miners who had an RDP a statistically significant excess of lung cancer risk and a
exposure of 110WLM with those who had an exposure of trend of increasing risk with increasing cumulative RDP
3WLM. An RR of 1.98 (95% CI: 1.10, 3.59; p = 0.016) was exposure. The study also found an excess, although not sta-
reported. tistically significant, mortality from liver and lung cancer.
The authors indicated that the excess is unrelated to cumu-
487. Darby et al. [D22] reported on RDP exposure and non- lative RDP exposure and noted that, in the early years of
lung cancer in a group of Swedish iron ore miners. These mining, the Wismut mining company provided miners with
authors observed that, when the mortality from all cancers alcohol and cigarettes free of charge. Tirmarche et al. [T9]
other than lung in miners was compared with that expected reported an excess of larynx cancer in French miners; how-
for the northernmost county of Sweden, the O/E ratios were ever, Villeneuve et al. [V4] found no significant relationship
higher in men with exposures of >100WLM than in men between RDP exposure and other cancer sites.
with lower exposures, but the trend was not significant. As in
the western Bohemian study [T51], excesses were seen for 491. The update of data for the Eldorado miners [H35]
cancer of the gall bladder and extrahepatic bile duct and for involved 17,660 workers. The update extended the mortal-
multiple myeloma; however, the increases were not statisti- ity analysis by almost 20 years and added 30 years of new
cally significant. information on cancer incidence. A total of 5,332 deaths
occurred between 1950 and 1999, and 2,355 workers devel-
488. Darby et al. [D12] carried out a collaborative analysis oped at least one cancer between 1969 and 1999. Mortality
of 11 miner studies to look for risks of cancer other than lung and cancer incidence were compared with those of the gen-
cancer. The miner populations included 10 of the 11 miner eral Canadian population. Lung cancer was the only cancer
cohorts covered by the joint analysis by Lubin et al. [L10] site with an excess for both mortality and cancer incidence.
(the Radium Hill study [W15] was excluded since follow-up In the internal analysis, there was no meaningful evidence of
was incomplete). The 11th miner cohort added in the analy- any causal relationship between RDP exposure and increased
ses by Darby et al. was a cohort of Cornish tin miners [H29]. risk of any cancer other than lung cancer.
Overall, the study [D12] included some 64,209 men who had
worked for an average of 6.4 years, accumulated an average
exposure of 155 WLM and been followed for an average C. Effects other than cancer
of 16.9 years. External mortality data were available for 10
of the studies (but not for the Chinese study of Xuan etal. 492. A full discussion of this subject is provided in annexB,
[X1]). In total, some 1,179 non-lung cancer deaths were Epidemiological evaluation of cardiovascular disease and
other non-cancer diseases following radiation exposure. uranium miners. The cohort included 590,001 male subjects
This section provides a few additional observations from who were employed for at least 6 months between 1946 and
epidemiological studies of miners. 1989 at the former Wismut uranium company in eastern
Germany. As for other studies of Wismut miners, exposures
493. Villeneuve and Morrison [V2] investigated the mor- to RDPs, long-lived radionuclides and external gamma radi-
tality from coronary heart disease (CHD). In this study, the ation were estimated using a detailed jobexposure matrix.
cohort consisted of 1,743 underground miners and 321 mill- As of 31 December 1998, the cohort included (about)
ers or surface workers. Men in this cohort had a mean expo- 16,598deceased miners, with 5,417 deaths from cardiovas-
sure to RDPs of 378.6WLM over an average of 5.7 years. cular diseases. Linear Poisson regression models were used
As for other analyses of these miners, exposures were based to estimate the ERR per unit of cumulative radiation expo-
on the analysis of Corkill and Dory [C12]. Smoking data sure after adjusting for attained age and calendar period.
from a 1993 survey were used to update data from previ- The study found no trend in risk of circulatory diseases with
ous surveys in 1960, 1966, 1970 and 1978. Smoking status increasing cumulative exposure to RDPs (ERR was 0.0006
(current, former or never smokers) was determined for 59% (95% CI: -0.004, 0.006) per 100 WLM), external gamma
of the cohort. Finally, data on the mortality experience of radiation (ERR was -0.26 (95% CI: -0.6, 0.05) per Sv) or
the cohort were available up to 1990. Multivariate Poisson long-lived radionuclides (ERRwas -0.2 (95% CI: -0.5, 0.06)
regression analysis was used to estimate the relative risk of per 100kBqhm3. The authors concluded that their results
CHD from RDP exposure, with adjustments for attained age, did not support an association between cardiovascular
duration of exposure and smoking status. Unlike previous disease mortality and exposure to radiation among uranium
studies of this cohort, the analyses [V2] used internal com- miners.
parisons to control for bias potentially introduced through
the healthy worker effect. This study found that workers 496. More recent data are also available from Canada.
with high cumulative exposures to RDPs (over 1,000WLM) Howe [H35], in the update of the Eldorado cohort study,
had an elevated risk of CHD (RR = 1.5; 95% CI: 0.77, 2.75) reported that for most of the causes of death, the cohort as a
compared with those with no exposure. However, no statis- whole as well as various subcohorts had reduced risks rela-
tically significant trend of increasing risk with increasing tive to the population. In particular, the authors stated that,
exposure was found, nor was there a statistically significant although an increase of hypertensive disease was observed
interaction between cumulative RDP exposure and smoking (significant in only one of the subcohorts examined), the
status. The authors found that smoking status was a signifi- study indicated a statistically significant deficit in males of
cant predictor of CHD. cardiovascular diseases such as stroke and ischaemic heart
disease. The authors go on to suggest that this is probably a
494. Villeneuve et al. [V6] further explored the rela- consequence of the healthy worker effect, since heart disease
tionship between mortality from CHD and RDP exposure would be likely to prevent people working in a strenuous
using both external and internal cohort comparisons in their physical occupation such as mining. Villeneuve et al. [V6]
most recent update of this cohort. There was no association found that there was no apparent trend between cumulative
between cumulative exposure in WLM and CHD mortality. exposure to radon and the relative risk of death from CHD
A reduced CHD mortality rate was observed relative to the (p = 0.63). Furthermore, this finding was unchanged after
population of Newfoundland males (SMR = 0.86; 95% CI: adjusting for lifetime smoking status, which was available
0.74, 0.98); the authors attributed this reduction to a healthy for approximately 54% of the cohort. Additionally, cumula-
worker effect. tive exposure to radon was found to be unrelated to diseases
of the circulatory system, acute myocardial infarction and
495. Kreuzer et al. [K30] reported an investigation of the cerebrovascular disease. All of these findings are consistent
mortality from cardiovascular diseases in a cohort of German with those of Kreuzer et al. [K30].
VII. Implications for risk assessment
497. Epidemiological studies of underground miners provide with the BEIR IV [C19] estimate of 140 per 106 person-
the current basis for estimating the risk of exposure to radon years per working level month for male non-smokers. The
and its decay products. Studies of smoking and non-smoking approach in reference [S10] was necessarily limited because
miners show that exposure to RDPs carries an enhanced risk the authors did not have access to data on individual miners
of lung cancer. However, miners were not exposed to RDPs and could only utilize published relative risks within catego-
alone but rather to RDPs in association with many other ries of cumulative exposure (J h m3 or WLM); similarly,
agents, among them silica (quartz), various metals, includ- no attempt could be made to evaluate patterns of error for
ing arsenic, and diesel exhaust. Traditionally, the risks from different mining periods within a study. For the ERR model,
domestic radon exposure have been developed by extrapola- the authors estimated that the most likely range for the ERR
tion from the data for miners; however, the risks from residen- per unit exposure parameter for this group of studies was
tial radon can now be estimated directly using the results of 0.0090.00005(Jhm3)1 (0.51.5%WLM1).
pooled residential casecontrol studies (see sectionV).
Figure XIX. Distribution of absolute risk for Colorado

A. General studies of exposure uncertainty miners with no exposure prior to 1950 [S10].
498. There is a great deal of interest in dosimetry-based

estimates of risk from exposure to RDPs (see section II).
There is a discrepancy between the dosimetry-based and the
miner-epidemiology-based approaches, with differences in
estimates of a factor of 23. The miner epidemiology data
Mean 1 = 85.16 x 10-6
provide the basis for investigating biological mechanisms and
PROBABILITY DENSITY
modifiers such as time since exposure and age at exposure.

As discussed in sectionIV, there is considerable uncertainty
in the exposures of miners, with uncertainty increasing the
further we go back in time. In view of the ongoing impor-
tance of miner studies in understanding the risk from expo- 95% Confidence
sure to radon and RDPs at work and in the home, it is useful interval
to consider the effects of uncertainty in miner exposures on
the epidemiological analyses performed using miner data.
499. A 1989 report considered the effects of uncertainty in

exposure estimates for the studies then available of miners in -100 -60 -20 20 60 100 140
Ontario, Beaverlodge and Port Radium (Canada), Czecho- -80 -40 0 40 80 120 160
slovakia, Sweden, and the Colorado Plateau (United States) RISK, 1 (106 WLM)-1
[S10]. Several subgroups of the Colorado Plateau cohort
were also studied. The focus of the study was on adjusting
the exposureresponse parameter in the simple linear model 500. A subsequent paper by Chambers et al. [C15] reviewed
for excess relative and excess absolute risk. The authors used the factors affecting exposure estimation for seven groups of
a Bayesian error-in-variable relative risk approach to ana- uranium miners. These included the temporal and spatial var-
lytically assess the effect of uncertainty on the exposure iability of radon and RDP levels in the workplace, changing
response relationship. FigureXIX shows the posterior prob- mining methods and ventilation practices, and uncertainties
ability density factor for the absolute risk coefficient for about the miners work histories. Bayesian methods were used
Colorado miners with no mining exposure prior to 1950. At to develop posterior probability density functions of absolute
that time (i.e. follow-up to 31 December 1982), the cohort and excess relative risk coefficients for each of the cohorts.
with no exposure before 1950 included 168 miners with FigureXX shows the posterior probability density function
lung cancer. The mean lifetime risk was estimated at about for the ERR. The authors noted that the estimated RDP expo-
85 cases per 106 person-years per working level month, sures in WLM are uncertain in all the miner studies. For the
with a range of about 60150 cases per 106 person-years per reasons given in reference [S10], the studies of United States
working level month [S10]. The estimate may be compared miners [H17, P14, S10], Ontario miners [M19, M23], and
301
Czechoslovak miners [S25] were considered at the time to s tudies). Overall, Chambers et al. [C15] estimated the ERR
provide the strongest basis for risk estimation. The strengths to have a 95% uncertainty range of 0.51.5per 100WLM,
of these groups are that they are all large, well-traced cohorts comparable to the estimates of Lubin et al. [L10].
for which considerable information existed on which to base
risk estimates for the period of interest. To the best of the 501. The pooled analysis by Lubin et al. [L10] considered
authors knowledge, there was no systematic bias with regard the impact of uncertainties in the estimates of RDP exposure
to the magnitude of the group exposures estimated in these only in the most general way and only within the context
studies. However, the uncertainties in exposures of individual of modification of the exposureresponse relationship by
miners could be very large, particularly for exposures associ- exposure rate and exposure duration. Exposure uncertainty
ated with the early years of mining. Of these three groups, was considered greatest in the earliest years of mining, i.e.
the United States miners were exposed to the highest RDP those years in which exposure rates were highest. Accord-
concentrations, the Czechoslovak miners were exposed to ing to Lubin et al. [L10], exposure uncertainty would there-
intermediate levels, and the Ontario miners were exposed to fore have tended to attenuate the effects of high exposures
the lowest levels. While figureXX showed the posterior prob- and potentially induce an inverse exposure-rate pattern
ability density function for all cohorts, figureXXI illustrates [L22]. They estimated an ERR and associated 95% CIs as
the posterior probability density function developed by com- depicted graphically in figureXXII. Lubin et al. [L22] report
bining the three studies considered best, together with that a combined estimate of ERR of 0.49 (95% CI: 0.2, 1.0) per
from combining all the studies (with and without a notional 100WLM, where the joint 95% CI is based on a random-
correction for bias in the Swedish and the Beaverlodge effects model.
Figure XX. Excess relative risk (posterior) probability Figure XXI. Combined excess relative risk (posterior)
density functions with unadjusted variances [C15]. probability density functions [C15].
United States
PROBABILITY DENSITY
PROBABILITY DENSITY
Port
Radium Bias corrected All studies
Newfoundland
Czechoslovakia
Ontario Best three
Sweden
Beaverlodge
-1 0 1 2 3 4 -1 0 1 2 3
EXCESS RELATIVE RISK (% PER WLM) EXCESS RELATIVE RISK (% PER WLM)
502. BEIR VI [C20] also investigated the role of uncertainty Committees preferred uncertainty limit was derived using
in estimating lung cancer risk, and developed an extensive a simple constant relative risk model fitted to the miner data
table summarizing the sources of uncertainty in estimating at cumulative exposures of below 50WLM. On this basis,
lifetime risk from residential exposure to radon. The BEIRVI BEIR VI estimated an ERR of 1.17 per 100WLM, with a
estimates of lung cancer risk were based on analyses of the 95% uncertainty interval from 0.2 to 22.5 per 100WLM.
data from miner epidemiological studies. The BEIR VI Com-
mittee acknowledged that there were uncertainties in expo- 503. Notwithstanding the different data and methods that
sures to RDPs and other potential factors, such as exposure have been used to develop combined estimates of ERR from
to cigarette smoke and arsenic. No systematic bias in the esti- the studies of miners, there is a remarkable consistency in
mates of miner exposure to RDPs was identified. BEIR VI the ranges of ERR per 100WLM that have been estimated.
also suggested that random errors might result in an under- As discussed in the preceding paragraphs, the 95% CI for the
estimate of the slope (risk) of the exposureresponse rela- ERR was estimated by Chambers et al. [C15] as 0.51.5 per
tionship. In addition to extensive qualitative discussion, the 100WLM; by Lubin et al. [L10] as 0.21.0 per 100WLM;
BEIR VI Committee applied quantitative methods for uncer- and by BEIR VI [C20] as 0.222.5 per 100 WLM, with
tainty analysis, acknowledging that their analysis should be central estimates of ERR ranging from 0.49 to 1.17 per
considered illustrative, not to replace the Committees new 100WLM. On the basis of the most recent results of miner
comprehensive qualitative analysis, since not all sources of studies as described earlier in this annex (see para.427), an
uncertainty could be identified and characterized. The BEIRVI estimate of a combined ERR of 0.59 (95% CI: 0.35, 1.0)
per 100WLM is consistent with previous estimates but with 0.59 (95% CI: 0.25, 1.0) per 100WLM, a nominal absolute
somewhat narrow 95% CIs. By multiplying a notional life- lifetime risk of about 4.7 104 (95% CI: 2.8 104, 8 104)
time risk of lung cancer of, say, 8%, and an average ERR of for 100WLM can be calculated.
Figure XXII. Estimates of excess relative risk of lung cancer per WLM (adapted from [L10]).
Yunnan tin
Czech uranium
Colorado uranium
Ontario uranium
Newfoundland fluorspar
Swedish iron
New Mexico uranium
Beaverlodge uranium
Port Radium uranium
Radium Hill uranium
French uranium
Combined
0.0005 0.002 0.005 0.02 0.05 0.2

0.001 0.01 0.1
EXCESS RELATIVE RISK (WLM-1)
B. Biologically based models populations with different baseline lung cancer incidence
rates. The combined cohort includes 5,098 miners and
504. Several investigators reported analyses of experimen- 125lung cancer deaths in the French cohort and 5,002 miners
tal animal data and epidemiological data with multistage and 449 lung cancer deaths in the Czech cohort. The corre-
models to study mechanisms of carcinogenesis and assess sponding mean total cumulative exposure levels were 37 and
risks from the inhalation of RDPs (e.g. [B20, B28, B29, C20, 57WLM, respectively, for the two cohorts. A two-mutation
C29, C30, C31, C33, H26, K22, L16, L23, L33, L34]). The carcinogenesis model with clonal expansion of cells in the
main difference between the approaches was in the choice of intermediate stage was fitted to the individual miner data.
exposureresponse model to be used for each of the cellular Linear exposure-effect relationships were used for the two
processes in the biologically based model. Age-dependent mutational steps. The authors found that the fitted linear effect
cancer incidence data do not yet provide the basis for deter- of radon on the first mutational step was an order of magni-
mining the most appropriate model, as evidenced by results tude larger than for the second mutational step. Although the
of a model comparison using lung cancer data for radon- baseline lung cancer risk in the Czech miner cohort was con-
exposed rats [H26]. The BEIR VI Committee [C20], as noted siderably higher than that for the French miners, both data
earlier, acknowledged the importance of biologically based sets could be described with the same parameter values for
models and indicated that, when biological mechanisms are the relative effect of exposure to RDPs on the mutation rates.
better understood, such models might become the preferred The authors argued that the uniform description of the effect
approach to assessing the risks. Similar views are expressed of RDP exposure for two miner cohorts with distinctly differ-
by Krewski et al. [K22], who applied the two-stage clonal ent baseline lung cancer risks (0.09 for the French and 0.23
expansion (TSCE) model to two cohorts important to assess- for the Czech miners) demonstrated the possibility of using
ing the risks from RDP exposure, namely the Colorado the model for risk transfer across populations. In addition,
Plateau miners and the Chinese tin miners. the biologically based model implicitly describes age and
exposure-rate effects, and thereby allows for extrapolation
505. An important project, within the framework of the to lifetime exposures to low radon concentrations. Lifetime
European Union project FIGH-CT1999-00013, looked at risks were calculated for a 75-year continuous exposure to
a multistage model analysis of the data from the French 1WLM/a (~256Bq/m3). The lifetime ERR calculated from
and Czech uranium miner cohorts [T30]. One of the issues the model solution in references [B27, B28] was 1.1 for the
being investigated was how risks can be transferred between combined cohorts.
506. Heidenreich et al. [H32] provided further analysis of 509. More recent studies such as those reported in refer-
the French and Czech cohorts using the biologically based ences [B27, B28, H32, H36, K22, M11, T30] suggest that
TSCE model together with an analysis of the Chinese and mechanistic or biologically based models, which allow the
Colorado cohorts. The model allows an action of radiation opportunity to investigate mechanisms of carcinogenesis,
on initiation, promotion and transformation in cancer induc- are likely to find increasing application. Tirmarche et al.
tion. While all four studies indicate a highly significant action [T30], for example, reported estimates of final and second
of radiation on promotion, the action on initiation is not sig- mutation rates based on an analysis of the French and Czech
nificant in the French cohort and is barely significant in the miner cohorts. One observation from their analysis is that
Colorado miner cohort. No action on transformation is found an inverse dose-rate effect cannot be excluded for exposure
in the Colorado miners, while the other data sets indicate a rates of >30WLM/a.
borderline significance. The doubling exposure rate for initia-
tion is about 3.5WLM/a in the new data sets, while it is higher 510. Harley et al. [H4, H36] applied a biologically based
in the historic data sets. For transformation, the doubling rate model derived from an evaluation of the number of nuclei tra-
is about 20WLM/a for the new data sets, while again the versed by an alpha particle that will cycle as a function of time
historic data give higher estimates. The action of radiation on following unit exposure to RDPs. The model was developed
promotion is different in the four data sets. The larger power in two steps. First, the number of basal cell nuclei traversed by
of the French and Czech cohorts requires less extrapolation an alpha particle following an exposure of 1WLM was deter-
when the risk at very low exposures is estimated. mined from biological data. Secondly, the number of nuclei
traversed and the measured cycling rates in normal bronchial
507. A 1990 study [M11] reanalysed the data for the Colo- epithelium were used to calculate the dividing population as
rado Plateau uranium miners in order to investigate RDP a function of time after exposure. The cycling rates decreased
exposure, cigarette smoking and lung cancer using a two- with a half-time of about 15 years. The authors compared
mutation model as the biological basis for their assessment. their model fit with the combined excess risk data from the
The authors concluded that exposures to both RDPs and joint analysis of 11 underground mining cohorts [L10], and
cigarette smoke affect the first mutational step and the rate suggested that their model may explain why the tumour risk
of cell division but that the second mutational step was inde- decreases with time since exposure and with attained age, in
pendent of RDP and cigarette smoke exposures. The authors that both could reflect the reduction in cycling frequency of
also concluded that the age-specific risks arising from joint cell nuclei repopulating the basal stem cells.
exposure to RDPs and cigarette smoke are more than additive
but less than multiplicative. An inverse dose-rate effect was 511. Little [L21] fitted multistage cancer models with
observed, in that fractionally lower RDP exposure resulted clonal expansion to the Colorado miner data, allowing for up
in higher lung cancer risks. The authors also obtained the to three mutational steps. Both radiation and smoking were
same estimates of lung cancer risk from exposure to residen- allowed to affect the mutation rates as well as cell prolifera-
tial radon for both smokers and non-smokers. This observation in the intermediate stages. The best fit of the data was
tion is consistent with observations from the European [D17] obtained for a three-mutation model in which the first and
and North American [K1] pooled residential radon studies of second mutation rates increased with RDP exposure, and the
no significant heterogeneity across categories of smoking. first mutation rate increased with smoking rate, in a strongly
These studies showed an ERR of 0.2per 100WLM for non- non-linear way. This three-mutation model was slightly
smokers at age 70 exposed at a rate of 0.2WLM/a. superior to a two-stage model in which the first mutation
rate depended in a non-linear fashion on radon and smoking,
508. Luebeck et al. [L16] provided further discussion based in combination with a reduction of intermediate cell death/
on an analysis of the data for the Colorado Plateau uranium differentiation rate with radon exposure.
miner cohort using a TSCE model. Exposure to RDPs was
suggested to affect both the rate of initiation of intermediate 512. The preceding examples show that current multistage
cells in the pathway to cancer and their rate of proliferation. cancer models with clonal expansion are not specific enough
However, the effect of radon on the rate of initiation was to determine the doseresponse relationships for the cellular
not statistically significant. The results of reference [L16] processes in the model from a fit to cancer incidence data.
showed that, depending on total radon exposure, the lifetime This was shown in model intercomparison on a large data
ERR per unit exposure first increased with duration of expo- set of radon-exposed rats [H21]. An alternative approach to
sure, reached a maximum and then declined. Non-smoking this problem of specificity was applied in the two-mutation
miners who were exposed to RDPs for 10 years were found model fit of Leenhouts to the Colorado uranium miner data
to have approximately the same risk (as measured by life- [L23]. He used a stepwise fitting approach in combination
time ERR per unit exposure) as a non-smoking individual with biologically motivated mutation equations. The radia-
who spent 1020 years in a residence with very low levels tion effect in this model was limited to the mutation rates,
of radon. These authors stated that if the inverse dose-rate and no effect of radiation on proliferation rates was assumed.
effect observed in miners at much higher total doses were Using a stepwise approach, Leenhouts fitted the background
extrapolated naively to durations (and exposure rates) more parameters to the lung cancer incidence of non-smokers, the
typical for homes, the risk (lifetime ERR per unit exposure) smoking coefficients to the lung cancer incidence of smok-
would be grossly overestimated. ers, and the radiation parameters to the miner data. From
the model solution, the following risks were calculated at the results in BEIRVI. However, there are wide variations
age 75 for a lifelong exposure to 0.1WLM/a: EAR of 0.008 in these studies in size, duration of follow-up, reliability of
for non-smokers, increasing to 0.0014 for smokers, which exposure estimation, availability of smoking data and other
corresponds to ERR values of 0.19 and 0.009, respectively. factors. For example, it is questionable whether the follow-
ing cohorts should be used for risk assessment: (a) Radium
Hill cohort, because of limited follow-up and the low qual-
C. Risk projection ity of the exposure data; (b) Port Radium, Newfoundland
fluorspar and (without further re-evaluation using the
513. The ICRP [I3] recommends that radon risk assess- revised dosimetry) Swedish iron miner cohorts, because
ment be based on epidemiological studies of miners. The of the low quality of the exposure data; and (c) Chinese
BEIR VI Committee also base their risk estimates on an tin mining cohort, because of extreme confounding from
analysis of pooled miner data [C20]. Both reports predate arsenic exposure. In addition, the French cohort data [C20,
the pooled analyses of residential casecontrol radon stud- L4, L10] are being updated, and the new Wismut cohort
ies. As discussed below, the pressent report suggests that the described in section V, is being developed. The current
risk of lung cancer from domestic exposure to radon can be European project in which a joint analysis is being per-
estimated using the results of the pooled residential case formed of the extended French cohort and the Czech cohort
control radon studies [D17, D21, K1, K26, L26]. is an important step, as these two cohorts are both of high
quality. In addition, the Eldorado cohort, consisting of
514. It is important to develop reliable risk estimates of miners at the Port Radium and Beaverlodge uranium mines
lung cancer due to radon exposure in the workplace or in and the Port Hope uranium processing facility, has been
the home. Many published evaluations (e.g. [C20, U2, U17, updated [H35]. One important aspect of this update is the
W18]) are available, as described in previous sections. extensive review of work histories and the use of updated
Whether there is a risk from residential radon exposure has exposure algorithms, both of which significantly improve
been widely debated in the literature (e.g. [B34, C24, C25, the quality of the epidemiological studies carried out on
C34, F8, F12, H29, P10]). However, notwithstanding the this cohort.
wide range of results from residential casecontrol stud-
ies and the important effects of confounding by smoking 517. The BEIR VI model was developed from a pooled
and other factors, overall the pooled European [D17, D21], analysis of 11 underground mining cohorts and takes
North American [K1, K26] and Chinese [L26] casecontrol account of the reduction of relative risk with increasing time
residential radon studies clearly demonstrate an association since exposure, adjusting for attained age and exposure rate.
between risk of lung cancer and residential radon exposure. Estimates of lifetime risks developed with the model also
There is a remarkable coherence both among the pooled incorporated sex and smoking status. BEIR VI developed
residential studies and the downward extrapolation of radon two models, an exposure-age concentration model and an
risk estimates from miner studies. exposure-age duration model. The general structure of the
BEIR VI model is illustrated below:
515. Uncertainties associated with downward extrapola-
tion from miner studies include, but are not limited to: uncer- ERR = [ 5-14 w5-14 + 5-14 w5-14 + 25+ w25+ ] age z
tainties in the reconstruction of miner exposures; possible
exposure to other carcinogens; the high but uncertain level where
of smoking among miners; and the fact that exposures in
= slope of the exposurerisk rela-
mines historically were at relatively high levels compared
tionship for the assumed refer-
with levels in homes and in present-day mines. Uncertain-
ence categories of the modifying
ties associated with residential radon studies include, among
factors.
other factors: lack of contemporary radon measurements in
residences (e.g. while it may be possible to measure radon 5-14 15-24, 25+ = weighting factor for time periods
levels today in homes previously occupied by subjects in res- 514, 1524 and >25 years post-
idential studies, there will be large uncertainties associated exposure (values of 5-14, etc., are
with assumptions about changes to home ventilation and in provided in reference [C20] and
the habits of subjects over time); uncertainties about smok- range from 0.31 to 0.81).
ing; and low statistical power. w5-14, w15-24, w25+ = radon exposures in the time win-
dows 514, 1524 and >25years.
516. Many studies of lung cancer risks in miners exposed
age = parameter to describe the decline
to RDPs (see section IV) and several joint analyses of
in ERR with increasing age.
11 miner cohorts have been published [C20, L4, L10].
BEIR VI [C20] reported values of
Tirmarche et al. [T30] discussed risk estimates among the
0.131.00.
general population and reported a comparison of different
models used to estimate lifetime risk. These authors esti- z = parameter to describe the expo-
mated a lifetime ERR in the range 0.082.31, according to sure-rate effect. BEIR VI [C20]
the exposure scenario. These results are in the envelope of reported values of 1.010.2.
518. For exposure conditions in modern Saskatchewan biological and physical mechanisms of carcinogenesis, given
uranium mines, the power to detect any excess risk arising the new information that has emerged from the pooling of
from workplace exposure to radon is likely to be very small. residential radon casecontrol studies, the reconciliation of
A study carried out for the Canadian Nuclear Safety Com- the dosimetric and epidemiological evaluations is now much
mission [S55] investigated the feasibility of conducting epi- less important for estimating risks from residential radon.
demiological studies of underground miners working under Experimental studies will continue to play an important role
todays exposure conditions. To carry out this assessment, in understanding the mechanisms and risks arising from
two hypothetical cohorts were considered: a retrospec- exposure to radon at work and at home, and biologically
tive cohort of miners employed in Saskatchewan uranium based models will play an increasingly important role in the
mines between 1975 and 2000, and a prospective cohort future; however, at this time, the epidemiological studies of
that included miners employed from 2000 to 2030. The miners and the residential casecontrol studies provide the
cohorts were developed using demographic data provided strongest basis for risk assessment.
by the mining companies, dose data from the National Dose
Registry, and reference baseline cancer and mortality rates 520. In the past, radon risk estimates for residential expo-
from all of Canada and Saskatchewan. More than 50% of sures were based on downward extrapolation of evidence
modern Saskatchewan uranium miners smoke. Adjustments from studies of miners who were exposed at higher exposures
were made for different smoking prevalences in miners and for shorter times. Pooled analyses of European, North Amer-
the reference population. In 2000, the average underground ican and Chinese residential casecontrol studies provide
miner in northern Saskatchewan was exposed at work to strong evidence supporting the evidence from miner studies
about 0.11WLM from RDPs (with an upper 95% CI of about that exposure to high levels of radon and its decay products in
0.43 WLM). At the same time, annual exposure to RDPs homes leads to an increased incidence of lung cancer.
at home was estimated to be about 0.4 WLM/a (ranging
upward to about 10WLM/a). The feasibility analysis simu- 521. Both the miner and the residential studies have advan-
lated incremental risks of lung cancer from radon exposure tages and disadvantages, some of which are briefly summa-
using a relative risk model and an ERR of 0.89%WLM1 rized below. The advantages of miner studies discussed in
based on the Ontario cohort, since it has provided the largest sectionIV include:
and best exposure data of the Canadian uranium miner stud-
ies. Sensitivity analyses were carried out with respect to both Relatively high (relative to domestic) cumulative
reference risk and exposures. Two statistical measures were exposures and exposure rates, which allowed the
estimated using probabilistic simulation, standardized mor- development of dose (exposure)response rela-
tality ratio (SMR) and regression analysis, which produced tionships, at least at high cumulative exposures.
an estimate of excess lung cancer risks for a working level The ability to examine factors that modify the
month. Both cohorts were modelled to 2030. SMRs were simple linear doseeffect relationship (time since
distributed on an average of 1.01, with most (80%) falling in exposure, age at exposure, exposure rate).
the range 0.931.08. Similarly, the slope estimated from the Information on risks over a lifetime, not just a
regression analysis had a mean of 1.01, with 80% of the slope window of 30 years or so. Miner studies will
estimated to be in the range 0.0830.105WLM1. This quite require continued follow-up to realize this poten-
large range reflected the statistical uncertainty estimated in tial to the full.
the cohorts. The results of the regression analyses showed
little probability (power) of detecting the predicted excess Exposure estimates based on contemporary meas-
risks in the cohorts, because the probability of the lower con- urements (albeit incomplete, most often area
fidence level on the slopes exceeding zero is only about 3% measurements rather than individual measure-
(i.e. much less than the objective of 80%) for most combi- ments and subject to uncertainty). While some
nations of scenario, cohort and follow-up period. Moreover, evaluations of the effects of the uncertainties in
exposure at home accounted for about 98% of the total for these measurements on the resulting risk esti-
modern Saskatchewan miners. mates were carried out, more remains to be done
in this area.
519. There is now a great deal of information available Information on all causes of death and cancer
concerning the risks from exposure to radon and its decay incidence other than lung cancer.
products. The studies of underground miners exposed to
high levels of radon in the past have formed the principal 522. Many residential casecontrol studies (section V),
source of information on the risks, and serve as the basis for have been published. Individually, they have limited sta-
developing exposureresponse models and evaluating modi- tistical power, and meta-analysis has suggested that the
fiers of effects such as time since exposure and age at expo- results of the studies are inconsistent. However, more recent
sure. A great deal of study has also been given to dosimetric pooled analyses, especially those of European [D17, D21]
evaluations, both as a means for transferring risk estimates and North American [K1, K26] studies, combined the data
from a miner population to other circumstances and also in on all the individuals in a number of residential studies and
their role as a source of ab initio risk estimates. While dosi- have greater power than the individual component studies.
metric evaluations remain important for understanding the The pooled residential radon studies provide strong, direct
evidence of risk from residential radon. The pooled residen- exposures, and the European pooled analysis, in
tial studies have certain advantages over the miner studies: particular, carried out calculations quantifying the
effect of this uncertainty on the risk estimates.
Exposures received under aerosol conditions sim-
ilar to those of interest. Data for both men and women for a wide variety
of ages.
Exposures received at concentrations similar to
those of interest (thus reducing the need to extrap- 523. Notwithstanding the strengths and weaknesses of risk
olate from the relatively high rates of exposure in estimates from studies of miners and of residential radon,
mines). there is now a remarkable coherence between the risk esti-
Reduced confounding from possible exposure to mates developed from epidemiological studies of miners and
occupational carcinogens such as arsenic. pooled residential casecontrol radon studies. While both the
miner studies and the residential casecontrol radon stud-
Detailed individual smoking histories for study
ies are subject to various limitations arising from exposure
participants.
uncertainty and confounding by smoking, for example, both
Detailed individual exposure data based on meas- types of study are suitable for risk estimation. The miner
urements in the homes where the individuals had studies provide a strong basis for evaluating risks from RDP
lived. Nonetheless, exposure uncertainties are exposure to people at work and at home, and for investigat-
also part of residential studies. For example, the ing the effects of modifiers to the exposureresponse rela-
measurements were usually made some time after tionship [S2]. However, the results of the pooled residential
the period over which the risk was to be assessed, studies now provide a direct method of estimating risks to
and in some instances, there were alterations to people at home without the need for (downward) extrapo-
the home between the time when the resident lation from miner studies. The measurement-adjusted risk
lived there and the time when the measurement coefficients reported, for example from the European pool-
was made. Data are available regarding the uncer- ing study, provide an appropriate basis for estimating risks to
tainties in the assessment of residential radon people at home.
VIII. Overall Conclusions
524. This annex, Sources-to-effects assessment for radon to underground miners (derived from updated studies of
in homes and workplaces, discusses: potential sources of cohorts of uranium miners) suggest that the two approaches
exposure of workers and the public to radon; issues of cur- are less different than initially thought. The Committee
rent interest in the dosimetry of radon and its decay prod- therefore continues to recommend a radon dose conver-
ucts; information from animal experiments and experiments sion factor of 9nSv(Bqhm3)1 to evaluate the effective
at the cellular and subcellular levels that are important in dose from radon inhalation. The dose conversion conven-
understanding the mechanisms of carcinogenesis; epidemio- tion recommended in ICRP Publication 65 [I2] is approxi-
logical studies of miner and residential exposure to radon; mately 30% lower than this factor but the difference is not
and approaches to risk projection. considered significant.
525. During daily life, everyone is exposed to radon, an 529. Studies of miners exposed to radon and its decay
inert radioactive gas that occurs naturally and is present products provide a direct basis for assessing lung can-
everywhere in the atmosphere. The levels of radon indoors cer risk. The United States National Research Councils
vary widely both within countries and between countries, 6thCommittee on the Biological Effects of Ionizing Radia-
with (nominal) geometric mean concentrations of radon in tion (BEIRVI) [C20] reported an excess relative risk from
air indoors ranging from less than 10Bq/m3 in the Middle exposure to radon that was equivalent to 1.8% (95% CI:
East to up to around 100 Bq/m3 in a number of European 0.3%, 35%) (MBqhm3)1 for miners with cumulative expo-
countries. sures of below 30MBqhm3. There are various sources of
error in the exposure assessment of miners, especially in the
526. The annual per caput dose from inhalation of radon earliest years of mining, when exposures were at their high-
gas and its decay products represents typically about one- est. Other factors that complicate the analysis of data on
half of the effective dose received by members of the public miners include: the high percentage of miners who smoke;
from all natural sources of ionizing radiation. For certain workplace exposure to dust contaminants, such as arsenic,
occupations, radon gas is the predominant source of occupa- diesel exhaust in the dust and other pollutants; and periods
tional radiation exposure. spent working in non-uranium mines. The power to detect
any excess risks due to the exposures that miners nowadays
527. Radon decay products are well established as lung receive is likely to be small, in part because the exposures
carcinogens. However, the doses to other organs and tissues are much smaller than those in the early years of mining.
arising from the inhalation of radon and its decay products Because of the high exposures in the early days of mining,
are quite small, usually at least an order of magnitude smaller it is possible to detect trends in lung cancer incidence and
than those to the lung. Moreover, epidemiological data pro- to investigate factors that affect the exposureresponse rela-
vide little support for increased risks of mortality other than tionship, such as the age at exposure, the effect of exposure
from lung cancer. rate and the reduction of risk with increasing time since
exposure, as well as the effect of confounding factors such
528. A factor for calculating the dose from a given expo- as smoking.
sure to radon and its decay products is needed for risk
management, including regulatory purposes, and to allow 530. The BEIR VI model developed from the pooled
comparison with other sources of radiation exposure. There analysis of 11 cohorts of underground miners provides a
are two approaches for deriving a dose conversion factor. well-established basis for estimating risks from occupa-
A dosimetric approach derives the dose from a given tional exposures to radon, and accounts for factors such as
exposure based on the deposition characteristics of radon the reduced risk with increasing time since exposure. Since
decay products in the respiratory tract. An epidemiologi- the BEIR VI report was published, studies of various miner
cal approach was used by the International Commission cohorts have been updated, and confirm the general patterns
on Radiological Protection (ICRP) to derive the dose con- of risk with dose and with time since exposure that were
version factor from epidemiological studies using the ratio reported by BEIRVI. They also provide updated coefficients
of the risk of lung cancer in miners to the overall risk of to take account of the effects of time since exposure on age-
cancer in the survivors of the atomic bombings in Japan. ing populations. Miner studies therefore provide a strong
In the UNSCEAR 2000 Report, there was a difference of basis for evaluating risks from exposure to radon and for
about a factor of 2 between the two approaches. However, investigating the effects of modifiers to the doseresponse
the most recent data that have been published on the risks relationship.
309
531. Biological and cellular models of the multistage much higher than that for non-smokers, smokers account for
process of carcinogenesis are used to analyse the data from nearly 90% of the population risk of lung cancer.
studies on miners, and offer the possibility to assess uncer-
tainties in our understanding of the mechanisms for the 533. Although there are major uncertainties in extrapolat-
development of cancer and their modelling for the purposes ing the risks of exposure to radon from the miner studies
of risk estimation. in order to assess the risks in the home, there is neverthe-
less remarkably good agreement between the risk factors
532. The extrapolation of radon concentrations in the air in derived from the miner studies and from the pooled residen-
mines to those in homes provides an indirect basis for assess- tial casecontrol studies. The ERR per unit radon concen-
ing the risks from residential exposure to radon. However, tration in air estimated in this annex from miner studies is
there are now over 20 analytical studies of residential radon 0.12 (95% CI: 0.04, 0.2) per 100Bq/m3 (see para.424); that
exposure and lung cancer. These studies typically assess the from the pooled residential casecontrol studies (based on
relative risk from exposure to radon on the basis of estimates the restricted analysis) for Europe is 0.094 (95% CI: 0.034,
of residential exposure over a period of 2530 years prior 0.175) per 100 Bq/m3 [D17, D21] and for North America
to the diagnosis of lung cancer. More recent pooled analy- is 0.18 (95% CI: 0.02, 0.43) [K1, K26] per 100Bq/m3 (see
ses of residential casecontrol studies support a small but table24). The studies of uranium miners also provide impor-
detectable lung cancer risk from residential exposure, and tant information on the effects of modifiers to the exposure
this risk increases with increasing radon concentrations. The response relationship, and further follow-up is encouraged.
excess relative risk of lung cancer from long-term residential The pooling of residential casecontrol studies in Europe,
exposure to a radon concentration of 100 Bq/m3 is estab- North America and China now provides an appropriate
lished with reasonably good precision and is considered to basis for estimating the risks from long-term residential
be about 16% for both smokers and non-smokers (after cor- exposure to radon. On the basis of current information, the
rection for uncertainties in the exposure assessment), with an Committee considers the use of measurement-adjusted risk
uncertainty of about a factor of 3 higher or lower than this coefficients from pooled studies as an appropriate basis for
value. Because the baseline lung cancer rate for smokers is estimating the risks to people at home.
Appendix
Quantities, units and conversion factors relevant to radon and its decay products
Term Definition Unit and Selected Conversions
Absorbed dose The energy absorbed through exposure to radiation divided by Gy

the mass of the body or by the mass of the part of the body that 1 Gy = 1 J/kg = 100 rad
absorbs the radiation.
Effective dose The sum over all tissues and organs of the equivalent doses Sv
weighted by the tissue weighting factor, which represents the 1 Sv = 100 rem
contribution of that organ or tissue to the total detriment resulting
from uniform irradiation of the whole body.
Equilibrium equivalent The concentration of radon in air, in equilibrium with its short-lived Bq/m3
concentration decay products, which would have the same potential alpha energy 1Bq/m3 = 5.56 109 J/m3
concentration as the existing non-equilibrium mixture.
Equilibrium equivalent exposure Time integral of the corresponding equilibrium equivalent concentra- Bqhm3
tion of radon to which the individual is exposed over a given time 1Bqhm3 = 5.56 109 Jhm3
period. 1Bqhm3 = 1.57 106WLM
Mache unit A measure of radon concentration (historically radium emanation), Mache unit
where 1000 Mache units equals the amount in equilibrium with 1 Mache unit = 275pCi/L
1/2000 mg of radium.
Potential alpha energy The concentration of short-lived radon decay products in air in J/m3
concentration terms of the alpha energy released during complete decay through 1 J/m3 = 1.80 108Bq/m3
polonium-214.
Potential alpha energy exposure Time integral of the potential alpha energy concentration in air to Jhm3
which the individual is exposed over a given time period. 1 Jhm3 = 1.80 108Bqhm3
1 Jhm-3 = 282WLM
Radon levels Radon concentration in air. pCi/L

1pCi/L = 0.037Bq/L
1pCi/L = 37Bq/m3
Relative risk coefficient The ratio of the risk in an exposed population to that in a similar
unexposed population per unit exposure.
Working level Any combination of the short-lived decay products of radon in WL

one litre of air that will result in the emission of 1.3 105MeV of 1WL = 100pCi/L (assuming
potential alpha energy. 100% equilibrium, i.e. F = 1)
1WL = 250pCi/L (assuming
40% equilibrium, i.e. F = 0.4)
Working level month The cumulative exposure from breathing an atmosphere at a WLM
concentration of 1WL for a working month of 170 hours. 1WLM = 3.54 103 Jhm3
1WLM = 6.38 105Bqhm3
1WLM = WL exposure time
(h/a)/(170 h/WLM)
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This publication contains:
VOLUME II
Scientific Annexes
Annex C. Non-targeted and delayed effects of exposure to ionizing radiation
Annex D. Effects of ionizing radiation on the immune system
Annex E. Sources-to-effects assessment for radon in homes and workplaces
FOR UNITED NATIONS USE ONLY
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ISBN 978-92-1-142270-2
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EFFECTS OF

UNSCEAR 2006 Report

UNITED NATIONS PUBLICATION

Non-targeted and delayed effects of exposure to ionizing radiation

I. RADIATION-INDUCED GENOMIC INSTABILITY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

II. BYSTANDER EFFECTS AND RADIATION EXPOSURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

III. Relationship between Radiation-Induced Genomic Instability and Bystander Effects. . . . . . . . . . 37

IV. ABSCOPAL EFFECTS OF RADIATION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

V. CLASTOGENIC FACTORS INDUCED BY IONIZING RADIATION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

VI. IMPACT OF NON-TARGETED AND DELAYED EFFECTS OF RADIATION ON FUTURE GENERATIONS . . . . . . . . . . . . 45

VII. IMPLICATIONS OF NON-TARGETED AND DELAYED EFFECTS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55

Somatic Germ line Foetal

Carcinogenesis Heritable Developmental

Figure II. Radiation-induced genomic instability.

Multiple subpopulations appear within a colony

Table 1 In vitro studies of radiation-induced genomic instability

Year End point Cell type Radiation typea Comments Reference

1991 Plating efficiency Chinese hamster ovary cells X-rays [C13]

1992 Mutation frequency Chinese hamster ovary cells X-rays [C12]

1992 Plating efficiency Chinese hamster ovary cells X-rays [C12]

1993 Chromosomal aberrations Human lymphocytes X-rays [H7]

1993 Chromosomal aberrations GM10115 humanhamster hybrid cells X-rays [M2]

1993 Plating efficiency HeLa cells X-rays Dose response [F8]

1993 Plating efficiency GM10115 humanhamster hybrid cells X-rays [M2]

1994 Chromosomal aberrations HeLa cells X-rays [B20]

1994 Giant cell formation HeLa cells X-rays [B20]

1994 Plating efficiency HeLa cells X-rays [B20]

1994 Plating efficiency Human keratinocyte cells Gamma radiation; [O5]

1995 Chromosomal aberrations Human lymphocytes X-rays [H8]

1996 Chromosomal aberrations TK6 human lymphoblasts X-rays [G8]

1996 Chromosomal aberrations Human lymphocytes Alpha particles [K5]

1996 Mutation frequency TK6 human lymphoblastoid cells X-rays [G8]

Year End point Cell type Radiation typea Comments Reference

1998 Chromosomal aberrations Human fibroblasts X-rays; neutrons; [K18]

1998 Chromosomal aberrations GM10115 humanhamster hybrid cells X-rays [D1]

1998 Chromosomal aberrations Human lymphocytes Gamma rays [H9]

1998 Chromosomal aberrations GM10115 humanhamster hybrid cells 125

1998 Chromosomal aberrations Human lymphocytes Gamma rays [L32]

1998 Plating efficiency GM10115 humanhamster hybrid cells X-rays [D1]

1999 Plating efficiency Human keratinocyte cells Gamma rays; [C14]

2000 Chromosomal HF19 human fibroblasts No instability [G25]

2000 Chromosomal aberrations Human lymphocytes Alpha particles; X-rays [A6]

2001 Chromosomal aberrations TK6 human lymphoblasts Fe ions; gamma rays

2001 Chromosomal aberrations Human lymphocytes Gamma rays [B11]

Year End point Cell type Radiation typea Comments Reference

2001 Chromosomal aberrations Human lymphocytes Fe ions

2001 Chromosomal aberrations Human lymphocytes Alpha particles [K19]

2001 Mutation frequency TK6 human lymphoblasts Fe ions; gamma rays

2001 Mutation frequency Human lymphoid cells Gamma rays [G9]

2001 Plating efficiency Human lymphoid cells Fe ions

2002 Apoptosis Mouse fibroblast clones; V79 Chinese X-rays [C11]

2002 Chromosomal aberrations Human fibroblasts Gamma rays [B21]

2002 Chromosomal aberrations TK6 human lymphoblasts Fe ions; gamma rays

2002 Mutation frequency TK6 human lymphoblasts Fe ions; gamma rays

2003 Chromosomal aberrations TK6 human lymphoblasts Gamma rays [E15]

2003 Mutation frequency TK6 human lymphoblasts Fe ions; gamma rays

Year End point Cell type Radiation typea Comments Reference

2004 Cell viability; apoptosis; Human lymphoblast cells X-rays [R13]

2004 Chromosomal aberrations Scid mouse cells X-rays [U26]