Anatomic Pathology / THE ATTRIBUTION OF LUNG CANCERS TO ASBESTOS EXPOSURE

90 Am J Clin Pathol 2002;117:90-95 American Society for Clinical Pathology

The Attribution of Lung Cancers to Asbestos Exposure
A Pathologic Study of 924 Unselected Cases
Franco Mollo, MD,
1
Corrado Magnani, MD,
2
Patrizia Bo, MD,
1
Paola Burlo, MD,
1
and Maurizio Cravello, MD
3
Key Words: Asbestos bodies; Asbestosis; Lung cancer; Attributable risk
A b s t r a c t
We studied a series of 924 nonselected surgical
cases of lung carcinoma (without occupational history
in clinical records) by histologic examination and light
microscopic determination of asbestos body (AB)
concentration to determine cancers attributable to
asbestos exposure. Lower lobes showed higher
concentrations, but no significant associations were
recorded between concentrations and histologic type of
the lung carcinomas. Histologic asbestosis was
demonstrated in 56 cases considered definitely
asbestos-related. In 12 of them, the demonstration of
asbestosis was attained only after repeated examination
of additional sections, suggested by the finding of more
than 1,000 ABs per gram of dry weight (gdw), an
indicator of occupational asbestos exposure. In the 56
cases, the median AB concentration was 3,281/gdw. In
5 other cases without demonstration of ABs in
histologic sections, concentrations higher than this
median and interstitial fibrosis were observed. The AB
count after digestion of pulmonary tissue may show
greater sensitivity than the search in histologic sections
as an indicator of substantial asbestos exposure.
Extrapolation of our estimate on a national scale
suggests about 2,000 cases per year of asbestos-related
cancers of the lung in Italy; 281 cases were reported
(from all occupational causes) in the years 1990-1995.
Attributable risk for lung cancer in Europe has been
reported as between 2% and 50% for asbestos exposure in
males, but after exclusion of the extreme values, most of the
remaining estimates are within the range of 10% to 20%.
1
The wide interval reflects the different extension of asbestos
use and, therefore, the different prevalence of exposure and
the different definition of exposure. The attributable fraction,
evaluated with a method based on the correlation of incidence
rates of lung cancer and mesothelioma, was estimated as
5.7% in Glasgow
2
and 3.9% in our region.
3
Surveys
conducted in the Nordic countries and in the United
Kingdom in general populations indicated a proportion of
asbestos-related lung cancer in the range of 7% to 36%
among men, with differences related to the age distribution of
respondents and the economic profile of the area.
1
Since
population studies suggest probabilities but do not allow
conclusive evidence in individual cases, several criteria have
been proposed for the attribution of a lung cancer to definite
asbestos exposure. Despite this, a serious underreporting of
these occupationally related cancers is being recognized.
4
At present, the balance of evidence supports the proposition
the asbestos load itself in lung tissue is the main determinator
of lung carcinogenesis,
5
but forensic medicine still debates
whether the asbestosis is a prerequisite for the attribution or
whether it is just an indicator of substantial exposure. The
discussion of this topic is beyond the purposes of this article.
Anyway, the pathologic demonstration of asbestosis is consid-
ered, beyond dispute, as decisive proof of linkage (at least
contributing if smoking is associated) between a lung cancer and
previous exposure to asbestos: we have found no contradictory
evidence in the literature. The criteria for the histologic diag-
nosis of asbestosis, therefore, are crucial in this respect.
Anatomic Pathology / ORIGINAL ARTICLE
Am J Clin Pathol 2002;117:90-95 91 American Society for Clinical Pathology
The minimal features that permit the diagnosis of
asbestosis have been described, in the Report of the Pneu-
moconiosis Committee of the College of American Pathol-
ogists (CAP) and the National Institute for Occupational
Safety and Health (NIOSH), as discrete foci of fibrosis in
the walls of respiratory bronchioles associated with accu-
mulations of asbestos bodies.
6
Bellis et al
7
validated the
applicability of these criteria in the Piedmont region
(northwestern Italy). The fibrosis with possible pigmenta-
tion of the walls of respiratory bronchioles was defined as
small airway lesions (SALs), and these features were
considered as asbestosis grade 1 (AG1) when associated
with asbestos bodies (ABs) on the sections. In fact, similar
lesions have been regarded as a form of interstitial
fibrosis.
8,9
Fibrotic thickening with possible carbon and
iron pigmentation of the walls of the respiratory bronchi-
oles and of alveolar ducts has been observed in patients
who had been exposed to asbestos and named asbestos
airway disease by other authors.
10
In the series of Bellis
et al,
7
the AG1 cases compared with subjects without
SALs were associated significantly with indicators of
asbestos exposure such as bilateral pleural plaques, high
concentrations of ABs in the digested lung, and a history
of occupational exposure.
The criteria settled by the International Expert
Meeting on Asbestos, Asbestosis and Cancer convened in
Helsinki in 1997
11
are not very much different in
substance from those described by CAP and NIOSH for
the diagnosis of asbestosis on histologic sections.
However, a new concept was introduced by the Helsinki
Criteria, that is, the acceptability of the diagnosis of
asbestosis when, together with interstitial lung fibrosis, the
count of lung asbestos fibers by electron microscopy was
in the range recorded for asbestosis by the same labora-
tory. According to this statement, when interstitial fibrosis
is present, the demonstration of a substantial asbestos
burden in the digested tissue examined by electron
microscopy may replace the finding of ABs in the histo-
logic sections examined by light microscopy.
Even in absence of interstitial fibrosis, concentrations
higher than 1,000 ABs per gram of dry weight of lung
tissue (ABs/gdw) by light microscopy indicate exposures
of the occupational type. This proposition results from
pathologic studies in various countries, including our
region,
12-15
and has been validated by international work-
shops.
16,17
But until now, the light microscopic counts of
ABs have not been systematically taken into consideration
along the diagnostic path for the recognition of asbestosis
in a fibrotic lung.
The objective of the present study was the pathologic
assessment of the prevalence in our region of asbestos-
related carcinomas, recognized because of the association
with histologic asbestosis according to CAP and NIOSH
criteria, in a large surgical series of unselected lung
cancers. In a previous study, Mollo et al
18
found histologic
asbestosis in 6.7% of 165 hospital autopsy cases with lung
carcinoma, but this result could seem to be biased by post-
mortem selection.
Materials and Methods
We studied 924 unselected cases of pulmonary carci-
nomas, consecutively examined at the Department of
Biomedical Sciences and Human Oncology, Turin (north-
western Italy), after pneumonectomy or lobectomy, from
December 1992 through December 1998. These surgical
specimens were sent to the laboratory of pathology without
records about occupational histories. There were 345 pneu-
monectomies and 579 lobectomies (359 upper lobes and 220
intermediate and/or lower lobes).
Pathologic Investigations
The identification of ferruginous bodies as true typical
ABs was performed according to the criteria described on
the basis of the comparison between light and electron
microscopic findings.
19,20
The concentration of ABs/gdw
was determined in samples of normal lung tissue taken
from each available lobe. The optical count was performed
after membrane filtration of the material obtained by
hypochlorite digestion of the pulmonary tissue.
21
When 2
or 3 samples were examined, the count was expressed as
the mean value resulting from the different counts. We
screened 2 to 5 sections of lung tissue without neoplastic
invasion for SALs and for features of histologic asbestosis
according to the CAP and NIOSH criteria and previous
experience
7
Image 1. When the diagnosis of histologic
asbestosis was not justified according to these criteria
because ABs were not evident on the sections, 2 to 4 addi-
tional sections were prepared and carefully screened if
interstitial fibrosis (IF) was present and the AB count was
higher than 1,000/gdw. As for minimal interstitial fibro-
sis, the CAP and NIOSH criteria
6
were applied; further-
more, particular attention was given to recommendations
suggested for the differential diagnosis between intersti-
tial fibrosis due to asbestos and that attributable to other
diseases.
22
Job Inquiries
In the cases of carcinoma that, through the aforemen-
tioned examinations, were associated with histologic
asbestosis, an effort was made to obtain personal or proxy
interviews, to examine official documents concerning the
past jobs of the subjects, or both.
Mollo et al / THE ATTRIBUTION OF LUNG CANCERS TO ASBESTOS EXPOSURE
92 Am J Clin Pathol 2002;117:90-95 American Society for Clinical Pathology
Statistical Methods
The concentration of ABs was compared among the
different categories of subjects, classified according to sex,
age (10-year classes), pulmonary lobe sampled, histologic
type of the neoplasm, and period of diagnosis (1995 or
earlier or 1996 or after).
AB concentration is positively skewed; therefore,
values were transformed to their logarithm before the
analyses: For this purpose, zero values were substituted by a
trivial value (0.1).
Analyses were conducted computing descriptive statis-
tics and cumulative distributions and comparing subgroups
using nonparametric statistics, such as the Wilcoxon-Mann-
Whitney or the Kruskal-Wallis or the median test
23
as appro-
priate. Analyses were conducted using SAS, version 6.12
(SAS Institute, Cary, NC).
24
Results
The range of AB concentrations in the whole series of
924 unselected lung cancers was 0 to 728,000. The
concentrations were different in the two sexes: among
men, the average concentration was 1,952 ABs/gdw (SD =
26,672; median, 188); among women, it was 382 ABs/gdw
(SD = 763; median, 95). The difference was statistically
significant (P < .001). Table 1 shows the distribution of
subjects by classes of AB concentration, separately for
men and women. The cases of lung carcinoma with a
concentration of ABs/gdw higher than 1,000 were 116:
106 of 806 men and 10 of 118 women, corresponding to
13.2% and 8.5%, respectively, of the corresponding totals
Table 2. Histologic asbestosis was diagnosed at the first
histologic examination in 44 cases and in another 12 after
the examination of additional sections when the AB count
was more than 1,000/gdw. These 56 cases (54 men and 2
women) were considered definitely asbestos-related. The
median value of AB concentrations observed in these cases
was 3,281/gdw. The AG1 cases were 34, or 63% of the
histologic asbestosis cases and 3.7% of the whole series. In
5 cases of lung cancer, all in occupationally exposed
subjects and associated with interstitial fibrosis and with a
count of ABs higher than the median concentration
recorded in histologic asbestosis, the diagnosis of histo-
logic asbestosis could not be attained; in fact, no typical
ABs were identified in the sections, despite the substantial
concentration in the digested tissue and the repeated histo-
logic examinations. Conversely, 2 cases (both men) with
histologic asbestosis diagnosed at the first examination had
fewer than 1,000 ABs/gdw.
Concentrations of ABs by pulmonary lobe are given in
Table 3 and by histologic type in Table 4. Samples from
upper lobes showed lower AB concentrations than samples
from lower lobes or from the total lung. The difference was
significant (P = .02) by the Wilcoxon test (which compares
the 2 frequency distributions), but not when only the median
was considered. Differences by histologic type were not
statistically significant.
Image 1 In the center of the field, there is a respiratory
bronchiole with a fibrotic and pigmented wall. At this magni-
fication, no asbestos bodies are recognizable, and this
pattern could be considered a small airway lesion (H&E,
original magnification 40).
Table 1
Cases of Lung Carcinoma by Sex and Asbestos Body Count
*
Asbestos Bodies/gdw
Total 1,000 1,001-2,000 2,001-3,000 3,001-4,000 4,001-5,000 5,001-9,000 >9,000
Men 806 (87.2) 700 (86.8) 48 (6.0) 22 (2.7) 9 (1.1) 7 (0.9) 9 (1.1) 11 (1.4)
Women 118 (12.8) 108 (91.5) 7 (5.9) 2 (1.7) 0 (0.0) 0 (0.0) 1 (0.8) 0 (0.0)
Total 924 (100.0) 808 (87.4) 55 (6.0) 24 (2.6) 9 (1.0) 7 (0.8) 10 (1.1) 11 (1.2)
gdw, gram of dry weight of lung tissue.
*
Data are given as number (percentage). For the Total column, percentages are based on 924; percentages for the first, second, and third rows are based on the total numbers of
men, women, and patients, respectively.
Anatomic Pathology / ORIGINAL ARTICLE
Am J Clin Pathol 2002;117:90-95 93 American Society for Clinical Pathology
Reliable information about the occupational history was
obtained in 25 cases (20 with histologic asbestosis and 5
with interstitial fibrosis and AB counts higher than those
recorded in histologic asbestosis). This retrospective job
inquiry confirmed definite asbestos exposure in all of them.
Discussion
In our material, no significant associations were recorded
between the concentrations of ABs and the cancer histologic
type, while lower lobes showed higher concentrations. One may
find in the literature different statements about these topics.
5
In
previous case-control investigations on autopsy material, Mollo
et al
25
found a significant association between adenocarcinoma
and asbestos exposure using a cutoff level of 10,000 ABs/gdw
as an indicator of heavy exposure, but the pattern was much less
evident using a cutoff level of 1,000 ABs/gdw. The present
results, achieved using nonparametric analyses on the frequency
distributions (and not just a cutoff level of 1,000 Abs/gdw) on
unselected lung cancers from surgery, are consistent with
remarks suggesting that the pathologic features of the lung
cancer do not differ substantially between subjects exposed and
subjects not exposed to asbestos.
26-28
The median value of AB concentrations in our asbestos-
related cases (3,281 ABs/gdw) is very much lower than that
recorded by others.
29
These data may be related to possible
differences concerning not only the technical procedures or
the criteria for unquestionable identification of ferruginous
bodies as typical ABs and for the pathologic diagnosis of
minimal interstitial fibrosis compatible with asbestosis but
also the severity of exposure, the type of fibers (mainly
amphiboles or chrysotile), and the degree of asbestosis in the
studied series.
The major outcome of the present investigation is that a
thorough pathologic examination should be performed in all
cases of pulmonary carcinoma (also when occupational
history is not included in clinical reports). In our series, 34
cases of histologic asbestosis (of 56 asbestos-related cancers)
were AG1, that is, they showed minimal features recogniz-
able only by careful microscopic screening of the sections.
Furthermore, to detect the asbestos-related cases among
cancers presented for pathologic examination, the AB
concentration should be determined in all cases in addition to
an examination for histologic asbestosis. In particular, cases
with interstitial fibrosis may call for more in-depth histologic
study, even though the association between these findings
may present some exceptions in single cases.
As a matter of fact, we observed 2 cases of lung carci-
noma with minimal asbestosis in which the AB/gdw counts
were lower than the concentration suggesting previous expo-
sure of the occupational type. It may be an occasional
Table 2
Cases With More Than 1,000 ABs/gdw by Sex and Histologic
Evidence of Asbestosis
*
Asbestosis
No. of Subjects With
>1,000 ABs/gdw Yes No
Men 106 52 (49.1) 54 (50.9)
Women 10 2 (20) 8 (80)
Total 116 54 (46.6) 62 (53.4)
ABs, asbestos bodies; gdw, gram of dry weight of lung tissue.
*
Data are given as number (percentage). Two additional cases of asbestosis showed
fewer than 1,000 ABs/gdw (see text) and are excluded from the table.
Table 3
ABs/gdw by Pulmonary Lobe From Which the Sample
Was Obtained
*
95th
Lobe Mean SD Median Percentile
Upper 615 1,697 162 2,447
Intermediate or lower 1,677 13,116 154 2,395
Multiple or unspecified 2,957 39,349 204 2,750
ABs, asbestos bodies; gdw, gram of dry weight of lung tissue.
*
P = .02, Wilcoxon; P = .11, median test.
Table 4
ABs/gdw by Carcinoma Histologic Type
*
Histologic Type No. of Tumors Mean ABs/gdw SD Median 95th Percentile
Squamous 459 1,037 9,111 173 1,887
Small cell 19 488 721 218 2,646
Large cell 63 12,469 91,642 155 6,442
Adenocarcinoma 298 1,000 4,359 185 3,058
Bronchioloalveolar 27 418 633 179 2,231
Other types 28 733 2,035 231 2,424
Not specified 30 302 653 129 689
ABs, asbestos bodies; gdw, gram of dry weight of lung tissue.
*
P = .88.
Mollo et al / THE ATTRIBUTION OF LUNG CANCERS TO ASBESTOS EXPOSURE
94 Am J Clin Pathol 2002;117:90-95 American Society for Clinical Pathology
finding. On the other hand, ABs form mainly on long fibers
of amphiboles and not (or in negligible amount) on
chrysotile fibers,
30,31
but also the latter may have pathogenic
effects inducing interstitial fibrosis.
32
Conversely, ABs may be masked in the histologic
sections when heavy anthracosis is present, or they may be
unrecognizable when perpendicularly oriented in respect to
the plane of the section Image 2; when only a few ABs are
occasionally present in the sections and they are not well
oriented, the diagnosis of minimal histologic asbestosis may
be missed. The optical examination of ABs obtained from the
digested lung and observed lying on the membrane may be an
easier method for their recognition and a more reliable light
microscopic indicator of the previous asbestos exposure.
On the other hand, it is noteworthy in this regard that
according to the Helsinki Criteria, interstitial fibrosis associ-
ated with a significant electron microscopic count of
uncoated asbestos fibers may be regarded as asbestosis, and
a good correlation has been demonstrated between ABs
counted by light microscopy and uncoated fibers 5 m or
greater in length counted by electron microscopy.
33
There-
fore, it seems reasonable to suggest that the interstitial
fibrosis associated with a significant concentration of ABs in
light microscopy could be regarded as an actual indicator of
pneumoconiosis due to asbestos. From a conceptual view-
point, asbestosis is a pulmonary fibrosis caused by
asbestos
34
; the demonstration of a substantial AB burden in
the fibrotic lung is important, but it could be proved in the
digested tissue and not necessarily in the histologic sections.
Interstitial fibrosis without identification of ABs in
histologic sections but with a concentration of ABs higher
than the median recorded in histologic asbestosis was
observed in 5 cases. Such a concentration in a fibrotic lung
of an exposed subject is very significant from a forensic
point of view, and in our opinion, these lung cancers are to
be regarded as asbestos-related. Nevertheless, the criteria
for the attribution of a lung cancer to asbestos exposure
may be different in different countries, and sometimes
(perhaps not only in Italy) they are matters of litigation. But
apart from the medicolegal debates in the individual cases,
even if we add these cancer cases to those associated with
actual histologic asbestosis, the percentage of our definitely
or reasonably asbestos-related lung cancers would not
change very much, from 6% to 6.6% of the total series.
Instead, more important underestimation (unfortunately not
pathologically demonstrated in our material) may have
occurred in our estimates. In fact, ABs form mainly on
amphibole fibers,
30,31
so that the AB burden (both in
sections and in digested tissues) may not adequately reflect
a noxious exposure that possibly occurred in the past, and
certainly was not negligible for the induction of the lung
cancer.
32
In fact, the occupational exposure to chrysotile
also is to be considered among the factors responsible (at
least as a major contributing factor together with smoking)
for the increased risk of pulmonary carcinoma.
35
Our estimate of the fraction (about 6%) of lung cancers
attributable to asbestos, based on this study of unselected
surgical material and also on previous results from
autopsies,
18
is on the same order of magnitude recorded in
epidemiologic studies of general populations, such as those
of the United States (5%),
36
of Scotland (5.7%),
2
and even of
our region, Piedmont (3.9%).
3
Furthermore, the present type of investigation allows the
pathologist to recognize individual cases of lung cancer that
should be considered for compensation owing to occupa-
tional exposure to asbestos (at least to amphiboles). It is
noteworthy that since the incidence of the lung cancer in
Italy during the 1990s was about 32,000 cases per year, the
extrapolation of our pathologic estimate could suggest that in
this country, about 2,000 cases per year should be linked
with asbestos exposure. The number of cases of lung cancer
reported during the period 1990-1995 to the Italian National
Institute of Work Injuries Insurance as possibly due to the
occupation (not only to asbestos exposure) was 281, and 91
persons eventually were compensated.
In our series, occupational histories had not been
recorded before the study, and the lung fibrosis associated
with several cancers had not been detected in x-ray chest
films or suspected as a pneumoconiosis disorder. It might be
supposed that the lung cancer cases related to asbestos expo-
sure through the present work were otherwise destined to
Image 2 At higher magnification, asbestos bodies are
recognizable in the wall of the respiratory bronchiole
showed in Image 1; this is minimal histologic asbestosis
(H&E, original magnification 400).
Anatomic Pathology / ORIGINAL ARTICLE
Am J Clin Pathol 2002;117:90-95 95 American Society for Clinical Pathology
remain unrecognized, while they have now given rise to the
proper medicolegal actions.
From the
1
Department of Biomedical Sciences and Human
Oncology, Turin University, Turin, Italy;
2
Cancer Epidemiology
Unit of the Center for Cancer Epidemiology and Prevention,
Piedmont Region, and S. Giovanni Hospital, Turin, Italy; and
3
Forensic Medical Service, Local Health Agency n.1, Piedmont
Region, Turin, Italy.
Address reprint requests to Dr Mollo: Dipartimento di
Scienze Biomediche e Oncologia Umana, Sezione di Anatomia
Patologica, via Santena 7, 10126 Torino, Italy.
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