Nanotechnology and Nanoparticles PDF

Biointerphases vol.
2, issue 4 (2007) pages MR17 - MR172
Nanomaterials and nanoparticles:

Sources and toxicity
Cristina Buzea*(1), Ivan. I. Pacheco Blandino**(2), and Kevin Robbie***(1)
(1)
Department of Physics, Queen's University, Kingston, Ontario K7L 3N6, Canada
(2)
Gastrointestinal Diseases Research Unit & Department of Physiology, Queens

University at Kingston General Hospital, 76 Stuart St., Kingston, ON K7L 2V7, Canada
* E-mail: [email protected]
** E-mail: [email protected]
*** E-mail: [email protected]
author to whom correspondence should be addressed
Biointerphases vol. 2, issue 4 (2007) pages MR17 - MR172
Abstract
This review is presented as a common foundation for scientists interested in nanoparticles, their
origin, activity, and biological toxicity. It is written with the goal of rationalizing and informing
public health concerns related to this sometimes-strange new science of nano, while raising
awareness of nanomaterials toxicity among scientists and manufacturers handling them. We show
that humans have always been exposed to tiny particles via dust storms, volcanic ash, and other
natural processes, and that our bodily systems are well adapted to protect us from these potentially
harmful intruders. The reticuloendothelial system in particular actively neutralizes and eliminates
foreign matter in the body, including viruses and non-biological particles. Particles originating from
human activities have existed for millennia, e.g. smoke from combustion and lint from garments,
but the recent development of industry and combustion-based engine transportation has profoundly
increased anthropogenic particulate pollution. Significantly, technological advancement has also
changed the character of particulate pollution, increasing the proportion of nanometer-sized
particles - nanoparticles and expanding the variety of chemical compositions. Recent
epidemiological studies have shown a strong correlation between particulate air pollution levels,
respiratory and cardiovascular diseases, various cancers, and mortality. Adverse effects of
nanoparticles on human health depend on individual factors such as genetics and existing disease,
as well as exposure, and nanoparticle chemistry, size, shape, agglomeration state, and
electromagnetic properties. Animal and human studies show that inhaled nanoparticles are less
efficiently removed than larger particles by the macrophage clearance mechanisms in the lung,
causing lung damage, and that nanoparticles can translocate through the circulatory, lymphatic, and
nervous systems to many tissues and organs, including the brain. The key to understanding the
toxicity of nanoparticles is that their minute size, smaller than cells and cellular organelles, allows
them to penetrate these basic biological structures, disrupting their normal function. Examples of
toxic effects include tissue inflammation, and altered cellular redox balance toward oxidation,
causing abnormal function or cell death. The manipulation of matter at the scale of atoms,
nanotechnology, is creating many new materials with characteristics not always easily predicted
from current knowledge. Within the near-limitless diversity of these materials, some happen to be
toxic to biological systems, others are relatively benign, while others confer health benefits. Some
of these materials have desirable characteristics for industrial applications, as nanostructured
materials often exhibit beneficial properties, from UV absorbance in sunscreen to oil-less
lubrication of motors. A rational science-based approach is needed to minimize harm caused by
these materials, while supporting continued study and appropriate industrial development. As
current knowledge of the toxicology of bulk materials may not suffice in reliably predicting toxic
forms of nanoparticles, ongoing and expanded study of nanotoxicity will be necessary. For
nanotechnologies with clearly associated health risks, intelligent design of materials and devices is
needed to derive the benefits of these new technologies while limiting adverse health impacts.
Human exposure to toxic nanoparticles can be reduced through identifying creation-exposure
pathways of toxins, a study that may some day soon unravel the mysteries of diseases such as
Parkinsons and Alzheimers. Reduction in fossil fuel combustion would have a large impact on
global human exposure to nanoparticles, as would limiting deforestation and desertification. While
nanotoxicity is a relatively new concept to science, this review reveals the result of lifes long
history of evolution in the presence of nanoparticles, and how the human body in particular has
adapted to defend itself against nanoparticulate intruders.
Keywords: nanomaterials, nanoparticles, particulate matter, ultrafine particles, nanoparticle

classification, sources of nanoparticles, toxicity of nanoparticles, nanotoxicology, environmental
nanoparticles, occupational nanoparticles, anthropogenic nanoparticles, nanoparticles translocation,
nanoparticles interaction with cells, nanoparticles applications.
Contents
List of abbreviations
Definitions
1. Introduction
1.1. Nano* etymology
1.2. Main differences between nanomaterials and bulk materials
1.3. Nanomaterials and nanotoxicology publications statistics
1.4. Introduction to nanoparticles toxicity
2. Nanoparticle classification
2.1. Dimensionality
2.2. Nanoparticle morphology
2.3. Nanoparticle composition
2.4. Nanoparticle uniformity and agglomeration
3. Sources of nanoparticles and their health effects
3.1. Natural sources of nanoparticles
3.1.1. Dust storms and health effects
3.1.2. Forest fires and health effects
3.1.3. Volcanoes and health effects
3.1.4. Ocean and water evaporation and health effects
3.1.5. Organisms and health effects
3.2. Anthropogenic nanomaterials
3.2.1. Diesel and engine exhaust nanoparticles and health effects
3.2.2. Indoor pollution and health effects
3.2.3. Cigarette smoke and health effects
3.2.4. Buildings demolition and health effects
3.2.5. Cosmetics and other consumer products, and health effects
3.2.6. Engineered nanomaterials and health effects
3.3. Environmental and occupational exposure to toxic substances
3.3.1. Metals and other dusts
3.3.2. Carcinogens and poorly soluble (durable) particles
3.4. Aerosol pollution, monitoring, and health effects
3.4.1. Aerosols size and composition
3.4.2. Aerosols concentration. Air quality index
3.4.3. Satellite monitoring of aerosol concentration and size
3.4.4. Health effects associated to air pollution
4. Nanotoxicology - toxicology of nanoparticles
4.1. Respiratory tract uptake and clearance

4.1.1. Particle size dependent inhalation
4.1.2. Upper airway clearance mucociliary escalator
4.1.3. Lower airways clearance phagocytosis and passive uptake
4.1.4. Nanoparticle size dependent phagocytosis
4.1.5. Concentration dependent phagocytosis
4.1.6. Lung burden
4.1.7. Translocation and clearance of inhaled nanoparticles
4.1.8. Adverse health effects in the respiratory tract.
4.2. Cellular interaction with nanoparticles
4.2.1. Cellular uptake
4.2.2. Oxidative stress, inflammation, and genotoxicity
4.2.3. Adverse health effects and treatment
4.2.4. Non-invasive terminology to be questioned
4.3. Nervous system uptake of nanoparticles
4.3.1. Neuronal uptake via olfactory nerves
4.3.2. Neuronal uptake via blood-brain-barrier
4.3.3. Adverse health effects of neuronal nanoparticles uptake and treatment
4.4. Nanoparticles translocation to the lymphatic systems
4.5. Nanoparticles translocation to the circulatory system
4.5.1. Long-term translocation
4.5.2. Short-term translocation of metals
4.5.3. Short-term translocation of non-metals
4.5.4. Nanoparticles interaction with and uptake by blood cells
4.5.5. Adverse health effects of circulatory system uptake
4.6. Liver, spleen, kidneys uptake of nanoparticles
4.6.1. Organs nanoparticles uptake
4.6.2. Adverse health effects of liver and kidney uptake
4.7. Gastro-intestinal tract uptake and clearance of nanoparticles
4.7.1. Exposure sources
4.7.2. Size and charge dependent uptake
4.7.3. Translocation
4.7.4. Adverse health effects of gastro-intestinal tract uptake
4.8. Dermal uptake of nanoparticles
4.8.1. Penetration sites
4.8.3. Adverse health effects of dermal uptake
4.9. Nanoparticles uptake via injection
4.10. Nanoparticles generation by implants
4.11. Positive effects of nanoparticles
4.11.1. Nanoparticles as antioxidants
4.11.2. Anti-microbial activity
5. Physico-chemical characteristics dependent toxicity
5.1. Dose-dependent toxicity
5.2. Size-dependent toxicity
5.3. Surface area-dependent toxicity
5.4. Concentration-dependent toxicity
5.5. Particle chemistry and crystalline structure dependent toxicity

5.6. Aspect ratio dependent toxicity
5.7. Surface coating and functionalization
5.8. Adaptability to nanomaterials inhalation
5.9. Comparison studies
6. Applications of nanoparticles
6.1. Electronics
6.2. Transportation and telecommunication
6.3. Imaging
6.4. Biomedical applications
6.5. Pollution remediation
6.6. Cosmetics
6.7. Coatings
6.8. Materials
6.9. Mechanical engineering
7. Conclusions and future directions
Acknowledgments
References
List of abbreviations
m - micrometer
1D - One Dimensional
2D - Two Dimensional
3D - Three Dimensional
AFM - Atomic Force Microscop(e)(y)
AQI Air Quality Index
CNTs - Carbon NanoTubes
DNA - DeoxyriboNucleic Acid
EDS Energy Dispersive Spectrometry
EPA - Environmental Protection Agency
GLAD Glancing Angle Deposition
HIV Human Immunodeficiency Virus
MISR - Multi-angle Imaging SpectroRadiometer
MODIS - MODerate-resolution Imaging Spectroradiometer
MWCNTs - Multiple-Wall Carbon NanoTubes
NASA - National Aeronautics and Space Administration
nm nanometer
PM Particulate Matter
ROS - Reactive Oxygen Species
SEM - Scanning Electron Microscopy
SWCNs - Single-Wall Carbon Nanotubes
TEM Transmission Electron Microscope
Definitions
Aerosol a material that, while not gaseous itself, remains suspended in air for prolonged
periods. Typical examples include dust, and fine-droplet liquid paint or hairspray.
Aggregate/aggregation a material that is composed of a large number of small components
which have come together as clusters, usually with branching, porous shapes. Aggregation is the
process whereby the many small components form clusters, and can be driven by gravity or other
forces.
Alzheimer's disease - a progressive, irreversible, neurodegenerative disease characterized by
loss of function and death of nerve cells in several regions of the brain, leading to loss of attention,
memory, and language. Its cause is unknown.
Antibody - a protein produced by the immune system as a response to a foreign substance, or
antigen.
Antigen a foreign substance that triggers the production of antibodies by the immune system.
Apoptosis or programmed cell death is the process of cellular suicide that can be initiated for
several reasons: when extensive cellular damage occurs, when the cell is no longer needed within
the organism, and in embryonic development, among others. Apoptosis is different from cell
necrosis (a form of traumatic cell death due to physical or biological injuries) in its biochemical and
morphological aspects. Aberrations in apoptosis contribute to various diseases, such as cancer.
Atomic Force Microscopy - a scanning-probe form of surface microscopy that can image and
manipulate matter at the nanometer scale.
Autoimmune diseases a group of disorders where overactive functioning of the immune
system results in the immune system producing antibodies or autoreactive T cells (a type of white
blood cells) against its own tissue.
Cancer disease characterized by rapid and uncontrolled cell division.
Chelator a chemical agent that binds reversibly to a metal ion, forming a metallic complex.
Chronic disease disease lasting a long time, which is ongoing or recurring, not caused by an
infection and not contagious.
Clearance the removal of particles or substances out of an organism, usually via urine or stool.
Crohn's disease a chronic inflammatory disease of unknown cause that may affect any part of
the gastrointestinal tract, most commonly the small bowel, as well as other organs. Symptoms of the
disease include diarrhea, abdominal pain, and excessive weight loss.
Cytokine - a small protein released by cells that has a specific effect on interactions between
cells, on communications between cells, or on the behavior of cells.
Cytoplasm - includes both the fluid (cytosol) and the organelles contained within a cell.
Degenerative disease - disease characterized by progressive deterioration of function or
structure of tissue.
DNA is a nucleic acid found within the nucleus of each cell, carrying genetic information on cell
growth, division, and function. DNA consists of two long strands of nucleotides twisted into a
double helix and held together by hydrogen bonds. The sequence of nucleotides determines
hereditary characteristics. Each cell contains an identical, complete copy of the organisms DNA,
with differing cell characteristics determined by differences in gene expression.
Endemic disease disease constantly present in and limited to people living in a certain
location.
Endogenous substances originating within, or synthesized by an organism (e.g. hormones and
neurotransmitters).
Endoplasmic reticulum - a membrane network that extends throughout the cytoplasm and is
involved in the synthesis, processing, secretion, and transport of proteins throughout the cell.
Endothelium - the layer of cells that line the interior surface of all parts of the circulatory
system, including the heart, and blood vessels. Specialized endothelial cells perform important
filtering functions in the kidney and at the blood-brain barrier.
Enzyme a protein that acts as a catalyst in a biochemical reaction.
Epidemiology - the branch of medical sciences that studies various factors influencing the
incidence, distribution, and possible control of diseases in human population.
Etiology set of causes or origin of a disease.
Exogenous - substances originating outside an organism.
Fibroblast a connective-tissue cell that secretes collagen and other components of the
extracellular matrix. It migrates and proliferates during wound healing and in tissue culture.
Gene a sequence of nucleotides (DNA) that defines a protein. Genes are the fundamental unit
of heritability, and their collection in an individual organism (its genome) represents a code or
protocol for the growth and development of that individual. Genes are arranged along the length of
chromosomes, of which each species has a fixed number.
Genotype the genetic constitution of an organism.
Granuloma tissue resulting from aggregation of inflammation-fighting cells unable to destroy
foreign substances.
Hydrophilic - having an affinity for water, or causing water to adhere.
Hydrophobic - having no affinity for water, or repelling water.
Inflammation - a localized protective response, produced by tissue injury that servs to destroy
or arrest both the agent and the affected tissue. Blood vessel permeability locally increases, and the
area becomes heavily populated with white blood cells. Signs of inflammation are redness,
swelling, pain, and sometimes loss of function.
Ischemia - decrease in the blood supply to an organ, tissue, limb, or other part of a body caused
by the narrowing or blockage of the blood vessels. Ischemia may lead to a shortage of oxygen
(hypoxia) within the tissue and may result in tissue damage or tissue death.
Lavage - washing out or clearance of a body cavity, organ, or system.
Lung burden - the product of exposure rate and residency time of particulate matter inhaled into
the lungs.
Lymph a fluid containing white blood cells, proteins, and fats; can also carry bacteria, viruses,
and cancer cells around the body. Lymph is collected from the tissues and returned to the
circulatory system.
Lymphatic system the network of vessels, nodes, and organs (spleen, thymus) that produce,
store, and carry lymph. The lymphatic system lacks a central pump, such as the heart in the
circulatory system, and must rely on muscles pumping.
Lymphoedema - a condition in which lymph nodes become enlarged and prevent lymph fluid
from passing through them.
Macrophage - a phagocytic tissue cell of the reticuloendothelial system that is derived from the
blood monocyte. The monocyte migrates from the blood into tissues where it transforms into a
macrophage. Macrophages are present in most tissues. Macrophages ingest and process degenerated
cells and foreign invaders, such as viruses, bacteria, and particles. The long-lived macrophages are
reservoirs of HIV.
Mesothelioma a rare form of cancer occurring in the lining of the lungs and chest cavity.
Mitochondrion - an organelle responsible for most of the oxidative metabolism in the cell.
Mitochondria generate energy (in the form of ATP, adenosine triphosphate) by breaking down
glucose (a type of sugar).
Monocyte - the largest form of a white blood cell, with a kidney-shaped nucleus; its function is
the ingestion of foreign invaders, such as bacteria, tissue debris, and particles. Monocytes belong to
the group of phagocytes, and mature into various macrophages in tissue.

Murine pertaining to the rodent family, i.e. rats and mice.
Nanoparticulate matter a collection of particles with at least one dimension smaller than 1
micron yet larger than atoms and molecules.
Neutrophil - an immune cell that ingests and degrades foreign organisms. Neutrophils are the
most abundant type of white blood cells, and are the first to reach the site of an infection to attack
foreign antigens.
Oxidative stress - an imbalance in favour of pro-oxidant versus antioxidant chemicals,
potentially leading to damage to biomolecules.
Parkinson's disease - a progressive disorder of the nervous system manifested by muscle
tremors and rigidity, decreased mobility and slow voluntary movements.
Particulate matter airborne particles of solids and/or liquids with sizes ranging from several
nanometers to several hundred microns.
Phagocyte - cell that ingests and kills foreign intruders via the process called phagocytosis.
Three examples are: monocytes, macrophages, and neutrophils.
PM0.1 particulate matter having a diameter smaller than 0.1 microns (100 nm).
PM10 particulate matter having a diameter smaller than 10 microns.
PM2.5 particulate matter having a diameter smaller than 2.5 microns.
Pneumoconiosis lung disease due to permanent deposition of substantial amounts of particules
in the lungs and by the tissue reaction to its presence. Its severity varies from relatively harmless
forms of sclerosis to destructive fibrosis and scarring of the lungs.
Protein molecule containing a long chain of amino acids in the order specified by a gene's
DNA sequence. Proteins can be, for example, enzymes, hormones, and antibodies.
Quantum dot - semiconductor crystals with a diameter of a few nanometers, having many
properties resembling those of atoms.
Receptor - A protein or large molecule on the surface of a cell that binds selectively to specific
substances (ligands).
Reperfusion - restoration of blood flow.
Reticuloendothelial system - a part of the immune system that consists of phagocytic cells,
including macrophages and macrophage precursors, specialized endothelial cells lining the
sinusoids of the liver, spleen, and bone marrow, and reticular cells of lymphatic tissue
(macrophages) and bone marrow (fibroblasts).
Rheumatoid arthritis - chronic, autoimmune, inflammatory disorder affecting the connective
tissue lining the joints. Symptoms include pain, swelling, stiffness, and deformities. It can extend to
organs.
Scleroderma a degenerative, autoimmune disease of the connective tissue, characterized by
the formation of fibrous tissue (collagen) which surround the joints, blood vessels and sometimes
internal organs.
Systemic lupus erythematosus - a chronic, autoimmune disorder. Symptoms include fatigue,
butterfly-shaped facial rash, inflammation of the joints, tendons, connective tissues, and organs:
heart, lungs, blood vessels, brain, kidneys, and skin.
Toxicology - the branch of medical and biological science studying the nature, adverse effects,
detection, and treatment of poisons on living organisms. A fundamental principle of toxicology is
that any substance is poisonous if given in a large amount. From the study of cancer-causing
substances, carcinogens, it appears that there are some materials for which there is no safe dose, no
level of exposure below which they do not cause cancer.
Transcription factor - a protein that binds to enhancer elements in DNA to regulate the level of
transcription and expression of certain genes.
Translocation the process of transit of particles or substances within an organism.

Ulcerative colitis a chronic disease of unknown cause characterized by inflammation of the
colon producing ulcerations. Symptoms are: abdominal pain, cramps, loose discharges of pus,
blood, and mucus from the bowel, and weight loss.
Ultra fine particles (UFP) - nanoparticles with size smaller than 100 nm.
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1. Introduction
Every person has been exposed to nanometer sized foreign particles; we inhale them with every
breath, and consume them with every drink. In truth, every organism on Earth continuously
encounters nanometer-sized entities. The vast majority causes little ill effect, and go unnoticed, but
occasionally an intruder will cause appreciable harm to the organism. The most advanced of the
toxic intruders are viruses, composed as they are of nucleic acid-based structures that allows them
to not only interfere with biological systems, but also to parasitically exploit cellular processes to
replicate themselves. Among the more benign viruses are the ones causing the familiar human
symptoms of the common cold or flu, which are the evident manifestations of biochemical battles
occurring between these foreign intruders and our immune systems, whose nanometer sized
constituents (chemicals, and proteins) usually destroy and remove the viral invaders. A growing
number of recent studies show, however, that nano- and micro-organisms may play a role in many
chronic diseases where infections pathogens have not been suspected, diseases that were previously
attributed only to genetic factors and lifestyle. Among these diseases are: leukemia (caused by
viruses from the Retrovirus and Herpes virus families) [1], cervical cancer (Papilloma virus) [2],
liver cancer (Hepatitis virus) [3], gastric ulcer (Helicobacter pylori) [4], nasopharyngeal cancer
(Epstein-Barr virus) [5], kidney stones (nanobacteria) [6], severe acquired respiratory syndrome
SARS (Corona virus) [7], heart disease (Chlamydia pneumonia) [8], juvenile diabetes (Coxsackie
virus) [9], Alzheimers disease (Chlamydia pneumoniae) [10], pediatric obsessive-compulsive
disorder (Streptococcal bacteria) [11], psychotic disorders (Borna virus) [12], and prion diseases
such as mad cow disease (proteins - prions) [13].
One is tempted to think that nanoparticles (such as dust, or ash particles), while similar in size to
viruses, would be more benign, as these materials lack the viruses ability to replicate. Nevertheless,
while non-replicating bodily intruders do not directly take control of cellular processes, some have
been shown to sufficiently interfere with cellular function to influence basic process of cells, such
as proliferation, metabolism, and death. Many diseases can be associated with dysfunction of these
basic processes, the most notable being cancer (uncontrolled cells proliferation), and
neurodegenerative diseases (premature cell death). In addition, several diseases with unknown
cause, including autoimmune diseases, Crohns, Alzheimers, and Parkinsons diseases, appear to
be correlated with nanoparticles exposure. Conversely, the toxic properties of some nanoparticles
may be beneficial, as they are thereby able to fight disease at a cellular level, and could be used as a
medical treatment, by for example targeting and destroying cancerous cells.
Very small particles, so-called nanoparticles, have the ability to enter, translocate within, and
damage living organisms. This ability results primarily from their small size, which allows them to
penetrate physiological barriers, and travel within the circulatory systems of a host. While natural
processes have produced nanoparticles for eons, modern science has recently learned how to
synthesize a bewildering array of artificial materials with structure that is engineered at the atomic
scale. The smallest particles contain tens or hundreds of atoms, with dimensions at the scale of
nanometers - hence nanoparticles. They are comparable in size to viruses, where the smallest have
dimensions of tens of nanometers (for example, a human immunodeficiency virus, or HIV, particle
is 100 nm in diameter), and which in the emerging science of nanotechnology might be called
nano-organisms. Like viruses, some nanoparticles can penetrate lung or dermal (skin) barriers and
enter the circulatory and lymphatic systems of humans and animals, reaching most bodily tissues
and organs, and potentially disrupting cellular processes and causing disease. The toxicity of each
of these materials depends greatly, however, upon the particular arrangement of its many atoms.
Considering all the possible variations in shape and chemistry of even the smallest nanoparticles,
with only tens of atoms, yields a huge number of distinct materials with potentially very different
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physical, and toxicological properties. Asbestos is a good example of a toxic nanomaterial, causing
lung cancer and other diseases. Asbestos exists in several forms, with slight variations in shape and
chemistry yet significantly varying toxicity.
Nanometer sized particles are created in countless physical processes from erosion to
combustion, with health risks ranging from lethal to benign. Industrial nanoparticle materials today
constitute a tiny but significant pollution source that is, so far, literally buried beneath much larger
natural sources and nanoparticle pollution incidental to other human activities, particularly
automobile exhaust soot.
The misapprehension of nanotoxicity may create a general fear that all nanomaterials are toxic.
The online [14] and printed media [15] are inadvertently making no distinction between
nanostructured fixed structures, which are not likely to cause harm (such as computer processors),
and detachable or free nanoparticles, which are likely to cause adverse health effects. While
uncontained nanoparticles clearly represent a serious health threat, fixed nanostructured materials,
such as thin film coatings, microchip electronics, and many other existing nanoengineered
materials, are known to be virtually benign. Many synthetic nanoparticulate materials produce
positive health effects, for example functionalized fullerene chemicals that act as antioxidants. The
use of nanoparticles in medical diagnostics and treatment is driven by their safety, as well as utility.
In the following pages we outline existing sources of nanoparticles, both natural and man-made,
and the known effects of exposure to nanoparticles. In Chapter 1 we introduce basic concepts and
terminology relevant to nanoscience and nanotechnology, define concepts and terms, give examples
of nanoscale systems, and introduce the basics of nanoparticles toxicity. In Chapter 2 we briefly
discuss nanoparticles classifications. Chapter 3 reviews natural and anthropogenic nanoparticle
sources together with their associated health effects and treatment. In Chapter 4 we present current
opinions and research results related to the health implications and toxicology of nanoparticles, and
we define exposure pathways, and migration or translocation mechanisms within biological
systems, adverse health effects, and treatment. The mechanics and biochemistry of toxicity are
discussed in Chapter 5, as well as toxicity-related risk factors, such as particle size, shape,
chemistry, and surface properties. In Chapter 6 we provide an overview of current and developing
applications of nanomaterials. Finally, Chapter 7 contains conclusions and reflections.
1.1. Nano* etymology

The prefix nano, derived from the Greek nanos signifying dwarf, is becoming increasingly
common in scientific literature. "Nano" is now a popular label for much of modern science, and
many nano- words have recently appeared in dictionaries, including: nanometer, nanoscale,
nanoscience, nanotechnology, nanostructure, nanotube, nanowire, and nanorobot. Many words that
are not yet widely recognized are used in respected publications, such as Science and Nature. These
include nanoelectronics, nanocrystal, nanovalve, nanoantenna, nanocavity, nanoscaffolds,
nanofibers, nanomagnet, nanoporous, nanoarrays, nanolithography, nanopatterning,
nanoencapsulation, etc. Although the idea of nanotechnology: producing nanoscale objects and
carrying out nanoscale manipulations, has been around for quite some time, the birth of the concept
is usually linked to a speech by Richard Feynman at the December 1959 meeting of the American
Physical Society [16] where he asked, What would happen if we could arrange the atoms one by
one the way we want them?
The nanometer is a metric unit of length, and denotes one billionth of a meter or 10-9 m.
Popularly, nano is also used as an adjective to describe objects, systems, or phenomena with
characteristics arising from nanometer-scale structure. While micro has come to mean anything
12
small, nano emphasizes the atomic granularity that produces the unique phenomena observed in
nanoscience. While there are some exceptional examples, most of the exciting properties of nano
begin to be apparent in systems smaller than 1000 nm, or 1 micrometer, 1 m. For the purpose of
this review we will describe particles with any dimension smaller than 1 micrometer as
nanoparticles, and those somewhat larger as microparticles.
Nanostructured materials did not first come into existence with the recent emergence of the field
of nanotechnology. Many existing materials are structured on the micro- and nanometer scales, and
many industrial processes that have been used for decades (e.g. polymer and steel manufacturing)
exploit nanoscale phenomena. The most advanced nanotechnological fabrication process is
microelectronic fabrication, where thin film coatings and lithography are used to create micro- and
nano-sized features on computer chips. The natural world is replete with examples of systems with
nanoscale structures, such as milk (a nanoscale colloid), proteins, cells, bacteria, viruses etc.
Moreover, many materials that seems smooth to the naked eye have an intricate structure on the
scale of nanometers (Figure 1). Thus in many ways nanomaterials are not new. Recent advances in
synthesis and characterization tools, however, have fueled a boom in the study and industrial use of
nano-structured materials. A new vocabulary has emerged from this research, and its important
terms and concepts are defined below.
Nanomaterials are materials that have structural components smaller than 1 micrometer in at
least one dimension. While the atomic and molecular building blocks (~0.2 nm) of matter are
considered nanomaterials, examples such as bulk crystals with lattice spacing of nanometers but
macroscopic dimensions overall, are commonly excluded.
Nanoparticles are particles with at least one dimension smaller than 1 micron and potentially as
small as atomic and molecular length scales (~0.2 nm). Nanoparticles can have amorphous or
crystalline form and their surfaces can act as carriers for liquid droplets or gases. To some degree,
nanoparticulate matter should be considered a distinct state of matter, in addition to the solid, liquid,
gaseous, and plasma states, due to its distinct properties (large surface area and quantum size
effects). Examples of materials in crystalline nanoparticle form are fullerenes and carbon nanotubes,
while traditional crystalline solid forms are graphite and diamond. Many authors limit the size of
nanomaterials to 50 nm [17] or 100 nm [18], the choice of this upper limit being justified by the fact
that some physical properties of nanoparticles approach those of bulk when their size reaches these
values. However, this size threshold varies with material type and cannot be the basis for such a
classification. A legitimate definition extends this upper size limit to 1 micron, the sub-micron
range being classified as nano.
Nanoparticulate matter refers to a collection of nanoparticles, emphasizing their collective
behavior.
Nanotechnology can be defined as the design, synthesis, and application of materials and
devices whose size and shape have been engineered at the nanoscale. It exploits unique chemical,
physical, electrical, and mechanical properties that emerge when matter is structured at the
nanoscale.
Nanotoxicology was proposed as a new branch of toxicology to address the adverse health
effects caused by nanoparticles [19]. Despite suggestions that nanotoxicology should only address
the toxic effects of engineered nanoparticles and structures [20] we recommend that nanotoxicology
should also encompass the toxic effects of atmospheric particles, as well as the fundamentals of
virology and bacteriology. While significant differences exist between the health effects of nonbiological particles and viruses and bacteria, there are significant common aspects of intrusion and
translocation.
13
Figure 1. SEM images showing the complexity of the world at the micro and nanoscale: (a) the inner
surface of a birds eggshell, credit: Janice Carr, Sandra L. Westmoreland, courtesy Public Health
Image Library [21]; (b) the rough surface of table grape, credit: Janice Carr, courtesy Public Health
Image Library [21]; (c) the textured surface of a parsley leaf, credit Janice Carr, courtesy Public Health
Image Library [21]; (d) Kleenex paper, courtesy of Jim Ekstrom [22]; (e) pollen from a variety of
common plants, credit Louisa Howard, Charles Daghlian, courtesy Public Health Image Library [21];
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(f) green algae, credit Elizabeth Smith, Louisa Howard, Erin Dymek, Public Health Image Library [21];
(g) Gecko nano-adhesive system, with increasing magnification from left to right: gecko climbing
vertical glass, adhesive surface microstructure, individual setae, nanostructure of spatular endings,
courtesy of PNAS [23].
The new terminology of nano has united previously seemingly disparate fields, and a lexicon is
needed to find and appreciate the great wealth of existing nano research, not conveniently labeled
with the nano keyword.
Health sciences epidemiology terminology. In existing medical and toxicological terminology,
nanoparticles having a diameter smaller than 100 nm are often called ultrafine particles (UFP) or
ultrafine particulate matter. Ultrafine particles are labeled as a function of their size. For example,
particulate matter with constituents having diameters smaller than 10 microns is abbreviated PM10.
Particulate matter having a size smaller than 100 nm is labeled as PM0.1.
Environmental sciences terminology. Ambient particulate matter is categorized in three size
distributions: ultrafine particles less than 0.1 m in diameter (mainly resulting from combustion),
accumulation mode particles between 0.1 and 2.5 m in diameter (resulting from aggregation of
ultrafine particles and vapors), and coarse-mode particles larger than 2.5 m (mostly mechanically
generated) [24].
Proposed terminology. It is important, and timely, to unify the terminology used for describing
particle size in nanotechnology, health, and environmental sciences.
The materials under discussion can be classified as particles, regardless of their source. The size
of these particles varies between 1 nm to several microns, and they can therefore be classified as
Figure 2. Logarithmical length scale showing size of nanomaterials compared to biological components
and definition of 'nano' and 'micro' sizes.
15
either nanoparticles NP (any dimension smaller than 1 micron) or microparticles MP (all

dimensions larger than one micron). To further specify particle size, we propose a modification of
the health sciences epidemiology terminology, labeling particles by their largest dimension; for
example 10 nm in diameter are labeled NP10, while 10 m microparticles are labeled MP10.
Given that microparticles and nanoparticles vary in their conception by only their size, it can be
difficult to fully appreciate the differences between them. To illuminate the effect of the size
difference, the sizes of several natural micro- and nanostructures are shown in Figure 2, as
measured from scanning and transmission microscope images [25, 26]. Generally, the sizes of
nanomaterials are comparable to those of viruses, DNA, and proteins, while microparticles are
comparable to cells, organelles, and larger physiological structures (Figure 2). A red blood cell is
approximately 7 m wide, a hair 60 m, while lung alveoli are approximately 400 m.
1.2. Main differences between nanomaterials and bulk materials
Two primary factors cause nanomaterials to behave significantly differently than bulk materials:
surface effects (causing smooth properties scaling due to the fraction of atoms at the surface) and
quantum effects (showing discontinuous behavior due to quantum confinement effects in materials
with delocalized electrons) [27]. These factors affect the chemical reactivity of materials, as well as
their mechanical, optical, electric, and magnetic properties.
The fraction of the atoms at the surface in nanoparticles is increased compared to microparticles
or bulk. Compared to microparticles, nanoparticles have a very large surface area and high particle
number per unit mass. For illustration, one carbon microparticle with a diameter of 60 m has a
mass of 0.3 g and a surface area of 0.01 mm2. The same mass of carbon in nanoparticulate form,
with each particle having a diameter of 60 nm, has a surface area of 11.3 mm2 and consists of 1
billion nanoparticles (Figure 3). The ratio of surface area to volume (or mass) for a particle with a
diameter of 60 nm is 1000 times larger than a particle with a diameter of 60 m (Figure 3 b). As the
material in nanoparticulate form presents a much larger surface area for chemical reactions,
reactivity is enhanced roughly 1000-fold. While chemical reactivity generally increases with
decreasing particle size, surface coatings and other modifications can have complicating effects,
even reducing reactivity with decreasing particle size in some instances.
The atoms situated at the surface have less neighbors than bulk atoms, resulting in lower binding
energy per atom with decreasing particle size [27]. A consequence of reduced binding energy per
atom is a melting point reduction with particle radius, following the Gibbs-Thomson equation [27].
For example, the melting temperature of 3 nm gold nanoparticles is more than 300 degrees lower
than the melting temperature of bulk gold, as shown in Figure 3 c [27].
An example of a class of materials that clearly exploits quantum effects is quantum dots synthesized nanostructures with sizes as small as a few nanometers (Figure 4). The electronic
behavior of quantum dots is similar to that of individual atoms or small molecules, and quantum
dots are regarded as akin to artificial atoms [28]. Notably, the confinement of the electrons in
quantum dots in all three spatial directions results in a quantized energy spectrum. Another result of
quantum confinement effect is the appearance of magnetic moments in nanoparticles of materials
that are non-magnetic in bulk, such as gold, platinum, or palladium [27]. Magnetic moments result
from several unpaired electron spins in nanoparticles formed of several hundreds atoms. Quantum
confinement also results in quantified changes in the ability to accept or donate electrical charge (or
electron affinity), also reflected in the catalytic ability [27]. For example, the reactivity of cationic
platinum clusters in the decomposition of N2O is dictated by the number of atoms in the cluster,
namely 6-9, 11, 12, 15, 20 atom-containing clusters are very reactive, while clusters with 10, 13, 14,
19 atoms have low reactivity [27].
16
Figure 3. (a) Schematics illustrating a microparticle of 60 m diameter, about the size of a human hair shown in the left at scale (courtesy Chelsea Elliott), and the number of nanoparticles with diameter of
600 nm and 60 nm having the same mass as one microparticle of 60 m diameter. (b) Surface area
normalized to mass versus particle diameter. (c) Gold melting temperature as a function of particle
diameter, according to Gibbs-Thomson equation, shown inset; the gold bulk melting temperature is 1336
K [27].
Figure. 4. ( a ) TEM image of CdSe semiconductor nanoparticles, and ( b ) photograph of CdSe

nanoparticles in solution, photo-luminescent under UV illumination. Images courtesy of Graham
Rodway and Harry Ruda, University of Toronto.
17
Figure 5. Statistics on scientific articles published on (a) nanomaterials and (b) their toxicity (ISI Web
of Science).
1.3. Nanomaterials and nanotoxicology publications statistics

The number of publications on the topic of nanomaterials has increased at an almost exponential
rate since the early 1990s, reaching about 40,000 in the year 2005 (Figure 5), as indicated by a
search on ISI Web of Knowledge database [29]. There is also a notable rise in the number of
publications discussing their toxicity, particularly in the past two years. The total number of papers
on toxicity, however, remains low compared to the total number of publications on nanomaterials,
with only around 500 publications in the year 2005.
The large number of publications on nanomaterials can be explained by the fact that nanoscience
and nanotechnology encompass a wide range of fields, including chemistry, physics, materials
engineering, biology, medicine, and electronics. There are several reviews addressing
nanotoxicology aspects, however they are intended for a narrow, specialized audience. Several are
comparatively general [18], [20], [30-32], while others address selected aspects of nanoparticles
toxicology, such as: health effects of air pollution [33]; epidemiological reviews of exposure to
particles [34]; epidemiological studies of cardiovascular effects of airborne particles [35];
occupational aspects of nanoparticle [179]; particle inhalation, retention, and clearance [36];
pulmonary effects of inhaled particles [37], [38]; inhalation and lung cancer [39], [40]; toxicity of
combustion derived particles inhalation [41]; environmental factors in neurodegenerative diseases
[42]; oxidative mechanisms [43-50]; gastro-intestinal uptake of particles [51]; targeted drug
delivery [52]; particle characterizations methods [53]; screening strategies and future directions of
research [54]; and regulation of nanomaterials [55]. Existing reviews are either written in jargon
comprehensive only to specialists in a particular field, or are, if more accessible, very succinct [32],
[56]. Most nanotechnology reviews written to date focus on a specific sub-field, disregarding the
vast amount of existent knowledge on the general theme of nano. In this review, we attempt to bring
together a broader audience by unifying the language and experience of scientists working within
these diverse fields.
18
1.4. Introduction to nanoparticles toxicity

Human skin, lungs, and the gastro-intestinal tract are in constant contact with the environment.
While the skin is generally an effective barrier to foreign substances, the lungs and gastro-intestinal
tract are more vulnerable. These three ways are the most likely points of entry for natural or
anthropogenic nanoparticles. Injections and implants are other possible routes of exposure,
primarily limited to engineered materials.
Due to their small size, nanoparticles can translocate from these entry portals into the circulatory
and lymphatic systems, and ultimately to body tissues and organs. Some nanoparticles, depending
on their composition and size, can produce irreversible damage to cells by oxidative stress or/and
organelle injury. Figure 6 illustrates the size of an example cell and its organelles compared to
nanoparticles of various sizes, making it easy to understand why nanoparticles are able to enter cells
and interact with various cell components (nucleus, mitochondria, etc.).
In Figure 7 we summarize the possible adverse health effects associated with inhalation,
ingestion, and contact with nanoparticles. We emphasize that not all nanoparticles produce these
adverse health effects - the toxicity of nanoparticles depends on various factors, including: size,
aggregation, composition, crystallinity, surface functionalization, etc. In addition, the toxicity of
any nanoparticle to an organism is determined by the individuals genetic complement, which
provides the biochemical toolbox by which it can adapt to and fight toxic substances. While these
effects will be discussed in details in chapters 3 and 4, we summarize below the most extreme
adverse health effects produced by nanoparticles in order to immediately increase the awareness of
potential toxicity of some nanoparticles. Diseases associated with inhaled nanoparticles are asthma,
bronchitis, emphysema, lung cancer, and neurodegenerative diseases, such as Parkinsons and
Alzheimers diseases. Nanoparticles in the gastro-intestinal tract have been linked to Crohns
disease and colon cancer. Nanoparticles that enter the circulatory system are related to occurrence
of arteriosclerosis, and blood clots, arrhythmia, heart diseases, and ultimately cardiac death.
Translocation to other organs, such as liver, spleen, etc, may lead to diseases of these organs as
well. Exposure to some nanoparticles is associated to the occurrence of autoimmune diseases, such
as: systemic lupus erythematosus, scleroderma, and rheumatoid arthritis.
Figure 6 . Comparison of rat macrophage cells size to nanoparticles size (at scale). Human
macrophages are up to two times larger than rat macrophages. TEM image reproduced with permission
from Environmental Health Perspectives [57].
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Figure 7. Schematics of human body with pathways of exposure to nanoparticles, affected organs, and
associated diseases from epidemiological, in vivo and in vitro studies.
2. Nanoparticle classification
Nanoparticles are generally classified based on their dimensionality, morphology, composition,
uniformity, and agglomeration.
An important additional distinction should be made between nanostructured thin films or other
fixed nanometer-scale objects (such as the circuits within computer microprocessors) and free
nanoparticles. The motion of free nanoparticles is not constrained, and they can easily be released
into the environment leading to human exposure that may pose a serious health risk. In contrast are
the many objects containing nanostructured elements that are firmly attached to a larger object,
where the fixed nanoparticles should pose no health risk when properly handled. An example of this
important distinction is the material asbestos, which is perfectly safe in its primary state (basically a
type of solid rock), but is a significant health hazard when mined or worked in such a way as to
produce the carcinogenic nanometer-scale fibrous particles that become airborne (aerosol) and are
therefore readily absorbed in the lungs.
It is also very important to recognize that not all nanoparticles are toxic; toxicity depends on at
least chemical composition and shape in addition to simply size and particle ageing. In fact, many
types of nanoparticles seem to be non-toxic [58], [59], others can be rendered non-toxic [60], while
others appear to have beneficial health effects [61], [62]. An important lesson we are in the process
of learning from nanoscience is that simple classifications of physical behavior (and therefore
20
toxicity) are overly limiting and that we must study toxicology of each material and each
morphology, in addition to particle ageing, to obtain accurate information to inform policy and
regulatory processes.
2.1. Dimensionality
As shape, or morphology, of nanoparticles plays an important role in their toxicity, it is useful to
classify them based on their number of dimensions (Figure 8). This is a generalization of the
concept of aspect ratio.
1D nanomaterials. Materials with one dimension in the nanometer scale are typically thin films
or surface coatings, and include the circuitry of computer chips and the antireflection and hard
coatings on eyeglasses. Thin films have been developed and used for decades in various fields, such
as electronics, chemistry, and engineering. Thin films can be deposited by various methods [63] and
can be grown controllably to be only one atom thick, a so-called monolayer.
2D nanomaterials. Two-dimensional nanomaterials have two dimensions in the nanometer
scale. These include 2D nanostructured films, with nanostructures firmly attached to a substrate, or
nanopore filters used for small particle separation and filtration. Free particles with a large aspect
ratio, with dimensions in the nanoscale range, are also considered 2D nanomaterials. Asbestos
fibers are an example of 2D nanoparticles.
3D nanomaterials. Materials that are nanoscaled in all three dimensions are considered 3D
nanomaterials. These include thin films deposited under conditions that generate atomic-scale
porosity, colloids, and free nanoparticles with various morphologies [64].
2.2. Nanoparticle morphology
Morphological characteristics to be taken into account are: flatness, sphericity, and aspect ratio.
A general classification exists between high- and low-aspect ratio particles (Figure 8). High aspect
ratio nanoparticles include nanotubes and nanowires, with various shapes, such as helices, zigzags,
belts, or perhaps nanowires with diameter that varies with length. Small-aspect ratio morphologies
include spherical, oval, cubic, prism, helical, or pillar. Collections of many particles exist as
powders, suspension, or colloids.
2.3. Nanoparticle composition
Nanoparticles can be composed of a single constituent material (Figure 8) or be a composite of
several materials. The nanoparticles found in nature are often agglomerations of materials with
various compositions, while pure single-composition materials can be easily synthesized today by a
variety of methods; see chapter 3.2.6).
2.4. Nanoparticle uniformity and agglomeration
Based on their chemistry and electro-magnetic properties, nanoparticles can exist as dispersed
aerosols, as suspensions/colloids, or in an agglomerate state (Figure 8). For example, magnetic
nanoparticles tend to cluster, forming an agglomerate state, unless their surfaces are coated with a
non-magnetic material. In an agglomerate state, nanoparticles may behave as larger particles,
depending on the size of the agglomerate. Hence, it is evident that nanoparticle agglomeration, size
and surface reactivity, along with shape and size, must be taken into account when deciding
considering health and environmental regulation of new materials.
21
Figure 8. Classification of nanostructured materials from the point of view of nanostructure dimensions,
morphology, composition, uniformity and agglomeration state.
3. Sources of nanoparticles and their health effects

3.1. Natural sources of nanoparticles
Nanoparticles are abundant in nature, as they are produced in many natural processes, including
photochemical reactions, volcanic eruptions, forest fires, and simple erosion, and by plants and
animals, e.g. shed skin and hair. Though we usually associate air pollution with human activities
cars, industry, and charcoal burning, natural events such as dust storms, volcanic eruptions and
forest fires can produce such vast quantities of nanoparticulate matter that they profoundly affect air
quality worldwide. The aerosols generated by human activities are estimated to be only about 10%
of the total, the remaining 90% having a natural origin [65]. These large-scale phenomena are
visible from satellites and produce particulate matter and airborne particles of dust and soot ranging
from the micro- to nanoscales. Small particles suspended in the atmosphere, often known as
aerosols, affect the entire planets energy balance because they both absorb radiation from the sun
and scatter it back to space [66]. It has been estimated that the most significant components of total
global atmospheric aerosols are, in decreasing mass abundance: mineral aerosols primarily from
soil deflation (wind erosion) with a minor component (<1%) from volcanoes (16.8!Tg), sea salt
(3.6!Tg), natural and anthropogenic sulfates (3.3!Tg), products of biomass burning excluding soot
(1.8!Tg), and of industrial sources including soot (1.4!Tg), natural and anthropogenic nonmethane
hydrocarbons (1.3!Tg), natural and anthropogenic nitrates (0.6!Tg), and biological debris (0.5!Tg)
[67] (note: Tg here denotes terragram, equal to 1012 grams).
22
3.1.1. Dust storms and health effects

Terrestrial dust storms. Dust storms appear to be the largest single source of environmental
nanoparticles. Long-range migration of both mineral dust and anthropogenic pollutants from the
major continents has recently been the subject of intense investigation. Approximately 50% of
troposphere atmospheric aerosol particles are minerals originating from the deserts [68]. The size of
particles produced during a dust storm varies from 100 nm to several microns (Figure 9 d), with one
third to a half of the dust mass being smaller than 2.5 microns [65], [68]. Particles in the range 100200 nm can reach concentrations of 1500 particles/cm3 [69].
Meteorological observations and modeling have identified ten main sources of global dust
events, shown in Figure 9 e: (1) the Salton Sea, (2) Patagonia, (3) the Altiplno, (4) the Sahel
region, (5) the Sahara Desert, (6) the Namibian desert lands, (7) the Indus Valley, (8) the
Taklimakan Desert, (9) the Gobi Desert, and (10) the Lake Eyre basin [65].
Satellite imagery has revealed the dynamics of large-scale dust migration across continents, and
demonstrated that nanoparticles generated by major environmental events in one part of the world
can affect regions thousands of kilometers away, as shown in Figure 9. For example, dust storms
occurring every spring in Gobi dessert strongly affect air quality in Asia and North America [70],
[71]. The dust route across the Pacific can be seen in satellite images by the yellow color of the dust
itself (Figure 9 a) [72]. The dust migration pattern during the 1998 trans-Pacific transport is shown
in Figure 9 c, the dates representing the approximate daily location of the dust cloud [70]. During
this event, the dust cloud reached the west coast of North America within 56 days after emission,
with the region affected experiencing an intense haze and elevated particles concentrations, with an
average excess 2050 g/m3 with local peaks >100 g/m3 [70], [71].
Extraterrestrial dust. Nanoparticles exist widely in extraterrestrial space. Examples of dust
collected from space, from the moon, and on Mars are shown in Figure 10. The extraterrestrial dust
poses major environmental problems for astronauts as well as for equipment [73]. Lunar dust is
very fine grained compared to typical terrestrial dust (some of the larger grains being shown in
Figure 10 c), with more than 50% of particles found to be in the micron range or smaller [74]. The
lunar dust contains a considerable amount of magnetic nanoparticles [75], clinging to
electrostatically charged surfaces [74] such as the astronauts space suits (Figure 10 b), rendering it
nearly impossible to remove. On Mars, dust accumulating on the solar panels of the exploration
robots has limited the power available to them for locomotion, sensing, and communication [76].
Aiming to mitigate the environmental effects of extraterrestrial dust on humans and machines,
various research projects are directed towards the fabrication of filters or thin film coatings that
repel dust [76].
Health effects. Terrestrial airborne dust particles can lead to a number of health problems,
especially in subjects with asthma and emphysema [65].!The composition of dusts is important, as
iron or other metals rich-dust can generate reactive oxygen species on the lung surface that can scar
lung tissue [65]. In addition, viruses, bacteria, fungi, or chemical contaminants hitchhiking dust
particles may adversely affect health and the environment (Figure 9 f). In this regard it is important
to note that two hundred types of viable bacteria and fungi have been found to survive ultraviolet
light exposure during intercontinental journeys from Africa to America [65].
Extraterrestrial dust brought inside the Lunar Module became airborne and irritated lungs and
eyes of Apollo astronauts [77]. On longer missions to the moon or Mars, prolonged exposure could
increase the risk of respiratory diseases in the astronauts, and mechanical failures of spacesuits and
airlocks. Studies on rats have found that intratracheal administration of small amounts of lunar
material resulted in pneumoconiosis with fibrosis formation [78] (lung disease and abnormal tissue
growth).
23
Figure 9. Sand storms visualized at macro and microscale. (a) Satellite image showing dust blowing off
mainland China over the Sea of Japan and Pacific Ocean in April 2002, credit Jacques Descloitres,
MODIS Land Rapid Response Team, NASA/GSFC [72]. (b) Beijing during a dust storm. (c)
Approximate location of the dust cloud from a Gobi desert dust storm during April 1998, based on
satellite images, after [70]. (d) Asia dust storm samples collected during the 16 March 2002 dust storm
[68], courtesy of American Geophysical Union. (e) Ten major sources of dust in the world; (f) bacteria
collected from African dust that reached North America, both (e) and (f) reproduced with permission
from Environmental Health Perspectives [65].
24
Figure 10. Extraterrestrial dust. (a) SEM of interplanetary dust composed of glass, carbon and silicate
mineral nanoparticles, courtesy of NASA, http://antwrp.gsfc.nasa.gov/apod/ap010813.html. (b) Lunar dust
on the suit of an astronaut inside the lunar module on the lunar surface. The picture was taken after the
second extravehicular activity on this mission on 12.12.1972. Image ID:!AS17-145-22224, courtesy
of!NASA Johnson Space Center (NASA-JSC). (c) Larger lunar dust particles returned from the moon by
Apollo 17 in 1973. These orange glass spheres and fragments range in size from 20 to 45 microns,
courtesy of NASA Johnson Space Center (NASA-JSC) [83]. (d) Global Mars dust storm of 2001,
courtesy NASA/JPL/Malin Space Science Systems [84]. (e) Mars devil-streaked surface, courtesy
NASA/JPL/Malin Space Science Systems [84]. (c) Mars dust devil, courtesy NASA [84].
25
3.1.2. Forest fires and health effects

Forest fires and grass fires have long been a part of Earths natural history, and are primarily caused
by lightning strikes or by human activity. Major fires can spread ash and smoke (Figure 11 a) over
thousands of square miles (Figure 11 b, c) and lead to an increase of particulate matter (including
nanoparticles) exceeding ambient air quality standards [79]. Satellite maps show a unique picture of
global fire activity. Using daily global fire detection provided by MODIS on NASAs Terra
satellite, the fire activity for the entire surface of the Earth has been mapped every day since
February 2000 (Figure 11 d) [80]. As noticed in this figure, numerous fires occur throughout the
world in the savannas of Africa, Australia, and Brazil, in North America, Europe and Asia.
Figure 11. (a) TEM image of smoke aggregates from a fire in Zambia [85], courtesy of American
Geophysical Union. NASA satellite images showing smoke pollution from fires, indicated with red dots.
(b) South California fires. Credit Jacques Descloitres, MODIS Rapid Response Team, NASA/GSFC
[72]. (c) Smoke from fires of Central America spreads towards Golf of Mexico and U.S. in May 2003,
credit Jeff Schmaltz, MODIS Rapid Response Team, NASA/GSFC. (d) Distribution of active fires
detected by Terra's MODIS sensor across the planet during 10-19 July 2006, courtesy of NASA/MODIS
Rapid Response Team/Scientific Visualization Studio [72].
26
Health effects. Epidemiological studies showed that during the weeks of forest fires, medical
visits increase more than 50% in the affected regions [81]. Patients with pre-existing cardiopulmonary conditions reported worsening symptoms during smoke episodes. The usage of air
cleaners was associated with less adverse health effects on the lower respiratory tract [81]. Around
75% of fire-related deaths are due to respiratory problems related to smoke inhalation and not
necessarily burns. The treatment for smoke inhalation in an emergency room is usually oxygen. Due
to the fact that the symptoms may be delayed until 24-36 hours after inhalation, the patient must be
kept under observation for several days.
3.1.3. Volcanoes and health effects

When a volcano erupts, ash and gases containing particulate matter ranging from the nanoscale to
microns (Figure 12 a, b, c), are propelled high into the atmosphere, sometimes reaching heights
over 18000 meters. The quantity of particles released into the atmosphere is enormous; a single
volcanic eruption can eject up to 30 million tons of ash [65]. Volcanic ash that reaches the upper
troposphere and the stratosphere (the two lowest layers of the atmosphere) can spread worldwide
and affect all areas of the Earth for years. A primary effect of upper atmospheric particulate debris
is the blocking and scattering of radiation from the sun. One particularly harmful volcanic product
is particles composed of heavy metals, as these are known to be toxic to humans. While some
effects are seen worldwide, the highest levels of particulate matter are found in areas within tens of
km from the volcano [86].
Health effects. Short-term effects of ash on health include: respiratory effects (nose and throat
irritation, bronchitic symptoms), and eye and skin irritation. To assess the impact of long-term
exposure to volcanic particulate pollution, we can look to the barefoot agricultural populations
living in parts of the world containing volcanic soils, such as Africa, Mediterranean, and Central
America. A large percentage of this population is affected by diseases of lympho-endothelial origin.
The diseases include podoconiosis (Figure 12 d) [87-89] and Kaposis sarcoma (Figure 12 f) [81],
[90].
Podoconiosis is a noncomunicable disease producing lymphoedema (localized fluid retention) of
the lower limbs. The cause of this disease is believed to be the absorption through the skin of the
feet (podos) of nano and microparticles from the soil (konia) [91]. Lymphoedema occurs when the
lymphatic system fails to properly collect and drain the interstitial fluid of the body, resulting in the
long-term swelling of a limb or limbs (Figure 12 d). The lymphatic system is a secondary
circulatory system in the body that collects fluid from several sources, primarily that lost from the
circulatory system (blood), for example from damaged blood vessels in an area of inflammation
(e.g. after a burn, or other injury) [82]. The lymphatic system lacks a central pump, i.e. the
equivalent to the heart in the circulatory system, so it relies on a network of vessels and nodes that
pumps during usual (muscle) motion of the body. If the accumulation of the interstitial fluid is
faster than the pumping, then the tissue swells. In podoconiosis the effect is irreversible, and affects
about 10% of the populations in volcanic tropics. Soil particles with size ranging from 400 nm up to
25 microns, were found in the dermis of the foot of individuals with podoconiosis [87], [88]. These
particles were found in the macrophages, the cytoplasm of other cells, as well as in lymph node
biopsies, as indicated by scanning electron microscopy. Energy dispersive x-ray analysis techniques
showed compositions consistent with the elements present in black lava soil and red clay soil [89].
It is hypothesized that large quantities of small particles and chronic exposure overwhelm the
normal function of the lymphatic drainage system in the patients with podoconiosis, blocking
drainage of both particles and lymph fluid [87-89].
27
Figure 12. (a) The eruption plume of St. Helen volcano, in 1980, courtesy of NASA; (b) Rabaul Eruption
Plume, New Britain Island, 1994. The large scale of eruption can be compared to the Earth curvature,
courtesy of Image Science and Analysis Laboratory, NASA-Johnson Space Center [95]; (c) Scanning
electron microscope image of volcanic ash from the first volcanic eruption of Mount St. Helens,
Washington state, U.S.A. in 1980, courtesy of Chuck Daghlian, Louisa Howard [96]. (d) Podoconiosis impaired lymphatic system drainage affecting the limbs due to clogging with nano and microparticles
[92], courtesy of Elsevier. (e) Volcanic iron oxide rich soil in Rwanda, [97], courtesy Biomed Central.
(f) Aggressive African-endemic Kaposis sarcoma - cancer of blood and lymph vessels - of the foot [97],
courtesy Biomed Central.
28
Kaposis Sarcoma is a form of cancer affecting the blood and lymph vessels (Figure 12 f), and is
also related to human herpes virus infection [81]. Endemic Kaposis sarcoma [81], [90] is
characteristic to parts of the world containing volcanic soils [81]. It was found that iron particles
from the iron-rich volcanic soils (Figure 12 e) may be one of the co-factors involved in the etiology
(set of causes) of Kaposis sarcoma [81]. In chronic exposure to iron volcanic clays, ferromagnetic
nanoparticles penetrate the skin of barefoot agricultural workers leading to impaired lymphatic
drainage and local immunity, leaving the organism prone to infections (such as herpes virus).
Treatment. The treatment of podoconiosis in early stages involves elevation and elastic
stockings, while in more advanced stages the only treatment is surgical. Treatment of Kaposis
Sarcoma involves iron withdrawal, and iron chelators [81]. Both these diseases, podoconiosis and
Kaposis Sarcoma, could be prevented by wearing shoes or boots (not sandals or shoes with open
spaces) starting from early childhood [92].
3.1.4. Ocean and water evaporation and health effects

A large amount of sea salt aerosols are emitted from seas and oceans around the world [67].
These aerosols are formed by water evaporation and when wave-produced water drops are ejected
into the atmosphere (Figure 13 a). Their size ranges from 100 nm to several microns. An example
of sea salt nanoparticles is shown in Figure 13 b. Nanoparticles can also form in bodies of water
through precipitation, as a result of temperature changes and evaporation. An example of this
phenomenon is lake Michigan that rests in a limestone basin, the water containing high levels of
calcium carbonate. During most of the year the calcium carbonate remains dissolved in the cold
water, but at the end of summer the water temperature increases, lowering the solubility of calcium
carbonate. As a result, the calcium carbonate may precipitate out of the water, forming clouds of
nanometer-scale particles that appear as bright swirls when viewed from above, as shown in Figure
13 c [93].
Figure 13. (a) Sea spray from ocean waves, courtesy NASA; (b) TEM image of mineral dust mixture
with sea salt collected from the marine troposphere [67]; (c) the pale blue swirls in Lake Michigan
are probably caused by calcium carbonate (chalk) from the lake's limestone floor, credit Jeff Schmaltz,
MODIS Rapid Response Team, NASA/GSFC [93].
29
Health effects. No adverse health effects have been associated to sea salt aerosols. On the
contrary, beneficial health effects have been suggested from the use of salt aerosols in the
restoration of the mucociliary clearance in patients with respiratory diseases [94]. The unique
microclimate of salt mines is a popular way to treat asthma, particularly in Eastern Europe.
However, sea salt aerosols may transport pollutants and microorganisms that themselves may cause
adverse health effects.
3.1.5. Organisms and health effects

Many organisms are smaller than a few microns (Figure 14 c, d), including viruses (10 nm - 400
nm), and some bacteria (30 nm - 700 m). However, we should make a clear distinction between
what we call particles (microparticle or nanoparticle) and nano-organisms or their components
(including bacteria, viruses, cells, and their organelles). Cells, bacteria, and viruses are selforganizing, self-replicating, dissipative structures, with a shorter-lived structure than inorganic
solids. Nano-organisms generally dissipate when their supply of energy is exhausted. In contrast,
nanoparticles are typically inorganic solids that require no supply of energy to remain in a stable
form. They interact, dissipate, or transform via chemical reactions with their environment.
Many organisms, both uni- and multicellular, produce nanoparticulate inorganic materials
through intracellular and extracellular processes (Figure 14) [98]. For example, magnetite
nanoparticles are synthesized by magnetotactic bacteria and used for navigation relative to the
earths magnetic field (Figure 14 a), siliceous materials are produced by diatoms (Figure 14 b), or
calcium carbonate layers are produced by S-layer bacteria [98]. Magnetotactic bacteria (Figure 14
a) orient and migrate along the geomagnetic field towards favorable habitats using nanometer-size
magnetic particles inside the cell. These bacteria are aquatic microorganisms inhabiting freshwater
and marine environments. In figure 14 b are shown various diatom species frustules (siliceous
shells). Diatoms are unicellular algae with cell walls made of silica. They are abundant in plankton
communities and sediments in marine and freshwater ecosystems, where they are an important food
source for other marine organisms. Some may even be found in moist soils. Diatoms are used in
forensic science to confirm drowning as a cause of death and localize the site of drowning, based
upon the observation of diatoms in lungs, blood, bone marrow, and organs [99]. Nanobacterium is a
nano-organism that synthesizes a shell of calcium phosphate to cover itself, and resembles an
inorganic particle (Figure 14 e, f). The shell ranges in size between 20 to 300 nm, and due to its
porous nature it allows the flow of a slimy substance. This slime (presumably together with
electrical charge) promotes the adhesion to biological tissues and the formation of colonies.
Nanobacteria are very resilient, being temperature- and gamma radiation- resistant [101].
Health effects and treatment. Among these biological nanoparticles, diatoms might pose a
health risk to workers of diatomaceous earth mining and processing [102]; biogenic magnetite is
associated with neurodegenerative diseases [20], and nanobacteria shells were found in humans and
animals [6], [101]. Nanobacteria are ubiquitous within living organisms, humans and animals, being
identified in blood, serum, and organs [101]. These very small bacteria are suspected of being the
cause (at least in part) for many diseases involving calcifications, such as: artery plaque, aortic
aneurysm, heart valves, renal stone formation, chronic prostatitis, ovarian and breast tumors [6],
[101], [103]. They may also be the cause of rapid kidney stone formation in astronauts on space
travels, according to a NASA study, probably due to the fact that their multiplication rate in a
microgravity environment increases fourfold compared to the rate under normal condition of gravity
(of only about 3 days for doubling rate [104]). Definitive mechanisms relating nanobacteria to these
above mentioned diseases are unknown, however there are speculations that nanobacteria colonies
30
may act as nucleation sites for plaque or stone formation [105]. Specific therapies, such as laser
irradiation [106], or antibiotics [105], have shown reduced plaque formation, and even the
regression of plaques.
Figure 14. Organisms in the nanoscale range or producing solid -state nanoscale debris. (a) TEM of
Aquaspirillum magnetotacticum - bacterium showing magnetosomes (iron oxide granules). (b) SEM of
diatom silica frustules or skeletons. (a and b Dr. Dennis Kunkel/Visuals Unlimited. Reproduced with
permission from Visuals Unlimited [25]. (c) SEM of bacteriophage - a virus that infects bacteria,
courtesy of Ross Inman [100]. (d) SEM of Bacillus anthracis bacteria spores, that can live for many
years, enabling the bacteria to survive in a dormant state until they encounter a suitable host, credit
Laura Rose, courtesy of Public Health Image Library [21]. (e) SEM of cultured nanobacteria, (f)
Dividing nanobacteria covered with a hairy apatite layer, (e and f courtesy of PNAS [6]).
31
3.2. Anthropogenic nanomaterials

Humans have created nanomaterials for millennia, as they are byproducts of simple combustion
(with sizes down to several nm) and food cooking, and more recently, chemical manufacturing,
welding, ore refining & smelting, combustion in vehicle and airplane engines [107], combustion of
treated pulverized sewage sludge [108], and combustion of coal and fuel oil for power generation
[109]. While engineered nanoparticles have been on the market for some time and are commonly
used in cosmetics, sporting goods, tires, stain-resistant clothing, sunscreens, toothpaste, food
additives, etc., these nanomaterials, and new more deliberately fabricated nanoparticles, such as
carbon nanotubes, constitute a small minority of environmental nanomaterials. The quantity of manmade nanoparticles ranges from well-established multi-ton per year production of carbon black (for
car tires) to microgram quantities of fluorescent quantum dots (markers in biological imaging).
3.2.1. Diesel and engine exhaust nanoparticles and health effects

Diesel and automobile exhaust are the primary source of atmospheric nano- and microparticles
in urban areas [110]. Most particles from vehicle exhaust are in the size range of 20-130 nm for
diesel engines and 20-60 nm for gasoline engines (Figure 15 a) [24], [111] and are typically
approximately spherical in shape. Carbon nanotubes and fibers, already a focus of ongoing
toxicological studies, were recently found to be present in engine exhaust as a byproduct of diesel
combustion [112] and also in the environment near gas-combustion sources [113]. The aspect ratio
of these fibers is comparable to those of lung-retained asbestos, suggesting that strong carcinogens
may exist in exhaust. Prior to the release of this findings [112] they were thought not to exist in the
environment and their existence was attributed exclusively to engineering by material scientists.
Nanoparticles constitute 20% of the particles mass but more than 90% of the number of dieselgenerated particles [17]. Due to recent health concerns, particle size distribution and number
concentrations studies were conducted in various cities along different continents [115].
A high number concentration of nanoparticles can be located near freeways on scales of
hundreds of meters, showing that vehicular pollution is a major source of local contaminant
particulate matter that includes nanoparticles (Figure 15 b).
Figure 15. (a) TEM showing typical engine exhaust particles consisting of carbon aggregates (small
arrow) around a larger mineral particle (large arrow) [114]; (b) particle concentration decreases
exponentially with downwind distance from the freeway (particles diameter between 6-220 nm) [24]; (c)
Traffic in Los Angeles, courtesy EPA.
32
The daily profile of nanoparticles matches that of local vehicles usage [115]. High pollution
episodes or proximity to high-traffic roads can increase the mass concentration of nanoparticles by
several times from typically low background levels of approximately 0.5-2 g/m3 [20].
Health effects. Research has shown some heterogeneity in the magnitude of adverse health
effects of engine exhaust in different cities, probably related to the complexity and composition of
particles mixtures [49]. Generally, diesel exhaust is known to be toxic as it contains high levels of
polynuclear aromatic hydrocarbons (PAHs) including the known carcinogen benzo-a-pyrene (BaP)
[116].
Atmospheric particle pollution from automobile exhaust seems to have a major influence on
mortality, with a strong association between increased cardiopulmonary mortality and living near
major roads [117], [122]. The findings of this epidemiological study are in concordance with
measurements of nanoparticle concentration near highways, the concentration decreasing
exponentially over several hundreds meters from the traffic [24]. Childhood cancers were also
found to be strongly determined by prenatal or early postnatal exposure to oil-based combustion
gases, primarily engine exhaust [118].
Professional drivers show elevated rates of myocardial infarction (heart attack) [121]. Studies
done in non-smoking, healthy, young patrol officers have shown that nanoparticles from vehicular
traffic may activate one or more signaling pathways that cause pro-inflammatory, pro-thrombotic
and hemolytic (breakdown of red blood cells) responses [119]. It was noted that heart rate
variability was significantly associated with measures of pollution. Epidemiological studies
conducted on diesel locomotive drivers showed a correlation between occupational exposures to
diesel engine exhaust and incidence of lung cancer in the workers [120].
These findings suggest that pollutants emitted by vehicles harm the health of many people, and
that professional drivers, frequent drivers, passengers, and peoples living near major roads are at
elevated risk. Results seen in these studies suggest that exposure to exhaust nanoparticles leads to
increased risk of cardiovascular events over the long term.
3.2.2. Indoor pollution and health effects
Indoor air can be ten times more polluted than outdoor air, according to the Environmental
Protection Agency (EPA) [123]. Humans and their activities generate considerable amounts of
particulate matter indoors (Figure 16). Nanoparticles are generated through common indoor
activities, such as: cooking, smoking, cleaning, and combustion (e.g. candles, fireplaces). Examples
of indoor nanoparticles are: textile fibers, skin particles, spores, dust mites droppings, chemicals,
smoke from candles, cooking, and cigarettes. A quantitative determination of nanoparticle
emissions from selected indoor sources is given in Table 1 [124]. Particles have also been shown to
enter buildings from outdoors through ventilation systems [24]. As humans generally spend much
of their time indoors (more than 80%), indoor pollution directly affects our health.
Health effects. Long-term exposure to indoor cooking emissions may pose adverse health
effects due to particulate matter inhalation [125]. During cooking, the level of particulate matter
increases more than ten fold compared to non-cooking hours [125]. In many regions of the world,
death caused from indoor smoke from solid fuels is considerable, especially in Africa and Asia
(Figure 16 e). Poorly ventilated stoves using biomass fuels (wood, crop residue, dung, coal) are the
main responsible for the death of an estimated 1.6 million peoples annually, from which more than
a half are children under the age of five [126]. Word Health Organization estimates more than 50%
of the world population uses solid fuels for cooking and heating, including biomass fuels. Wood
burning is often disregarded as a source of nanoparticles and assumed to be benign to the
environment simply because wood is a renewable source.
33
Figure 16. Indoor air pollution from (a) heating, (b) cooking (Courtesy E.K. Schafhauser), (c) candle
smoke. (d) TEM of soot particle from indoors pollution [127], reproduced with permission from
Environmental Health Perspectives. (e) Death from indoor smoke from solid fuels according to World
Health Organization [126].
Table 1. Measured concentrations of nanoparticles resulting from various common indoor household
activities, after [124].
Nanoparticle source
Pure wax candle
Radiator
Cigarette
Frying meat
Heater
Gas stove
Scented candles
Vacuum cleaner
Air freshener spray
Ironing a cotton sheet
Concentration
(nanoparticles/cm3)
241,500
218,400
213,300
150,900
116,800
79,600
69,600
38,300
29,900
7,200
Estimated source strength (particles/min x 1011)

3.65
8.84
3.76
8.27
3.89
1.3
0.88
0.38
2.34
0.007
34
Figure 17. (a) Measured environmental tobacco smoke particles concentration versus nanoparticle
diameter. Nanoparticles are generated upon smoking one cigarette (after [128]). (b) Pathology of lung
showing centrilobular emphysema characteristic of smoking. The cut surface shows multiple cavities
heavily lined by black carbon deposits, content providers Dr. Edwin P. Ewing, Jr., courtesy of Public
Health Image Library [21].
3.2.3. Cigarette smoke and health effects

As a combustion product, tobacco smoke is composed of nanoparticles with size ranging from
around 10 nm up to 700 nm, with a maximum located around 150 nm (Figure 17 a) [128]. The
environmental tobacco smoke has a very complex composition, with more than 100,000 chemical
components and compounds [128].
Health effects. Environmental tobacco smoke is known to be toxic, both due to some of its gas
phases as well as nanoparticles. A plethora of studies have investigated the adverse health effects of
environmental cigarette smoke. Substantial evidence shows that, in adults, first or second hand
cigarette smoke is associated with an increased risk of chronic respiratory illness (Figure 17 b),
including lung cancer, nasal cancer, and cardiovascular disease, as well as other malignant tumors,
such as pancreatic cancer [129] and genetic alterations [130]. Children exposed to cigarette smoke
show an increased risk of sudden infant death syndrome, middle ear disease, lower respiratory tract
illnesses, and exacerbated asthma [129]. Cigarette smokers are more likely than nonsmokers to
develop many conditions including cancers and vascular diseases [131]. It was noted that the risk of
myocardial infarction decreases substantially within two years after smoking cessation, proving a
reversibility of inhaled nanoparticles induced vulnerability [132].
3.2.4. Buildings demolition and health effects

Particulate matter concentrations can rise to very high levels when large buildings are demolished,
especially the respirable ones with diameter smaller than 10 microns [133]. Older buildings are very
likely to have been constructed with parts containing known toxins. Consequently, respirable
asbestos fibers, lead, glass, wood, paper, and other toxic particles are often found at the site of
demolition [133]. In addition, the dust cloud can travel tens of kilometers and affect the neighboring
regions of the collapsed building site [133].
35
Figure. 18. (a) Dust cloud from the World Trade Center collapse spreads to neighboring streets.
Courtesy EPA. (b) Heavy dust accumulation in store closed to World Trade Center [135]. Particle
collected from the site of collapse and neighboring streets: (c) soot [135], d) glass fiber [135], (e), (f)
dust containing Ca, S and O [136], (g) lead and [g135], (h) titanium particle [136]. Images (b)-(h)
courtesy Environmental Health Perspectives.
36
Health effects of exposure to demolition particles and soot (Figure 18) are not entirely known.
Early clinical and epidemiological assessments of firefighters present at the site of the
environmental disaster generated by the attack on the World Trade Center on September 11, 2001,
indicated exposure-related health effects, with prevalence of respiratory symptoms, especially
increased cough and bronchial hyperactivity [134]. Long-term effects, however, remain to be seen.
3.2.5. Cosmetics, other consumer products and health effects

Cosmetics. The use of nanomaterials in cosmetics is not new. Black soot and mineral powders
have been used as cosmetics since thousands of years ago in ancient Egypt, and some of them
continue to be used today. Due to the recent development of nanotechnology, engineered
nanomaterials have been embraced by the cosmetics industry for several reasons.
a) Because of their ability to penetrate deeper into the protective layers of skin than any cosmetic
before, they are used as delivery agents for skin nutrients, such as synthetic peptides that instruct
cells to regenerate [137].
b) Some nanoparticles have antioxidant properties [138], feature that helps maintain a youthful
appearance of the skin. For example, functionalized fullerenes are now incorporated into cosmetic
products, such as creams, claiming radical scavenging properties [14].
c) Due to their small size and specific optical properties, they are thought to conceal wrinkles
and small creases [14]. For example, alumina nanopowder is used for optical reduction of fine lines
[14].
Many cosmetic and personal care products incorporate nanomaterials. For a compilation of
websites and product information see reference [140]. They include: personal care products
(deodorants, soap, toothpaste, shampoo, hair conditioner), sunscreen, cosmetics (cream, foundation,
face powder, lipstick, blush, eye shadow, nail polish, perfume and after-shave lotion).
There are two trends regarding the use of engineered nanoparticles in cosmetics. First, a swift
application of nanotechnology advances in the cosmetic industry, in addition to re-labeling of the
products that already contain nanoparticles, so that they are more appealing to the consumers [141].
Second, targeting of cosmetic companies that use nanoparticles. For the general public and
uninformed journalists there is not much of a difference between the various types of nanoparticles
currently used in cosmetics, such as lipid based nanoparticles, fullerenes, silicon, etc. Everything
labeled nanoparticle is considered dangerous to some. These trends result at least in part from the
lack of regulations for testing of cosmetic products before they are sold to the public [55], unlike
pharmaceutical products that are required to undergo several years of research before being
considered safe. Despite the fact that many of the cosmetic companies claim safety related research,
their results are not always disclosed to the public.
Other consumer products. Many consumer products incorporate nano or microparticles. A
non-comprehensive list of currently available consumer products that incorporate nanotechnology
can be found in reference [14]. The authors of this list make no distinction between nanostructured
fixed structures, which are not likely to cause harm (an example is their listing of computer
processors), and detachable or free nanoparticles, which can cause adverse health effects.
Titanium dioxide (TiO2) particles with diameter larger than 100 nm are considered biologically
inert in both humans and animals [142]. Based on this understanding, titanium dioxide
nanoparticles have been widely used in many products, such as white pigment, food colorant,
sunscreens and cosmetic creams [19]. However, adverse effects of titanium dioxide nanoparticles
have recently been uncovered [143], [276], [277], [278], [279]. New research is exploring the
potential use of nanostructured titanium dioxide photocatalyst materials for sterilizing equipment of
37
environmental microorganisms in the health care facility [144].

Silver nanoparticles are used as antibacterial/antifungal agents in a diverse range of applications:
air sanitizer sprays, socks, pillows, slippers, face masks, wet wipes, detergent, soap, shampoo,
toothpaste, air filters, coatings of refrigerators, vacuum cleaners, washing machines, food storage
containers, cellular phones, and even in liquid condoms [14].
Coatings of nanoparticles are widely used for modifying fabrics to create stain and wrinkle free
properties. In addition, one can find clothes with built-in sunscreen and moisture management
technology [14]. Fabric containing bamboo-charcoal nanoparticles claims antibacterial antifungal
properties [14]. They are intended for use as face cloth masks, shoes insoles. Nano-coatings are
applied to wetsuits for higher performance of athletes, or self-cleaning surfaces. Textiles with
30!nm embedded nanoparticles help prevent pollen from entering gaps in the fabric [14].
Nanoparticles or nanofibers are starting to be used in water-repellent, stain resistant plush toys, stain
repellent mattresses [14]. Nano-sealant sprays for fabrics or leather, and hydrophobic nanoparticle
solutions adhering to concrete, wood, glass, cloth, etc., allow the surfaces to deflect water [14]. The
most peculiar applications of nanofibers and nanoparticles discovered in our literature review are:
nanofibers that hide hair loss, and liquid condoms [14].
Health effects. All the health effects of the gamut of nanoparticles used in consumer products
are not yet known, though nanotoxicology has revealed adverse health effects of materials
previously considered safe. For example, silver, widely used as an antibacterial agent, proves to be
toxic to humans or animal cells when in nanoparticle form, its cytotoxicity being higher than that of
asbestos [113]. Inhalation of silver nanoparticles leads to their migration to the olfactory bulb,
where they locate in mitochondria [20], as well as translocation to circulatory system, liver,
kidneys, and heart [145]. Silver nanoparticles have been found in the blood of patients with blood
diseases [146] and in the colon of patients with colon cancer [147].
A controversial subject is the association between the uptake of aluminum and Alzheimers
disease. Epidemiological studies researching the connection between aluminum in antiperspirants,
antacids, or drinking water and Alzheimers disease are conflicting, some finding positive
associations and others none [148]. Due to their latent evolving nature and multi-part etiology, these
neurological diseases are difficult to associate with specific factors. For example, the exposure takes
place much earlier than the disease occurrence, hence the subjects may not recall possible exposure,
their memory being already affected by the disease. Moreover, subjects that suffer from advanced
neurodegenerative diseases are not likely to participate in epidemiological studies due to their
reduced ability to communicate and remember [148]. In addition, multiple factors are known to
contribute to Alzheimers disease, such as: genetics, increasing age, endocrine conditions, oxidative
stress, inflammation, smoking, infections, pesticides, electromagnetic fields [148].
In general, several questions arise related to the safety of nanoparticles as consumer products.
Are they biocompatible? Do the nanoparticles enter the lymphatic and circulatory systems? If not,
do they accumulate in the skin and what are the long-term effects of accumulation? Do they
produce inflammation? If they enter the lymphatic and circulatory system, is the amount
significant? What are the long-term effects of this uptake? Related to the beneficial antioxidant
properties of some nanomaterials, long-term effect need to be studied, in addition to the short-term
antioxidant effect. What is the long-term fate of these nanoparticles? Are they stored in the skin?
Do they enter circulation? What happens when the nanoparticles undergo chemical reactions and
lose their antioxidant properties? The answers to some of these questions are known, and will be
presented in the chapter dedicated to nanoparticles toxicity, however most of the remaining
questions still remain unanswered.
38
3.2.6. Engineered nanomaterials and health effects

The fabrication of nanomaterials is a broad and evolving field. Nanomaterials can be synthesized
by many methods including: gas phase processes (flame pyrolysis, high temperature evaporation,
and plasma synthesis); vapor deposition synthesis (electron, thermal, laser beam evaporation);
colloidal, or liquid phase methods in which chemical reactions in solvents lead to the formation of
colloids; and mechanical processes including grinding, milling and alloying. A review of
nanomaterial fabrication processes is given in [149]. A critical fact to consider with engineered
nanomaterials is that they can be synthesized in almost any shape and size by materials scientists.
Several examples are given in Figures 19, 20, and 21. Nanostructured materials shown in Figure 19
are firmly attached to a substrate and do not pose a health risk as long as they do not detach from
the substrate. Figure 20 shows nanostructured materials where nanostructures are free and can
become airborne, consequently posing a potential health risk. In Figure 21 man-made nanoparticles
engineered by glancing angle deposition [150], [151] are shown together with microorganisms, such
as bacteria and viruses.
Figure 19. Examples of nanostructured materials in thin film form, which are not toxic unless the
nanoparticles get detached: (a) Si rugate filter [153], (b) Si 12-layered structure [154], (c) MgF2
capping layered helical films [155], (d) Ti pillars [156], (e) Cu pyramids (unpublished), (f) Cu oblique
columns [156], (g) ZnO nanowires, credit: Y. Lu, courtesy of National Science Foundation, (h) porous
Ag [64], (i) porous Si [157]. The scale bars represent 100 nm.
39
Figure 20. Examples of free nanoparticles. (a) MWCNTs and (b) ground MWCNTs, [159], reproduced
with permission from Elsevier. (c) Silicon rods (Kevin Robbie, unpublished). (d) Carbon black, (e)
silver, (f) and titanium dioxide [113], reproduced with permission from Springer Science and Business
Media. (g) Gold nanorods [160], courtesy of National Academy of Sciences of US. (h) Silicon zigzags
(Kevin Robbie, unpublished). (i) Magnesium fluoride helices (Kevin Robbie, unpublished). The scale bar
represents 100 nm.
Figure 21. Engineered nanoparticles [64] together with selected microorganisms, shown at equal
magnification.
40
Health effects. As a main focus of this paper, the adverse health effects of engineered
nanoparticles will be discussed in Chapter 4. An important initiative by the National Institute for
Occupational Safety and Health was the creation of an online nanoparticles information library that
is updated with various compositions nanoparticles as well as with the known health effects of some
nanoparticles [152]. As the fields of nanotechnology and nanotoxicology are developing so quickly,
this is a great way to update the current knowledge on nanoparticles fabrication and toxicology.
3.3. Environmental and occupational exposure to toxic substances

3.3.1. Metals and other dusts
Small quantities of many metals, including copper, magnesium, sodium, potassium, calcium, and
iron are essential for proper functioning of biological systems. At higher doses, however, metals can
have toxic effects and exposure to high levels of environmental metals causes disease in humans
[158]. The metals listed below in this paragraph are known to be toxic upon inhalation, ingestion or
dermal exposure. Nanoparticles manufactured from these metals will have health effects not
necessarily easily predicted from previous studies of non-nanoparticulate quantities of the same
metals. As it could easily expose workers to these toxic materials, manufacturing of metal
nanoparticles should be considered a serious occupational hazard.
The inhalation of metallic or other dusts is known to have negative health effects. The type of
lung disease caused by dust inhalation depends on the nature of the material, exposure duration, and
dose. The inhalation of some metal fumes (e.g. zinc, copper) may lead to metal fume fever, a
influenza-like reaction [161]. Several metal dusts (e.g. platinum, nickel, chromium, cobalt) can lead
to asthma [161], while inhalation of other metallic dusts can cause pulmonary fibrosis, and
ultimately lung cancer. The percentage of lung cancers attributable to occupational hazards is about
15%, with exposure to metals being a major cause [161].
Beryllium. Beryllium alloys are used for making electrical and electronic parts, and molds for
plastic. Inhalation can cause lung damage leading to a pneumonia-like syndrome called acute
beryllium disease [162]. Beryllium exposure can also lead to hypersensitivity, and allergic reaction
characterized by an inflammatory immune response to even tiny amounts of beryllium.
Hypersensitivity can lead to chronic beryllium disease, where white blood cells accumulate around
absorbed beryllium particles and form granulomas leading to anorexia, weight loss, cyanosis of the
extremities, and heart enlargement [162]. Long-term exposure to beryllium causes cancer in animals
and increased risk of lung cancer in humans [163].
Lead. Exposure to lead occurs through the air, household dust, food, and drinking water. Airborne lead may be present in industrial emissions, such as those from smelters and refineries.
Exposure to high levels of lead and its compounds can cause serious disability. At highest risk are
workers involved in the manufacture of batteries, metals, and paints; the printing industry; or
chronically exposed to lead dust (e.g. through sanding of surfaces coated with lead) or insecticides.
Inhaled or ingested lead circulates in the blood and is deposited in bone and other tissue [158].
Following inhalation, about 50-70% of lead is absorbed into the blood, allowing it to circulate to
most organs. Manifestations of lead intoxication include impairment of mental functions, visualmotor performance, memory, and attention span, as well as anemia, fatigue, lack of appetite,
abdominal pain, and kidney disease, among others [158].
Cobalt. Diseases associated with exposure to cobalt are- asthma, acute illness (fever, anorexia,
malaise, and difficulty breathing, resembling a viral illness), and interstitial pneumonitis [161],
[162].
41
Cadmium. Cadmium is used in batteries, pigments, metal coatings, plastics, and is a by-product
of the burning of fossil fuels and cigarettes. As a result of industrial and consumer waste, cadmium
accumulates in soil at a rate increase by 1% per year [158]. Plants and feed crops growing in
contaminated soil take up cadmium, leading to contamination of vegetables and animals. High-dose
inhalation exposure leads to severe lung irritation, nausea, and vomiting. Long-term low-dosage
exposure in humans causes lung emphysema, impairment of the immune system, central nervous
system and liver damage [158]. Occupational exposure to cadmium has been linked to lung cancer
in humans, some studies associating cadmium exposure with cancer of the liver, bladder and
stomach, and possibly of pancreas [164].
Aluminum. Exposure to aluminum occurs through consumption of food and water, as well as
usage of many products containing aluminum, including antacids and anti-perspirants. The use of
antiperspirants combined with under-arm shaving is associated with an earlier age of breast cancer
diagnosis [165]. Aluminum excess can lead to anemia, bone disease, and dementia [166]. Exposure
to high levels of aluminum (and other metals, such as iron) is related to neurological disorders, such
as dialysis encephalopathy, Parkinson dementia, and especially Alzheimers disease [167]. Studies
of brain plaques associated with Alzheimer's disease show abnormally high aluminum [158], but
have not shown if this is a cause or effect of the disease. However, one can hypothesize that a
critical mass of metabolical errors is important in producing Alzheimers disease [168]. If
aluminum can reach the brain via the olfactory bulb by passing the blood brain barrier, or via the
circulatory system, then brain metabolical errors resulting from accumulations of this metal in parts
of the brain could contribute to the onset of Alzheimers disease [168]. Rats that received
subcutaneous injection of aluminum glutamate show pathological signs similar to those observed in
human Alzheimers disease [169]. They show a significant increase of aluminum content in the
brain (hippocampus, occipito-parietal cortex, cerebellum, striatum), and symptoms that include
trembling, equilibrium instabilities, and convulsions, followed by death one hour after the injection.
Nickel and chromium. Nickel is used for the production of stainless steel and other nickel
alloys with numerous applications. Occupational exposure to nickel via inhalation of dust and
fumes is associated with cancers of lung and sinus [158]. Chromium derived from smelting has also
been found to cause cancer.
Manganese. Manganese is both an essential nutrient and is known to have neurotoxic effects
[148], [170]. At high levels, manganese exposure to contaminated water or through inhalation
results in neurological impairment. Occupational exposure generally occurs only to those involved
in mining and welding. An example of welding-generated nanoparticles is given in Figure 22 a.
There is a clear association between manganese and neurological disease in miners exposed to
MnO2 dust [170]. The neurological disorder linked most closely to manganese is Parkinson's
disease [148], [170]. Some welders develop Parkinsons disease much earlier in their life, usually in
their mid forties, compared to the sixties in the general population [148]. Of concern for public
health is the risk of neurological diseases emerging after long latencies in regions with only mildly
elevated environmental manganese levels.
Iron. Iron is incorporated into numerous enzymes involved in cell division, DNA replication,
and cellular metabolism, and it is essential for oxygen transport and gas exchange. As with
manganese, low doses of iron are vital for survival. Several observations have been made linking
cellular iron content to the development of cancers [97]. In studies of animals administered
excessive amounts of iron, orally and by injection, an increased risk of of adenocarcinomas,
colorectal tumors, hepatomas, mammary tumors, mesothelioma, renal tubular cell carcinomas, and
sarcomas was observed. In humans, injection of iron compounds has been shown to cause sarcomas
at the sites of deposition. Patients with hemochromatosis (genetic disease characterized by
increased iron absorption) have an enhanced susceptibility to liver cancer. The accumulation of iron
42
in brain regions with decreased function, and cell loss has been observed in many neurological
diseases, such as Parkinsons disease, Alzheimers disease, etc. [171]. Inhalation of iron dust causes
a respiratory disease called pneumoconiosis [161].
Organic dust. Organic dusts originate from animals and/or plants and contain fragments and
fibres from wood, bone, fur, skin, leather, brooms, flour, grains, tobacco, carpets, paper, etc.
Organic dust from these various sources irritates the upper respiratory system, eyes, and skin,
causing bronchitis, allergic reactions, asthma, conjunctivitis, and dermatitis [158].
Silica. Exposure to silica, or silicon dioxide (SiO2), the main constituent of sand and granite,
produces silicosis, a disabling pulmonary fibrosis. A controversial subject in occupational medicine
is the association of silicosis with lung cancer [158]. In addition, exposure to silica is associated to
autoimmune diseases including: scleroderma, rheumatoid arthritis, systemic lupus erythematosus
[172].
Coal and coal ash. Coal dust produces pneumoconiosis in coal miners, their lungs retaining a
considerable amount of dust, of up to 30 g (roughly two table spoons of dust) [173].
Epidemiological study on more than 500 chimney sweeps showed an increased number of deaths
due to heart and respiratory diseases, lung, esophageal, and liver cancer [174].
Asbestos. Asbestos is a naturally occurring fibrous material consisting of very long chains of
silicon and oxygen (polysilicate or long chain silicate). A SEM image of asbestos can be seen in
Figure 22 b. Asbestos fibers have high tensile strength, flexibility and have flame retardant and
insulating properties. In ancient times, asbestos was woven and used in fabrics such as Egyptian
burial cloths and Charlemagne's tablecloth, which according to legend he threw in a fire to clean.
(Wikipedia, The Free Encyclopedia). Due to its desirable properties it was once used extensively in
construction materials (cement, floors, roofing, pipe insulation, and fire-proofing) and in materials
industry (brake pads) [175]. Asbestos exposure occurs when its handling produces small fibers,
nanoparticles, that are easily carried as a suspension in both air and water where they are absorbed
by inhalation and ingestion. Studies of occupational health show that exposure can cause lung
cancer and mesothelioma (a rare cancer of the membranes lining the abdominal cavity and
surrounding internal organs) [158]. Recent studies in a community with occupational and
environmental exposure to asbestos showed increased risk of autoimmune diseases, such as:
systemic lupus erythematosus, scleroderma, rheumatoid arthritis [172], [176]. These diseases affect
connective tissues, skin, and organs.
Figure 2 2 . ( a ) TEM of welding nanoparticles, courtesy of Pam Drake, National Institute for
Occupational Safety and Health NIOSH. (b) Asbestos fibers, courtesy of the U.S. Geological Survey.
43
Polymer fumes. Humans exposed to polytetrafluoroethylene (or Teflon, PTFE) and other
polymer fumes develop an influenza-like syndrome (polymer fume fever). The symptoms occur
several hours after exposure, and include chest pain, fever, chills, sweating, nausea and headache
[177]. Severe toxic effects, like pulmonary edema, pneumonitis and death, are also possible [178].
3.3.2. Carcinogens and poorly soluble (durable) particles

It is clear that some types of particles cause cancer, but it is not known which characteristics of the
particles are responsible for their carcinogenicity. Some particles are inherently toxic, such as metal
dust, welding fume, and quartz dust, while other particles have a much lower toxicity, but still cause
toxic effects under some circumstances. The latter category includes poorly soluble particles,
biodurable particles without known specific toxicity that include: diesel exhaust particles, carbon
black, coal-mine dust, titanium dioxide, and several others listed in Table 2 [39]. Poorly soluble
particles have been shown to cause cancer in rodents, however epidemiologic studies do not clearly
indicate increased cancer rates in humans exposed to these particles. The latest research on
nanoparticles shows that they can exhibit more pronounced toxicity than larger microparticles,
suggesting that environmental and health regulating agencies must take more consideration of
particle size distribution, shape, and agglomeration when establishing regulatory exposure
guidelines.
Table 2. Particles with proven lung carcinogenic effects in animals and/or humans (adapted from ref.
[39]). Some poorly soluble particles are shown to be carcinogenic only in rodents, while
epidemiological studies do not clearly indicate human carcinogenicity. Classification in animal studies
was done as follows: + means positive in more than one animal during inhalation studies, - means
negative or no inhalation studies, +/- indicates inadequate evidence in rats, and blank indicates
not decided yet.
Particle
Particulate matter (PM0.1,
PM2.5, PM10)
NiO
Quartz (crystalline silica)
Asbestos
Carbon black
Refractory ceramic fibers
Wood dust
TiO2
Diesel exhaust
Talc
Volcanic fly ash
Coal mine dust
Rockwool
Iron oxides
Graphite
Cement
Amorphous silica
Use/exposure
Ambient
Exhaust
Constructions
Insulation, mining
Pigments, toner, tires
insulation
Furniture making, saw mills
Pigments, sunscreens
Engines, cars
Cosmetics, mining
Ambient
Mining
Insulation
Pigments, paramagnetic
diagnostics
Occupational
Constructions, buildings
Cleaning, paints, drugs
Carcinogenic effect
Rat Human
Possibly carcinogenic?
(unknown fraction)
+
Carcinogenic
+
Carcinogenic
+
Carcinogenic
+
Possibly carcinogenic
+
Possibly carcinogenic
+/Carcinogenic (some types)
+
+
+
+
+
Not classifiable
+
Not classifiable
+/+/- Not classifiable
- Not classifiable
44
Figure 23. a) Los Angeles smog. b) Size distribution and composition of particulate matter over Los
Angeles during 2002-2003. NP - nanoparticles, MP microparticles (after [123]).
3.4. Aerosol pollution, monitoring, and health effects

3.4.1. Aerosols size and composition
Aerosol pollution is a combination of particulate matter and gaseous and liquid phases from natural
and anthropogenic sources. Ambient particulate matter is generally classified according to three size
distributions: nanoparticles smaller than 100 nm in diameter (mainly resulting from combustion),
accumulation mode particles between 100 nm and 2.5 m in diameter (from aggregation of smaller
particles and vapors), and coarse-mode particles larger than 2.5 m (mostly mechanically
generated) [24]. These three particle categories have distinct chemical compositions (Figure 23),
sources, and lifetime in the atmosphere. The larger particles, which settle faster due to gravity, are
removed from the atmosphere fastest. Smaller particles are transported over greater distances and
have longer lifetimes in the atmosphere [24]. Nanoparticles usually form atmospheric fractal-like
dendritic aggregates similar to the soot in Figure 16 d. The polydispersity (variation in particle
sizes) varies with the source, for example, primary particles in diesel aggregates ranging from 10 to
40 nm. Atmospheric measurements show that nanoparticles make up a small portion of the
particulate matter mass concentration compared to microparticles [123]. However, the number
concentration of nanoparticles is significantly larger than the number of microparticles.
45
Combustion-derived carbon particles, with traces of transition metals, make up about 50% of the
mass of typical urban particulate matter, while the remaining 50% includes salts, geological dust,
and organic matter [49]. As shown in this study of particulate matter in Los Angeles (Figure 23)
[123], when sorted by size, we see that the particles vary considerably in composition, with the
smallest nanoparticles being mostly carbon (organic and elemental), while the larger microparticles
are mostly metal. In general, environmental pollution particles differ in their quantities of nitrates,
sulfates, crustal materials, and carbon, with blown soil a major source in rural areas. Due to the high
chemical reactivity of atmospheric nanoparticles (resulting from their high surface area), they are
very likely to interact with water or other chemicals in the atmosphere to form new species. This
dynamic nature of aerosol nanoparticles means that their environmental impact will be long and
complex, as reactions create a cascade of products with varying effects while some particles will
be long-lived, or persistent, others may experience transformations to more or less damaging states.
3.4.2. Aerosols concentration. Air quality index
Nanoparticles with size smaller than 100 nm are present in large numbers in typical ambient air
with a level ranging between 5,000-10,000 particles per ml, increasing during pollution episodes to
3,000,000 particles/ml [49]. Their concentration varies from region to region, as well as from
season to season. Nanoparticles smaller than 100 nm make up about 70% of the total number of a
ambient aerosols in urban areas, while their mass contribution is only about 1% [180]. In certain
parts of the world the peak number concentration or airborne nanoparticles was found to increase
over time. For example, in California, the peak concentration of nanoparticles in January 1999
(1.45 !1011 particles/m3) was found to be three times higher than previously measured peaks [181].
At the other extreme are modern cleanroom facilities where air particles are almost eliminated
through careful design of airflow and filtering, and meticulous elimination of potential particle
sources. A typical cleanroom, with Class 10 or ISO 3 particle levels has only several hundred 100
nm particles per cubic meter.
Increased awareness of the influence of particle size and shape on health impact has led the
Environment Protection Agency to propose new ambient standards on fine particles smaller than 2.5
microns. The Air Quality Index (AQI) is a standard measure used by the Environmental Protection
Agency for monitoring daily air quality [123]. It quantifies air pollution and predicts health effects
of concern that may be experienced within a few hours or days of exposure to polluted air. The
calculation of the AQI includes five major pollutants: particulate matter, ozone, carbon monoxide,
sulfur dioxide, and nitrogen dioxide, all of which are regulated under the Clean Air Act. The AQI
has not been standardized internationally, and other countries use different systems for describing
air quality [123], [182]. The AQI values for particulate matter are shown in Table 3.
Table 3. Air quality index, AQI, values for concentrations of particulate matter with diameters smaller
than 2.5 (MP<2.5) and 10 microns (MP<10) [123].
AQI
0-50
51-100
101-150
151-200
201-300
MP<2.5
(g/m3)
0.0-15.4
15.5-40.4
40.5-65.4
65.5-150.4
150.5-250.4
MP<10
(g/m3)
0.54
55-154
155-254
255-354
355-452
Air quality descriptor

Good
Moderate
Unhealthy for sensitive groups
Unhealthy
Very unhealthy
46
Figure 24. Images of pollution over the world. While clouds appear solid-white, pollution appears as a
misty semi-transparent gray that masks the images geographic and aquatic features. (a) Smog layer
over upstate New York and North-Eastern Ontario, courtesy Earth Science and Image Analysis
Laboratory, Johnson Space Center. (b) Dust from the Sahara Desert, air pollution, and smoke lingers
over the Atlantic Ocean and Great Britain in April 2003 [72], credit Jacques Descloitres, MODIS Rapid
Response Team, NASA/GSFC. (c) Pollution in China blowing east towards the Yellow Sea, Korea and
Japan. Beijing, China's capital, lies under the densest portion of the aerosol pollution, credit NASAGSFC [183]. (d) Pollution over India. Haze follows the course of the Ganges River in northern India,
flowing eastward along the Himalaya Mountains, before turning south and spreading out in the Indian
Ocean, credit Jacques Descloitres, MODIS Rapid Response Team, NASA/GSFC [183]. (e) Optical depth
showing worldwide concentration of aerosols on June 2005, derived from data taken by MISR, NASA's
47
first Earth Observing System (EOS) spacecraft, launched on December 18, 1999. The MISR instrument
orbits the Earth about 15 times each day, observes the Earth continuously from pole to pole, and every 9
days views the entire globe between 82 degrees north and 82 degrees south latitude [184].
3.4.3. Satellite monitoring of aerosol concentration and size

Aerosols play an important role in the global atmosphere, directly influencing global climate and
human health. Dust, smoke, and haze locally impair visibility and health in both urban and rural
regions. Anthropogenic aerosol nanoparticles are especially abundant in the atmosphere, and they
constitute a significant uncertainty factor in estimating the climatic change resulting from human
pollution [67]. Satellite images clearly show particulate matter from both anthropogenic and natural
sources in industrialized and heavily populated parts of the world (Figure 24 a-d) [183].
Atmospheric aerosols are monitored worldwide via satellites, and several years worth of measured
global aerosol maps are available from NASA's MISR (Figure 24 e) [184]. Global aerosol data is
measured by imaging sequential columns through the atmosphere below the satellite as it orbits the
earth, in each of 4 wavelengths (blue, green, red, and near-infrared). These measures also give some
indication of particle size and shape, from the variation in scene brightness over several different
view angles and wavelengths. The MISR results distinguish desert dust from pollution and forest
fire particles: desert dust particles and sea salt are usually larger than aerosols originating from the
processes of combustion e.g. forest fires and burning of fossil fuels. MISR can help to determine
ground-level pollution concentrations necessary in understanding and assessing links between
pollution exposure and human health. A full assessment of the impact of pollution aerosol exposure
will require records of aerosol mapping for several decades - the typical timescale of pollutionlinked disease appearance.
3.4.4. Health effects associated to air pollution

Human exposure to inhaled ambient particles can have adverse health effects [19], [117], [158],
[185], [186]. Pulmonary and cardiovascular diseases result when inhaled particles interfere with the
normal function of bodily systems [48], [187], [188]. The health consequences of particle inhalation
vary greatly with particle composition, concentration, etc., from benign candle wax to carcinogenic
asbestos, or tobacco smoke.
As our understanding of nanoparticles has grown, so has our knowledge of disease resulting
from their exposure. Until recently it was believed that particles 10 microns or smaller were
responsible for disease resulting for particle pollution. But further study has shown that most of
these diseases are caused by particles smaller than 100 nm, similar in size to viruses. Nanoparticles
seem to be generally more toxic than microparticles, primarily do to their ability to penetrate living
cells, translocate within the body, and affect the function of major organs.
Cardiovascular diseases. The correlation between ambient particles exposure and heart disease
was accepted in the mid-nineties, when it was observed that hospital admission for cardiovascular
illness increased on days with high concentrations of particles [189]. Atmospheric particle pollution
from automobile exhaust seems to have a major influence on mortality, with a strong association
between increased cardiopulmonary mortality and living near major roads [117]. The risk of
myocardial infarction onset increases with elevated concentrations of particulate matter smaller than
2.5 m in the day before onset and with volume of vehicular traffic. Cardiovascular diseases and
effects associated with particulate pollution include: ischemic heart disease, hypertensive heart
48
disease [190], arrhythmia, heart failure, arteriosclerosis, brachial artery vasoconstriction, and
increased blood pressure in subjects with lung disease [117].
Respiratory illnesses. Pneumonia, bronchial asthma, chronic bronchitis, emphysema, lung
cancer, acute deterioration of lung function, and hospital admissions for respiratory illnesses were
all found to increase with higher levels of pollution [191], [192].
Malignant tumors. An epidemiological study researching the effects of chronic exposure to
particulate matter smaller than 10 m in nonsmoking subjects revealed a high incidence of lung
cancer [193]. This study also showed an 8% increase in risk of lung cancer for each 10 g/m3
increase in particulate matter smaller than 2.5 m [190]. To some surprise, levels of particulate
matter smaller than 2.5 m pollution were also found to correlate significantly with cancers of the
breast, endometrium, and ovary [192], an effect that might be explained by recent studies of
nanoparticles translocation to organs. Childhood cancers were also found to be strongly determined
by prenatal or early postnatal exposure to oil-based combustion gases, primarily engine exhaust
[118].
Mortality and morbidity. There is compelling evidence of correlation between particle
pollution levels on a given day, and overall mortality the following day [117], [158].
Epidemiological studies have shown that the increased morbidity and mortality, correlated with
increased particle pollution, are frequently the result of respiratory problems [97], but primarily due
to cardiovascular diseases [158], [194]. In 1998 it was estimated that around 4000 deaths were
related to atmospheric pollution in Canada. These deaths occur mainly in heavily industrialized
urban centers [158].
Analysis of mortality statistics for approximately 500,000 adults residing in the United States of
America covering a 16 year period of chronic exposure to air pollutants shows that cardiovascular
deaths increased by 0.69% for each 10 g/m3 increase in particulate matter [117], [190]. The study
found a strong correlation between a cause of death of either cardiopulmonary disease or lung
cancer, and levels of particulate matter smaller than 2.5 m [190].
Figure 25 shows the correlation of mortality rates with extreme levels of pollution during
London smog episodes of the 1950s through the 1970s [20]. The exposureresponse observations
of daily mortality exhibit two distinct regions, with a steeper slope at lower mass concentrations and
a shallower slope at higher. It has been suggested that a high concentration of aerosol nanoparticles
would promote particle aggregation [145]. Aggregation of nanoparticles at high particle
concentrations reduces toxicity by decreasing the reactive surface area and possibly limiting the
translocation of the particles.
Postneonatal infant mortality and birth defects. Positive associations between exposure to
particles and selected birth defects (such as atrial septal defects) were reported in studies in various
countries [195], [196]. It was found that outdoor air pollution above a reference level of 12.0 g/m3
of particulate matter smaller than 10 m contributes substantially to postneonatal infant mortality in
infants born with a normal birth weight [197].
Exacerbation of pre-existing diseases and other risks. Certain segments of the population
appear to be at greater risk to the toxic effects of particulate pollution. Patients suffering of various
diseases, such as: diabetes, chronic pulmonary diseases, heart diseases, or with previous myocardial
infarction are likely to suffer an increase in the severity of symptoms on days with high levels of
pollutants [48], [117]. In addition, the presence of inflammation may enhance the translocation of
nanoparticles into circulation [30], [255], [256], [259], [266], or via blood-brain-barrier [18], [203].
Cumulative exposure In addition to immediate effects, time-series studies have shown
cumulative effects over weeks, associated with elevated particle concentrations [48]. Further studies
are needed to assess the health effects of chronic exposure to nanoparticles.
49
Figure 25. Correlation between daily mortality rate and urban particle concentrations during the
London smog episodes in the winters of 1958-1972 (data from [198]). Also shown are the regression
lines for the steep and shallow slopes together with the inflection point at ~125 g/m3 (after [20]).
Treatment. Ambient particles induce oxidative stress in biological systems, either directly by
introducing oxidant substances, or more indirectly by supplying soluble metals, including transition
metals, that shift the redox balance of cells toward oxidation. Oxidative stress is believed to be the
primary mechanism by which nanoparticles generate disease. Consequently, dietary nutrients that
play a protective role in the oxidative process are suggested as potential mitigators of the toxic
effects of nanoparticle pollution. Antioxidant vitamins (such as vitamin C) have a protective effect
against lung diseases, and a high intake of fresh fruit and some vegetables appears to have a
beneficial effect on overall lung health [199] perhaps due to reducing the toxic effects of
environmental nanoparticles. Treatment of underlying health conditions also reduces the impact of
air pollution [199].
4. Nanotoxicology - toxicology of nanoparticles

4.1. Respiratory tract uptake and clearance
4.1.1. Particle size dependent inhalation
After inhalation, nanoparticles deposit throughout the entire respiratory tract, starting from nose
and pharynx, down to the lungs [37], [200]. Lungs consist of airways, that transport air in and out,
and alveoli, which are gas exchange surfaces, as shown in Figure 26 c, d. Human lungs have an
internal surface area between 75-140 m2 and about 300 million alveoli [30]. Due to their large
surface area, the lung is the primary entry portal for inhaled particles.
Spherically-shaped solid material with particle diameters smaller than 10 microns can reach the
gas exchange surfaces (Figure 26 d) [30], [37]. Larger diameter particles tend to be deposited
further up in the respiratory tract as a result of gravitational settling, impaction, and interception
[201]. Many larger-diameter fibers are deposited at saddle points in the branching respiratory
tree. Smaller diameter particles are more affected by diffusion and these can collect in the smaller
airways and alveoli. Fibres having a small diameter may penetrate deep into the lung, though very
long aspect ratio fibres will remain in the upper airways [30].
50
Figure 26. (a) SEM image of lung trachea epithelium, showing cilia (mucociliary escalator), courtesy
Louisa Howard. (b) Human alveolar macrophage (center, yellow) phagocytosis of Escherichia coli
(multiple ovoids, green), together with a red blood cell (red). Dr. Dennis Kunkel/Visuals Unlimited,
reproduced with permission from Visuals Unlimited [25]. (c), (d) Alveoli in the lung. Dr. David M.
Phillips/Visuals Unlimited, reproduced with permission from Visuals Unlimited [25]. (e) Deposition of
inhaled particles in the human respiratory tract versus the particle diameter, after [37].
51
As shown in Figure 26 e, the nasopharyngeal region captures mainly microparticles and

nanoparticles smaller than 10 nm, while the lungs will receive mainly nanoparticles with diameter
between 10 20 nm [37].
4.1.2. Upper airway clearance mucociliary escalator

Pulmonary retention and clearance of particles has been under study for many years. The
nineteen-fifties were marked by a great interest in pneumoconiosis and studies of the effects of
inhalation of radioactive particles, while in the nineties studies of occupational and environmental
particles generated a considerable amount of knowledge regarding the adverse health effects of
nano and microparticles in the respiratory tract [36].
The clearance of deposited particles in the respiratory tract is by physical translocation to other
sites, and chemical clearance. Chemical dissolution in the upper or lower respiratory tract occurs for
biosoluble particles in the intra-cellular or extra-cellular fluids, and will not make the subject of
further discussions in this review. Non-soluble particles will undergo a different much slower
clearance mechanism that we will discuss further in detail later. For relatively insoluble particles,
the elimination process is very slow in comparison to soluble nanoparticles [145].
In the upper airways, particle clearance is performed mainly by the mucociliary escalator [36].
The first contact of inhaled nanoparticles in the respiratory tract is with the lining fluid, composed
of phospholipids and proteins [202]. This contact leads to particle wetting and displacement towards
the epithelium by surface forces from the liquid-air interface [203]. When in contact with
esophageal epithelial cells, nanoparticles uptake by these cells is possible in the presence of preexistent inflammation [204]. The cilia of the bronchial epithelial cells (Figure 26 a) move the
covering mucous layer, including particles, away from the lungs and into the pharynx, a process
generally requiring up to several hours. The nanoparticles that are cleared from the lung via the
mucociliary escalator enter the gastro-intestinal tract [145], [206]. The clearance from the gastrointestinal tract will be discussed in chapter 4.7. The mucus layer contains protective antioxidants,
which can become depleted when a large number of oxidative compounds are inhaled [202].
4.1.3. Lower airways clearance phagocytosis and passive uptake

Phagocytosis. Particles smaller than 10 microns can reach the lower airways [207]. Particle
clearance from the lungs alveoli occurs primarily through macrophage phagocytosis. Macrophages
are cells that act as vehicles for the physical removal of particles from alveoli to the mucociliary
escalator or across the alveolar epithelium to the lymph nodes in the lung or to those closely
associated with the lungs [203]. When the lung is subject to prolonged exposure, white blood cells
from the circulatory system (neutrophils) are recruited to help.
Phagocytes engulf and break down pathogenic microorganisms, damaged or apoptotic cells, and
inert particles [209]. In addition to the professional cleaners, phagocytes (neutrophils and
monocyte/ macrophages, see Figure 26 b), most cells also have some phagocytic ability [209]. The
main difference between the phagocytic ability of professional and non-professional phagocytes is
related to the presence of dedicated receptors able to recognize molecules pertaining to pathogens,
molecules very different from those found in the human body [209]. Phagocytosis is a very complex
mechanism due to the diversity of receptors, its understanding requiring thorough knowledge of
chemical processes at molecular level. Many phagocytic receptors serve a dual function, adhesion
and particle internalization [209]. The phagocytosis of particles is more effective if the particles are
52
labeled with special molecules (such as antibodies or complement molecules) able to speed-up
phagocytosis, a labeling process called opsonisation. Opsonins are present in the lung-lining fluid
[207]. Hydrophobic particles will be readily coated by opsonins and subsequently available for
phagocytosis [208]. Coating of particles with hydrophilic polymers, such as polyethylene glycol,
diminishes the opsonisation of particles, consequently decreasing the probability of being
phagocytized [208]. However, unopsonized particles are nevertheless eventually phagocytized by
macrophages [210].
Phagocytosis takes up to several hours and involves several steps:
1) First, specific receptors on the phagocyte membrane bind with specific molecules (ligands)
localized on the surface of particle [209], [210]. Older studies suggest that the opsonisation with
complement protein 5a may be responsible for the chemotactic (pertaining to the movement of a
cell in a direction corresponding to a concentration gradient of a chemical substance) signal of
nanoparticles [20], while newer studies propose the electric charge may play a role in activating the
scavenger-type receptors for certain type of nanoparticles (such as: titanium dioxide, iron oxide,
quartz) [211]. For uncharged nanoparticles, such as carbon based (diesel exhaust), some authors
suggest that toll-like receptors are responsible for the recognition of these nanoparticles (as well as
bacteria, virus, and fungi) [212].
2) After the binding of the phagocyte receptor with a ligand, the cytoskeleton (a network of
protein filaments) of the phagocyte rearranges, resulting in pseudopod formation, and ultimately
leading to internalization of the particle with the formation of a phagocytic vesicle (phagosome)
[213].
3) The phagosome fuses with a lysosome (an organelle containing digesting enzymes), forming a
phagolysosome. The fusion process can take from 30 minutes up to several hours, depending on the
chemical interaction between the surface of the particle and the phagosome membrane [209].
Lysosoms release protease (which break down proteins) and NADPH oxidase (oxygen radicals)
[213]. This process assists in the chemical dissolution of the particle [213]. Depending on the type
of receptor used in the detection of the particle, macrophages may also release intercellular
chemical messengers alerting the immune system that an infection is present.
4) If the particle is digested by lysosome enzymes, the residues are removed by exocytosis
(release of chemical substances into the environment). If not, phagocytosis is followed by gradual
movement of macrophages with internalized particles towards the mucociliary escalator, a process
that can last up to 700 days in humans [20]. If the macrophage is unable to digest the particle and
the particle produces damage to phagosomal membrane due to peroxidation, the oxidative
compounds will likely interact with macrophages cytoskeleton, and lead to reduced cell motility,
impaired phagocytosis, macrophage death [214], and ultimately reduced clearance of particles from
the lung [215]. Macrophage death can lead to release of oxidative lysosome compounds outside the
cells. If particles cannot be cleared they can kill successive macrophages attempting to clear them,
and create a source of oxidative compounds, and inflammation with macrophage debris
accumulation (pus). Oxidative stress is associated to various diseases, such as cancer,
neurodegenerative, and cardiovascular diseases.
This mechanism of alveolar clearance is not perfect, as it allows smaller nanoparticles to
penetrate the alveolar epithelium and reach the interstitial space [20]. From the interstitial space
nanoparticles may enter the circulatory and lymphatic systems and reach other sites throughout the
body [24], [145].
Phagocytosis occurs in different areas of the body, phagocytes present in lungs, spleen, liver,
etc., having different names, according to their location, such as alveolar macrophages, splenic
macrophages, Kupfer cells, respectively [82].
53
4.1.4. Nanoparticle size dependent phagocytosis

Human alveolar macrophages measure between 14 to 21 m, while rat alveolar macrophages
measure between 10 to 13 m [38]. Macrophages can engulf particles of a size comparable to their
own dimensions, but are significantly less effective with particles that are much larger or smaller.
Experimental data show that, compared with larger particles, nanoparticles smaller than 100-200
nm are more capable of evading alveolar macrophages phagocytosis [203], entering pulmonary
interstitial sites, and interacting with epithelial cells to get access to the circulatory and lymphatic
systems [20], [145].
There are contradictory reports related to the phagocytosis of nanoparticles smaller than 100 nm.
In vitro studies show that nanoparticles activate, and are phagocytized by alveolar macrophages
[20]. However, macrophage lavage recovery studies show that nanoparticles smaller than 100 nm
are not efficiently phagocytized in comparison with particles between 1-3 m [20], [145]. A twelveweek inhalation study in rats showed that 20 nm nanoparticles of titanium dioxide are characterized
by longer retention time in the lungs and increased translocation to interstitial sites than larger
nanoparticles (250 nm) of the same material [216]. Small nanoparticles that evade the alveolar
macrophages penetrate the alveolar epithelium, resulting in a slower clearance rate from the lung
and possibly later translocation to the circulatory and lymphatic system.
4.1.5. Concentration dependent phagocytosis

At high concentrations, nanoparticles tend to cluster, forming aggregates often larger than 100
nm. Larger nanoparticles (>100 nm) can be readily phagocytized by alveolar macrophages [145],
[217]. Results of studies involving inhalation or intratracheal instillation of high concentrations of
nanoparticle (silver, iron, India ink, or titanium dioxide) smaller than 100 nm, which aggregate in
larger particles, suggest that most nanoparticles are indeed stopped by alveolar macrophages [145].
Rat studies based on inhalation of low concentrations of 15 nm diameter silver nanoparticles
showed that soon after inhalation (30 minutes), nanoparticles are distributed in the blood and brain,
and subsequently to organs, such as heart, kidney, while the lungs rapidly cleared of the
nanoparticles [145]. Hence, minute concentrations of nanoparticles with size smaller than 100 nm
can have a higher probability of translocating to the circulatory system and organs (and produce
damage) than high concentrations of the same particles, which are likely to form aggregates, and
which will be stopped from translocation by macrophage phagocytosis.
4.1.6. Lung burden

Insoluble particle burden in the lung can induce a range of toxicological responses differing from
those due to soluble particles [39]. Particles that are soluble or partly soluble (for example, cement)
will dissolve in the aqueous fluid lining the epithelium (and pass into the circulatory and lymphatic
systems), while the insoluble ones (such as carbon black) must be removed through other
mechanisms such as the mucociliary escalator. Particles that are not soluble or degradable in the
lung will rapidly accumulate upon continued exposure, as shown in Figure 27 for carbon black,
asbestos, multiwall carbon nanotubes, and grounded carbon nanotubes [159]. If the macrophage
clearance capacity is exceeded, then the lung defense mechanisms are overwhelmed, resulting in
injury to the lung tissue.
54
Figure 27. Rat lung lesions induced by nanoparticles of: (B,G,L) carbon black, (C,H,M) asbestos,
(D,I,N) multiwall carbon nanotubes, and (F,J,O) grounded nanotubes compared to saline solution
(A,F,K) [159]. Reproduced with permission from Elsevier.
The adverse effect of inhaled nanoparticles on the lungs depends on the lung burden (determined
by the rate of particle deposition and clearance) and on the residence time of the nanoparticles in the
lung [39], [203]. For example, carbon nanotubes are not eliminated from the lungs or very slowly
eliminated (81% found in rat lungs after 60 days) [159]. The persistent presence within the alveoli
of inhaled particles (Figure 27), especially those with mutagenic potential, increases the risk of lung
cancer [39].
4.1.7. Translocation and clearance of inhaled nanoparticles
Inhaled nanoparticles are shown to reach the nervous system via the olfactory nerves [18], [20],
[218], and/or blood-brain-barrier [18], [203]. Nanoparticles that reach the lung are predominantly
cleared via: mucociliary escalator into the gastrointestinal tract (and then eliminated in the feces)
[206], lymphatic system [219], and circulatory systems [20]. From the lymphatic and circulatory
systems, nanoparticles may be distributed to organs, including kidneys from where partial or total
clearance may occur.
4.1.8. Adverse health effects in the respiratory tract.
Adverse health effects. Recent research has lead to changes in terminology and brought about
the realization that no particles are completely inert, and that even low concentrations of particles
can have negative health effects [36]. The adverse health effects of nanoparticles depend on the
residence time in the respiratory tract [203]. Smaller particles have a higher toxicity than larger
particles of the same composition and crystalline structure, and they generate a consistently higher
inflammatory reaction in the lungs [216]. Smaller nanoparticles are correlated with adverse
reactions such as: impaired macrophage clearance, inflammation, accumulation of particles, and
epithelial cell proliferation, followed by fibrosis, emphysema, and the appearance of tumors [36],
55
[39], [216], [220-222]. Particle uptake and potential health effects may be dependent on genetic
susceptibility and health status [206].
Recent research has demonstrated that nanoparticles inhalation can affect the immune system
defense ability to combat infections [223]. Nanoparticles of various compositions are able to
modulate the intrinsic defensive function of macrophages, affecting their reactivity to infections. It
was found that several types of nanoparticles (such as ZrO2) enhance the expression of some viral
receptors, making macrophages exposed to nanoparticles hyper-reactive to viral infections and
leading to excessive inflammation [223]. On the other hand, exposure to other nanoparticles (SiO2,
TiO2) leads to a decrease in the expression of some other viral and bacterial receptors, leading to
lower resistance to some viruses or bacteria.
Adaptability. Organisms are capable of adapting to specific environmental stresses. Recent
studies suggest that pre-exposure to low concentrations of nanoparticles stimulates the phagocytic
activity of cells, while high concentration of nanoparticles impairs this activity [224], [225]. At the
same time, genotype is an important factor in adaptability [226].
Treatment. Treatments for nanoparticles inhalation include those that act to enhance
mucociliary clearance, and those that reduce the effects of oxidation and inflammation. Mucociliary
clearance can be enhanced two fold by inhalation of increasing concentrations of saline solutions
[227]. The saline solution acts as an osmotic agent increasing the volume of airway surface liquid.
Anti-inflammatory medicine (sodium cromoglycate) was found to strongly reduce airway
inflammation caused by diesel exhaust nanoparticles [117]. Sodium cromoglycate works by
reducing allergic responses (inhibits the release of mediators from mast cells - cells responsible for
the symptoms of allergy). Antioxidant vitamins (particularly vitamin C) [199], rosmarinic acid [46],
and a high intake of fresh fruit and some vegetables have a protective effect against lung diseases
[199].
In order to better understand the adverse health effects and possible treatment of inhaled
nanoparticles, the next chapter explores the biological interaction of nanoparticles at a cellular level.
4.2. Cellular interaction with nanoparticles
4.2.1. Cellular uptake
Like nanoorganisms (viruses), nanoparticles are able to enter cells and interact with subcellular
structures. Cellular uptake, subcellular localization, and ability to catalyze oxidative products
depend on nanoparticle chemistry, size, and shape [228]. The mechanism by which nanoparticles
penetrate cells without specific receptors on their outer surface is assumed to be a passive uptake or
adhesive interaction. This uptake may be initiated by Van der Waals forces, electrostatic charges,
steric interactions, or interfacial tension effects, and does not result in the formation of vesicles
[203], [229]. (Steric interactions occur when nanoparticles have molecules with size, geometries,
bondings, and charges optimized for the interaction with the receptors.) After this type of uptake,
the nanoparticles are not necessarily located within a phagosome (which offers some protection to
the rest of the cellular organelles from the chemical interaction with the nanoparticle). For example
C60 molecules enter cells and can be found along the nuclear membrane, and within the nucleus
[214]. This type of uptake and free movement within the cell makes them very dangerous by having
direct access to cytoplasm proteins and organelles. Upon non-phagocytic uptake, nanoparticles can
be found in various locations inside cell, such as the outer-cell membrane [133], [230], cytoplasm
[133], [230], mitochondria [57], [228], lipid vesicles [116], [230], along the nuclear membrane
[133], or within the nucleus [228], [230]. Depending on their localization inside the cell, the
nanoparticles can damage organelles or DNA, or ultimately cause cell death.
56
Nanoparticles are internalized not only by professional phagocytes such as alveolar macrophages
[30], [145], [228], but by various types of cells, including endothelial cells [230], pulmonary
epithelium [142], [231-236], gastrointestinal epithelium [204], red blood cells [203], [237], platelets
[238], and nerve cells [239].
Particle internalization location depends on nanoparticle size. For example, environmental
particles with size between 2.5 - 10 m were found to collect in large cytoplasmic vacuoles (Figure
28 c, d), while smaller nanoparticles (<100 nm) localize in organelles, such as mitochondria (Figure
28 e, f), leading to disruption of mitochondrial architecture [57]. Very small nanoparticles, such as
C60 molecules with a diameter of 0.7 nm, are able to penetrate cells via a different mechanism than
phagocytosis, probably through ion channels or via pores in the cell membrane [214].
Figure 28. TEM images showing effects of environmental particles size (P) on murine macrophage cells
RAW 264.7 treated with various size particles: (a,b) untreated, (c,d) 2.5 - 10 m size particles, (e,f)
particles smaller than 100 nm. M denotes mitochondria [57]. Reproduced with permission from
Environmental Health Perspectives.
57
Uptake location is likely to depend on material type, however current research does not provide
sufficient information to drawing conclusions on this subject.
4.2.2. Oxidative stress, inflammation, and genotoxicity
While the exact mechanism whereby nanoparticles induce pro-inflammatory effects is not known, it
has been suggested that they create reactive oxygen species (ROS), and thereby modulate
intracellular calcium concentrations, activate transcription factors, and induce cytokine production
[240]. Below we outline in a very simplified and schematic depiction the current understanding of
these very complex cellular mechanisms.
Oxidative stress generation. Both in vivo and in vitro studies have shown that nanoparticles of
various compositions (fullerenes, carbon nanotubes, quantum dots, and automobile exhaust) create
reactive oxygen species [20]. Reactive oxygen species have been shown to damage cells by
peroxidizing lipids, altering proteins, disrupting DNA, interfering with signaling functions, and
modulating gene transcription [240].
Oxidative stress is a response to cell injury, and can also occur as an effect of cell respiration,
metabolism, ischemia/reperfusion, inflammation, and metabolism of foreign compounds [46].
The oxidative stress induced by nanoparticles may have several sources [46]:
(i) Reactive oxygen species can be generated directly from the surface of particles when both
oxidants and free radicals are present on the surface of the particles. Many compounds hitch-hiking
on the surface of nanoparticles (usually present in ambient air) are capable of inducing oxidative
damage, including ozone (O3) and NO2.
(ii) Transition metals (iron, copper, chromium, vanadium, etc.) nanoparticle can generate
reactive oxygen species acting as catalysts in Fenton type reactions [46]. For example, the reduction
of hydrogen peroxide ( H2O2 ) with ferrous iron ( Fe2+ )
"
O2
+ H2O2 ##$OH + OH " + O2

Fe
results in the !formation of hydroxyl radical

( OH ) that is extremely reactive, attacking biological
!
molecules situated within diffusion range [46].
(iii) Altered functions
! of mitochondrion. As shown in several studies, small nanoparticles are
able to enter mitochondria [57], [228]!and produce physical damage, contributing to oxidative stress
[24].
(iv) Activation of inflammatory cells, such as alveolar macrophages and neutrophils, which can
be induced by phagocytosis of nanoparticles, can lead to generation of reactive oxygen species and
reactive nitrogen species [46], [241]. Alveolar macrophages participate in the initiation of
inflammation in the lung (see paragraph 4.1.3).
Nanoparticles have been shown to generate more free radicals and reactive oxygen species than
larger particles, likely due to their higher surface area [24], [231], [242].
Inflammation. Inflammation is the normal response of the body to injury. When generated in
moderation, inflammation stimulates the regeneration of healthy tissue, however when in excess, it
can lead to disease [49]. In vitro and in vivo experiments demonstrate that exposure to small
nanoparticles is associated with inflammation, with particle size and composition being the most
important factors [46]. Inflammation is controlled by a complex series of intracellular and
extracellular events. The oxidative stress results in the release of pro-inflammatory mediators or
cytokines - intercellular chemical messengers alerting the immune system when an infection is
present [215], [241]. Some nanoparticles can produce cell death via mitochondrial damage without
inflammation [228].
Antioxidants. The oxidative stress also results in the release of antioxidants - proteins that act to
58
remove the oxidative stress [46], [49]. In addition to the antioxidants released as a response to the
oxidative process, nanoparticles may interact with metal-sequestering proteins and antioxidants
(from body fluids and intracellularly), that will likely modify the surface properties of the
nanoparticle to some extent, rendering them less toxic [46].
DNA damage. Generation of reactive oxygen species to the point that they overwhelm the
antioxidant defense system (shifting the redox balance of the cell) can result in oxidation, and
therefore destruction, of cellular biomolecules, such as DNA, leading to heritable mutations [46],
[203]. For example, the chemical modification of histones (or binding proteins that support the
supercoiled structure of DNA) opens the coiled DNA and allows its alteration [49].
Epidemiological, in vitro and in vivo studies show that nanoparticles of various materials (diesel,
carbon black, welding fumes, transition metals) are genotoxic in humans or rats [41]. Oxidative
DNA damage markers showed higher levels on workdays for bus drivers from central areas
compared to bus drivers from suburban/rural areas of Copenhagen [46]. Nasal biopsies from
children living in Mexico City showed greater DNA damage compared to children living on less
polluted areas [46].
A general schematic, of the molecular events by which nanoparticles exert their toxic effects at
the cellular level, is given in Figure 29. In summary, nanoparticles can directly generate reactive
oxygen species on the their surfaces or by activation of macrophages [20], [46], [241]. Overall, the
generation of oxidative species leads to increased inflammation [215], [241], and increased
antioxidant production [49]. The activation of macrophages leads to modulation in intracellular
calcium concentration, that in turn activates further the reactive oxygen species production, which
in turn enhances further calcium signaling by oxidation of calcium pumps in the endoplasmic
reticulum, leading to calcium depletion [46], [240], [243]. Intracellular calcium modulation results
in impaired motility and reduced macrophage phagocytosis [46]. Non-phagocytized nanoparticles
are likely to access and interact with epithelial cells [46], thus enhancing inflammation. Ultimately,
the interaction of nanoparticles with cells may lead to DNA modifications, cell injury, and disease
[49].
Figure 29. Schematics of the molecular events by which nanoparticles exert their toxic effects at the
cellular level.
59
Figure 30. (a) Head MRI image. Courtesy of United States National Library of Medicine, National
Institute of Health. (b) MRI. Courtesy of National Institute of Neurological Disorders and Stroke.
4.2.3. Adverse health effects and treatment

Nanoparticles, due to their small size, can influence basic cellular processes, such as
proliferation, metabolism, and death. Many diseases can be associated with dysfunction of these
basic processes. For example, cancer results from uncontrolled cell proliferation, while
neurodegenerative diseases are caused in part by premature cell death [148]. Oxidative stress has
been implicated in many diseases, including cardiovascular and neurological disease, pancreatitis,
and cancer [46]. Severe inflammation is assumed to be the initiating step [50] in the appearance of
autoimmune diseases (systemic lupus erythematosus, scleroderma, and rheumatoid arthritis)
associated with exposure to some nanoparticles, such as silica and asbestos [172], [176].
Regarding the treatment of adverse health effects caused by nanoparticles cytotoxicity,
antioxidants [24], [49], [61], [62], [199], anti-inflammatory drugs [117], [244], and metal chelators
[240], [245] show promising effects. It has been reported that rats that underwent instillation of
nanoparticles into the lungs together with an antioxidant (nacystelin) showed inflammation reduced
by up to 60% in comparison to those exposed to nanoparticles alone [49]. Antioxidant therapy has
been found to protect against the development of hypertension, arteriosclerosis, cardiomyopathies,
and coronary heart disease [24], providing further evidence of the link between the oxidative stress
response and cardiovascular effects. The adverse health effects of transition metals can be
diminished by metal chelators [240].
4.2.4. Non-invasive terminology to be questioned

The process of nanoparticle uptake by cells is clinically used today in targeted drug delivery and
cell imaging (Figure 30). The safety of these techniques, however, depends on cellular uptake of
nanoparticles without affecting normal cellular function. Cellular imaging techniques are currently
named non-invasive techniques [246], [247], which means non-penetrating, however they should
perhaps be relabeled as minimally-invasive, given that the nanoparticles enter the cells and are
likely to affect cellular functions. Iron oxide and other magnetic nanoparticles have been used for
many years as magnetic resonance imaging (MRI) contrast agents. Depending on their size and
coating, MRI nanoparticles can localize in liver, spleen, lymph nodes, etc [246]. Some nanoparticles
were found to be teratogenic (causing birth defects) in rats and rabbits [246]. Minor side effects of
60
contrasting agents are nausea, vomiting, hives, and headache [248]. More serious adverse reactions
involving life-threatening cardiovascular and respiratory reactions are possible in patients with
respiratory disorders [248].
4.3. Nervous system uptake of nanoparticles
The nervous system is composed of the brain, spinal cord, and nerves that connect the brain and
spinal cord to the rest of the body. In addition to nanoparticle uptake due to inhalation (discussed
below), nervous system uptake may occur via other pathways (such as dermal). Uptake via
olfactory nerves and the blood-brain-barrier are the most studied pathways.
Figure 31. (a) Schematics of the nanoparticles neuronal uptake via olfactory bulb and blood-brain
barrier. (b) Cortical neurons (nerve cells) growing in culture. Neurons have a large cell body with
several long processes extending from it, usually one thick axon and several thinner dendrites. The axon
carries nerve impulses away from the neuron. Its branching ends make contacts with other neurons and
with muscles or glands. Dr. Dennis Kunkel / Visuals Unlimited. Reproduced with permission from
Visuals Unlimited [25]. (c) TEM images of iron accumulation in the brain of neurologically affected
patients. Iron is stored in ferittin, Ft, a protein involved in excess iron storage [171]. Reproduced with
permission from Elsevier.
61
4.3.1. Neuronal uptake via olfactory nerves

Neuronal uptake (Figure 31 a) of inhaled nanoparticles may take place via the olfactory nerves
[18], [20], [218] or/and blood-brain-barrier [18], [203].
The nasal and tracheo-bronchial regions have many sensory nerve endings [20]. As
demonstrated several decades ago with polio viruses (30 nm) and silver coated gold nanoparticles
(50 nm) in monkeys, intranasally instilled viruses and particles migrate to the olfactory nerves and
bulb with an axonal transport velocity of about 2.5 mm/hr [20]. The silver coated gold nanoparticles
that reached the olfactory bulb were preferentially located in mitochondria [20], raising a major
concern of their toxicity. More recent studies confirm the uptake of inhaled nanoparticles from
olfactory mucosa via the olfactory nerves in the olfactory bulb [18], [20], [218], [239]. For example,
rat inhalation studies with 30 nm magnesium oxide [200] and 20-30 nm carbon [239] nanoparticles
indicate that nanoparticles translocate to the olfactory bulb [200]. If inhalation occurred via one
nostril only, the accumulation was observed only in the side of the open nostril [20]. Experiments
show that microparticles with diameter larger than a micron do not cross the olfactory nerve, as
expected from the geometrical restrictions imposed by the diameter of the olfactory axons of only
100-200 nm (Figure 31 a) [20]. Translocation of nanoparticles into deeper brain structures may be
possible [145], as suggested by the movement of viruses through neurons [20].
4.3.2. Neuronal uptake via blood-brain-barrier

The passage of nanoparticle to the nervous system is also possible via the blood-brain-barrier
(Figure 31 a). The blood-brain-barrier is a physical barrier with negative electrostatic charge
between the blood vessels and brain [249], selectively restricting the access of certain substances
[18]. This anionic barrier is believed to stop most anionic molecules, while the cationic molecules
increase the permeability of the blood-brain-barrier by charge neutralization [18]. This route has
been extensively studied for the purpose of drug delivery to the brain [18], [249]. Regarding the
passage of nanoparticles, the blood-brain-barrier permeability is dependent upon the charge of
nanoparticles [249]. It allows a larger number of cationic nanoparticles to pass compared to neutral
or anionic particles, due to the disruption of its integrity [249]. As shown by magnetic resonance
imaging (MRI) with magnetic nanoparticles, the blood-brain-barrier in healthy subjects stops some
proteins and viruses present in the brain vascular system from translocating to the brain [18].
However, subjects with specific circulatory diseases (like hypertension) [18], brain inflammation
[18], respiratory tract inflammation (increased levels of cytokines that cross blood-brain-barrier and
induce inflammation) [203] may have increased blood-brain-barrier permeability, which will allow
nanoparticles access to the nervous system.
4.3.3. Adverse health effects of neuronal nanoparticles uptake and treatment

Experimental evidence suggests that the initiation and promotion of neurodegenerative diseases,
such as Alzheimers disease, Parkinsons disease, Picks disease, are associated with oxidative
stress and accumulation of high concentrations of metals (like copper, aluminum, zinc, but
especially iron) in brain regions associated with function loss and cell damage [245], [250]. Iron is
necessary in many cellular functions, especially in the brain, where it participates in many neuronal
processes. In excess, however, iron is toxic to cells. The brain continuously accumulates iron,
resulting in increased stored iron amounts with the age. In order to prevent its toxicity, organisms
62
developed a way to store excess iron in proteins called ferittin (Ft). Dysfunction of ferittin resulting
from excessive accumulation of iron (Figure 31 b) may lead to oxidative stress and myelin (the
electrically insulating coatings of axons) breakdown [171]. Metal homeostasis imbalance and
neuronal loss are both present in neurodegenerative diseases. (Homeostasis is a dynamic
equilibrium balancing act necessary for a proper function of a living system) It is not known if the
presence of metals in brain of subjects with neurodegenerative diseases is due to nanoparticles
themselves translocating to the brain or their soluble compounds [41].
Despite the fact that the etiology of neurodegenerative diseases is unknown, environmental
factors are believed to play a crucial factor in their progress, being able to trigger pro-inflammatory
responses in the brain tissue [42], [250]. Recent studies on DNA damage in nasal and brain tissues
of canines exposed to air pollutants shows evidence of chronic brain inflammation, neuronal
dysfunction, and similar pathological findings with those of early stages of Alzheimers disease
[203], [251]. Autopsy reports on humans suggest similar results [203]. Significant oxidative damage
was found in the brain of largemouth bass after exposure to C60 [252]. Rat inhalation studies with
stainless steel welding fumes showed that manganese accumulates in blood, liver, and brain [41].
Epidemiological studies show a clear association between inhalation of dust containing manganese
and neurological diseases in miners [170] and welders [148]. Some welders develop Parkinsons
disease much earlier in their life, usually in their mid forties, compared to the sixties in the general
population [148]. Brain inflammation appears to be a cumulative process, and the long-term health
effects may not be observed for decades [203]. Currently there are 1.5 millions peoples suffering
from Alzheimers in the United States of America [203] and an estimated 18 millions worldwide
[253].
Treatment. Antioxidants and metal chelators are treatment options for the adverse health effects
caused by the neuronal uptake of nanoparticles. In the therapy of neurodegenerative diseases,
metals chelators transported across the blood-brain-barrier seem to be a very promising approach
[245]. Functionalized fullerenes [61] and nanoparticles made of compounds holding oxygen
vacancies show great antioxidant properties [62]. Fullerols, or poly-hydroxylated fullerenes, are
excellent antioxidants with high solubility and ability to cross the blood-brain barrier, showing
promising results as neuroprotective agents [61]. CeO2, and Y2O3 nanoparticles have strong
antioxidant properties on rodent nervous system cells [62]. Cerium oxide tends to be nonstoichiometric, Ce atoms having a dual oxidation state, +3 or +4, leading to oxygen vacancies. Dual
oxidation state confers CeO2 and probably Y2O3 nanoparticles antioxidant properties that promote
cell survival under conditions of oxidative stress. It appears that the antioxidant properties depend
upon the structure of the particle but they are independent of its size within 6-1000 nm.
4.4. Nanoparticles translocation to the lymphatic systems

Translocation of nanoparticles to lymph nodes is a topic of intense investigation today for drug
delivery and tumor imaging [219]. Progression of many cancers (lung, esophageal, mesothelioma,
etc.) is seen in the spread of tumor cells to local lymph nodes [219]. The detection and targeted drug
delivery to these sites are the steps involved in the therapeutic treatment of cancer. Several studies
show that interstitially injected particles pass preferentially through the lymphatic system and not
the circulatory system, probably due to permeability differences [219]. After entering the lymphatic
system, they locate in the lymph nodes [219]. The free nanoparticles reaching the lymph nodes are
ingested by resident macrophages [254]. Nanoparticles that are able to enter the circulatory system
can also gain access to the interstitium and from there are drained through the lymphatic system to
the lymph nodes as free nanoparticles and/or inside macrophages [219], [254].
63
The adverse health effects of nanoparticle uptake by lymphatic system are not sufficiently
explored. However, one can hypothesize that oxidative stress created by certain types of
nanoparticles could lead to damage of lymphocytes (type of white blood cell), lymph nodes, and/or
spleen.
4.5. Nanoparticles translocation to the circulatory system

Inhalation or instillation studies in healthy animals show that metallic nanoparticles with size
smaller than 30 nm pass rapidly into the circulatory system [20], [41], [145], [219], [229], while
non-metallic nanoparticles with size between 4 and 200 nm pass very little or not at all [255-259].
In contrast, subjects suffering from respiratory and circulatory diseases have higher capillary
permeability, allowing fast translocation of metallic or non-metallic nanoparticle into circulation
[255], [256], [259].
4.5.1. Long-term translocation

Nanoparticles, unlike larger particles, are able to translocate across the respiratory epithelium
after being deposited in the lungs [20], [229]. Once they have crossed the respiratory epithelium,
they may persist in the interstitium for years, or they may enter the lymphatic system [219] and
circulatory system [145]. From the circulatory system long-term translocation to organs (such as the
liver, heart, spleen, bladder, kidney, bone marrow) is possible, depending on the duration of
exposure [20]. Smaller particles (20 nm) are cleared faster from the lung than larger particles (100
nm), probably because small nanoparticles are not efficiently phagocytized by macrophages and are
able to enter more rapid the circulatory and/or lymphatic systems [145].
4.5.2. Short-term translocation of metals

Evidence of rapid translocation of metal nanoparticles from lungs into the circulation and to
organs has been provided by animal studies. These results show the location of nanoparticles with
diameters of 30 nm (Au) [20], 22 nm (TiO2) [229] in pulmonary capillaries; 15 nm (Ag) [145], and
welding fumes [41] in blood, liver, kidney, spleen, brain, and heart. Animal studies on rats with
inhalation of titanium dioxide nanoparticles (22 nm diameter) show that they can translocate to the
heart and can be found in the heart connective tissue (fibroblasts) [229]. Within 30 minutes post
exposure, large quantities of intratracheally instilled gold nanoparticles (30 nm) have been found in
platelets inside of pulmonary capillaries of rats [20], motivating the hypothesis that nanoparticles
may induce aggregation of platelets, leading to the formation of blood clots. Figure 32 a shows an
electron microscope image of a capillary with red blood cells.
4.5.3. Short-term translocation of non-metals.

There is no conclusive evidence showing fast translocation of carbon-based nanomaterials into
systemic circulation. Short-term translocation of radiolabeled nanoparticles from lungs to the organs
is currently the subject of debate as a significant fraction of radioactive labels detaches from their
labeled nanoparticles, so radioactivity observed throughout the body may not indicate the actual
64
translocation of nanoparticles, but of radiolabels. Technetiums short lived isotope 99mTc, with an
atomic diameter of about 0.37 nm, is used in labeling nanoparticles that are subsequently injected or
inhaled by subjects. In many cases the radiolabel can separate from the nanoparticles and follow a
different translocation route. In the presence of oxygen, the radioactive label can transform into
pertechnetate (99mTcO4-) having a slightly larger diameter of roughly 0.5 nm. Most studies show
very little or no translocation of radiolabeled polystyrene nanoparticles with diameters of 56!nm and
200 nm [255], or carbon nanoparticles with diameters of 5 nm [256], 4-20 nm [257], 35 nm [259],
100 nm [258], while others show a rapid and substantial translocation into circulation for particles
sized 5-10 nm [194], 20-30 nm [239].
While the short-term extra-pulmonary translocation into circulation in healthy subjects is still
under debate, there seems to be agreement on the fact that nanoparticle fast translocation into
circulation may be enhanced by pulmonary inflammation [255], [256], [259], and increased
microvascular permeability [255]. Subjects suffering from respiratory or blood diseases may have
an increased susceptibility of nanoparticles translocation from lungs to circulation and organs.
Figure 32. (a) Red blood cells in a capillary. (b) Platelets, red, and white blood cells. Dr. Dennis
Kunkel/Visuals Unlimited, reproduced with permission from Visuals Unlimited [25]. (c) Particulate
debris entrapped inside the tissue formed around a vena cava filter removed after 156 days in a patient
with blood disease [146]. (d) EDS spectrum showing the composition of the debris shown in (c),
identified as stainless steel [146]. Figures c, d, reproduced from [146] with kind permission of Springer
Science and Business Media.
65
4.5.4. Nanoparticles interaction with and uptake by blood cells

There are three main types of cells in the blood (Figure 32 b): red cells in charge of oxygen
transport; white cells responsible for fighting infections; and platelets that help prevent bleeding by
forming blood clots. The uptake of nanoparticles by each type of blood cells is essentially different.
Nanoparticle uptake by red blood cells (that do not have phagocytic abilities, due to the lack of
phagocytic receptors) is entirely dictated by size [203], while the nanoparticle charge or material
type plays little importance [237].
In contrast, nanoparticle charge plays an essential role in their uptake by platelets and their
influence on blood clot formation [238]. Uncharged polystyrene particles do not have an effect on
blood clots formation. Negatively charged nanoparticles significantly inhibit thrombi formation,
while positively charge nanoparticles enhance platelet aggregation and thrombosis [238]. The
interaction between platelets and positively charged particles seems to be due to the net negative
charge that platelets carry on their surface [238]. The positively charged nanoparticles interact with
negatively charged platelets and reduce their surface charge, making them more prone to
aggregation. Until now it was thought that blood clots can be formed due to three main causes:
when the blood flow is obstructed or slowed down, when the vascular endothelial cells are
damaged, or due to the blood chemistry. However, it seems possible, in the view of recent findings
that nanoparticles may act as nucleating centers for blood clots [146], [260]. It is important to note
that pulmonary instillation of large nanoparticles (400 nm) caused pulmonary inflammation of
similar intensity to that caused by 60 nm particles, but did not lead to peripheral thrombosis [30].
The fact that the larger particles failed to produce a thrombotic effect suggests that pulmonary
inflammation itself is insufficient to cause peripheral thrombosis [30], and that thrombi formation
occur via direct activation of platelets [117], [238].
Microscopic and energy dispersive spectrometry (EDS) analysis of blood clots from patients
with blood disorders revealed the presence of foreign nanoparticles, as shown in Figure 32 c, d. The
blood clots were collected after half a year of wear of vena cava filters implanted in order to prevent
pulmonary embolism in patients affected by blood disorders [146]. Most notably, patients with the
same type of blood disorder show fibrous tissue clots embedding nanoparticle with different
composition: gold, silver, cobalt, titanium, antimony, tungsten, nickel, zinc, mercury, barium, iron,
chromium, nickel, silicon, glass, talc, stainless steel. The common denominator of the particles is
their size, ranging from tens of nanometers to few microns [146].
The uptake of nanoparticles by macrophages (a type of white cell) has already been discussed.
4.5.5. Adverse health effects of circulatory system uptake

Thrombosis. Translocation of nanoparticles into the circulatory system was correlated with the
appearance of thrombi (or blood clots) [117], [238]. The time frame of this process is very short,
thrombosis occurring during the first hour after exposure. Hamster studies of tracheally or
intravenously instilled nanoparticles of charged polystyrene (60 nm) [117] and diesel exhaust
particles (20-50 nm) [117], [261] significantly increased arterial or venous thrombus formation
during the first hour after administration. There is a clear dose-dependent response correlating the
quantity of pollutant administered and the observed thrombus sizes [30], [117]. Prothrombotic
effects persisted 24 h after instillation [30].
If inhaled nanoparticles were to be found in red blood cells located in pulmonary capillaries
[203], one would expect adverse health effects as blood-related diseases, such as anemia, due to
reduced oxygen transport capacity of the red blood cells.
66
Figure 33. Diagram of hypothetical mechanisms and pathways that link nanoparticles in the lung with
adverse cardiovascular effects (modified after [49] and [117]).
Cardiovascular malfunction. It is clear from clinical and experimental evidence that inhalation
of nano and microparticles can cause cardiovascular effects [262]. Despite the fact that there is an
intuitive relationship between inhaled nanoparticles and adverse respiratory effects, the causal link
between particles in the lung and cardiovascular effects is not entirely understood [49]. It was
thought that the pulmonary inflammation caused by the particles triggers a systemic release of
cytokines, resulting in adverse cardiovascular effects. However, recent studies on animals [145],
[263], and humans [194] have shown that nanoparticles diffuse from the lungs into the systemic
circulation, and then are transported to the organs, demonstrating that cardiovascular effects of
instilled or inhaled nanoparticles can arise directly from the presence of nanoparticles within the
organism [188]. Proposed mechanisms of cardiovascular effects are summarized in Figure 33 [49],
[117].
4.6. Liver, spleen, kidneys uptake of nanoparticles

4.6.1. Organs nanoparticles uptake
Endothelial cells (cells that line the vascular system) form a physical barrier for particles, having
very tight junctions, typically smaller than 2 nm [264]. Nevertheless larger values, from 50 nm [51]
up to 100 nm [264] have been reported, depending on the organ or tissue. A very tight endothelial
junction is present in the brain, often called the blood brain barrier. However, experiments
performed on rats injected with ferritin macromolecules (with size around 10 nm) into the
cerebrospinal fluid, demonstrated passage of ferritin into deep brain tissue. In certain organs, such
as liver, the endothelium is fenestrated with pores of up to 100 nm, allowing easier passage of larger
particles (Figure 34 a). In the presence of inflammation the permeability of the endothelium is
increased, allowing a larger passage of particle.
67
Figure 34. (a) Mouse liver with fenestrated hepatic endothelial cells [264]. SEM and EDS spectrum of
particles found in patients with diseased (b) liver and (c) kidneys [265]. Reproduced from [265] with
permission from Elsevier.
Micro and nanoparticle debris was detected by scanning electron microscopy in organs and blood of
patients with: orthopedic implants [265], drug addiction [265], worn dental prostheses [266], blood
diseases [146], colon cancer, Crohns disease, ulcerative colitis [147], and with diseases of
unknown etiology [265]. Coal workers autopsies reveal an increased amount of particles in the liver
and spleen compared to non-coal workers [41]. The workers with pronounced lung diseases have
more nanoparticles in their organs than healthier ones [41]. The pathway of exposure most likely
involves the translocation from lungs to circulation of the inhaled nanoparticles, followed by uptake
by the organs.
Rat inhalation studies with stainless steel welding fumes showed that manganese accumulates in
blood and liver [41]. Rat inhalation studies with 4-10 nm silver nanoparticles show that within 30
minutes the nanoparticles enter the circulatory system, and after a day can be found in the liver,
kidney and heart, until subsequently cleared from these organs after a week [145]. Clearance from
the liver can occur via biliary secretion into the small intestine [267].
A case study shows that the wear of dental bridges leads to the accumulation of wear
nanoparticles in liver and kidneys [266]. The most probable absorption pathway was assumed to be
via intestinal absorption [266]. Scanning electron microscopy and energy-dispersive microanalytical
techniques identified the chemical compositions of particles in the liver and kidney biopsies, as well
in stool, as the same as the porcelain from dental prostheses. The maximum size of particles found
in the liver (20 microns) was larger than in the kidneys (below 6 microns), suggesting that particles
are absorbed by intestinal mucosa, translocate to liver before reaching the circulatory system and
kidneys. After the removal of dental bridges, particles in stool are no longer observed.
4.6.2. Adverse health effects of liver and kidney uptake
Up to now there is little knowledge (or discussion) on the effect of nanoparticles on organs such as
liver, kidneys, spleen, etc. However, one can speculate that as long as there is translocation to and
accumulation of nanoparticles in these organs, potentially adverse reactions and cytotoxicity may
lead to disease.
Diseases with unknown origins have been correlated with the presence of micro- and
nanoparticles in kidneys and liver (Figure 34 b, c) [265]. For comparison, the liver and kidneys of
healthy subjects did not show any debris. Particles debris has been found also in the liver of patients
68
with worn orthopedic prosthesis [265].

Dental prosthesis debris internalized by intestinal absorption can lead to severe health
conditions, including fever, enlarged spleen and liver, suppression of bile flow, and acute renal
failure [266]. These symptoms appeared about a year after the application of dental porcelain
bridges. After the removal of dental bridges, and subsequent treatment with steroids, the clinical
symptoms declined [266].
4.7. Gastro-intestinal tract uptake and clearance of nanoparticles

4.7.1. Exposure sources
Endogenous sources of nanoparticles in the gastro-intestinal tract are derived from intestinal
calcium and phosphate secretion [268]. Exogenous sources are particles from food (such as
colorants titanium oxide), pharmaceuticals, water, or cosmetics (toothpaste, lipstick) [268], dental
prosthesis debris [266], and inhaled particles [145]. The dietary consumption of nanoparticles in
developed countries is estimated around 1012 particles/person per day [252]. They consist mainly of
TiO2 and mixed silicates. The use of specific products, such as salad dressing containing a
nanoparticle TiO2 whitening agent, can lead to an increase by more than 40 fold of the daily average
intake [252]. These nanoparticles do not degrade in time and accumulate in macrophages. A
database of foods and pharmaceuticals containing nanoparticles can be found in reference [268]. A
portion of the particles cleared by the mucociliary escalator can be subsequently ingested into the
gastro-intestinal tract. Also, a small fraction of inhaled nanoparticles was found to pass into the
gastrointestinal tract [145].
4.7.2. Size and charge dependent uptake

The gastro-intestinal tract is a complex barrier-exchange system, and is the most important route
for macromolecules to enter the body. The epithelium of the small and large intestines is in close
contact with ingested material, which is absorbed by the villi (Figure 35).
The uptake of nano- and micro-particles have been the focus of many investigations, the earliest
dating from mid seventeen century, while more recently entire issues of scientific journals have
been devoted to the subject [51]. The extent of particles absorption in the gastro-intestinal tract is
affected by size, surface chemistry and charge, length of administration, and dose [30].
The absorption of particles in the gastro-intestinal tract depends on their size, the uptake
diminishing for larger particles [269]. A study of polystyrene particles with size between 50 nm and
3 m indicated that the uptake decreases with increasing particle size from 6.6% for 50 nm, 5.8%
for 100 nm nanoparticles, 0.8% for 1m, to 0% for 3 m particles.
The time required for nanoparticles to cross the colonic mucus layer depends on the particle size,
with smaller particles crossing faster than larger ones: 14 nm diameter latex nanoparticles cross
within 2 minutes, 415 nm within 30 minutes, and 1000 nm particles do not pass this barrier [30].
Particles that penetrate the mucus reach the enterocytes and are able to translocate further [30].
Enterocyes are a type of epithelial cell of the superficial layer of the small and large intestine tissue,
which aid in the absorption of nutrients. When in contact with the sub-mucosal tissue, nanoparticles
can enter the lymphatic system and capillaries, and then are able to reach various organs [30]
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Figure 35. TEM image of a thin section cut through a segment of human small intestine epithelial cell.
One notices densely packed microvilli, each microvillus being approximately 1 micron long by 100 nm
in diameter. Courtesy of Chuck Daghlian, Louisa Howard, Katherine Connollly [96].
Diseases, such as diabetes, may lead to higher absorption of particles in the gastrointestinal tract
[30]. For example, rats with experimentally induced diabetes had a 100 fold increase in absorption
of 2 m polystyrene particles [30] relative to non-diabetic rats. Also inflammation may lead to the
uptake and translocation of larger particles of up to 20 m [266].
The kinetics of particles in the gastro-intestinal tract depend strongly on the charge of the
particles, positively charged latex particles are trapped in the negatively charged mucus while
negatively charged latex nanoparticles diffused across the mucus layer and became available for
interaction with epithelial cells [30].
Varying the characteristics of nanoparticles, such as size, surface charge, attachment of ligands,
or surfactant coatings, offers the possibility for site-specific targeting of different regions of the
gastro-intestinal tract. The fast transit of material through the intestinal tract (on the order of hours),
together with the continuous renewal of epithelium, led to the hypothesis that nanomaterials will not
remain there for indefinite periods [30]. Most of the studies of ingested nanoparticles have shown
that they are eliminated rapidly: 98% in the feces within 48 hours and most of the remainder via
urine [20]. However, other studies indicate that certain nanoparticles can translocate to blood,
spleen, liver, bone marrow, [269], lymph nodes, kidneys, lungs, and brain, and can also be found in
the stomach and small intestine [270]. Oral uptake of polystyrene spheres of various sizes (50 nm
3 m) by rats resulted in a systemic distribution to liver, spleen, blood, and bone marrow [269].
Particles larger than 100 nm did not reach the bone marrow, while those larger than 300 nm were
absent from blood [269]. In the study no particles were detected in heart or lung tissue. Studies
using iridium did not show significant uptake, while titanium oxide nanoparticles were found in the
blood and liver [20]. For several days following oral inoculation of mice with a relatively
biologically inert nanometer-sized plant virus (cowpea mosaic virus), the virus was found in a wide
variety of tissues throughout the body, including the spleen, kidney, liver, lung, stomach, small
intestine, lymph nodes, brain, and bone marrow [270].
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Figure 36. EDS spectrum and SEMs of particles of different size and morphology in patients with colon
cancer [147]. Particles are composed mainly of (a) calcium and silicon, (b) stainless steel, (c) silver.
Reproduced from [147] with permission from Elsevier.
The exact order of translocation from the gastro-intestinal tract to organs and blood is not
known, however a case study of dental prosthesis porcelain debris internalized by intestinal
absorption suggests that intestinal absorption of particles is followed by liver clearance before they
reach the general circulation and the kidneys [266].
4.7.4. Adverse health effects of gastro-intestinal tract uptake

Reaction reduced toxicity. In the intestinal tract there is a complex mix of compounds,
enzymes, food, bacteria, etc., that can interact with ingested particles and sometimes reduce their
toxicity [30]. It was reported that particles in vitro are less cytotoxic in a medium with high protein
content.
Crohn's disease, ulcerative colitis, cancer. Nanoparticles have been constantly found in colon
tissue of subjects affected by cancer, Crohns disease, and ulcerative colitis (Figure 36), while in
healthy subjects nanoparticles were absent [147]. The nanoparticles present in diseased subjects had
various chemical compositions and are not considered toxic in bulk form. Microscopic and energy
dispersive spectroscopy analysis of colon mucosa indicated the presence of carbon, ceramic
filosilicates, gypsum, sulphur, calcium, silicon, stainless steel, silver, and zirconium [147]. The size
of debris varied from 50 nm to 100 microns, the smaller the particle the further is able to penetrate.
The particles were found at the interface between healthy and cancerous tissue. Based on these
findings it was suggested that the gastrointestinal barrier is not efficient for particles smaller than 20
microns [266].
Crohns disease affects primarily people in developed countries, and occurs in both the native
population and in immigrants from under-developed countries. It affects 1 in 1000 people [244].
Crohns disease is believed to be caused by genetic predisposition together with environmental
factors [244]. Recently it was suggested that there is an association between high levels of dietary
nanoparticles (100 nm-1m) and Crohn's disease [244]. Exogenous nanoparticles were found in
macrophages accumulated in lymphoid tissue of the human gut, the lymphoid aggregates being the
earliest sign of lesions in Crohn's disease [244]. Microscopy studies showed that macrophages
located in lymphoid tissue uptake nanoparticles of: spherical anatase (TiO2) with size ranging
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between 100-200 nm from food additives; flaky-like aluminosilicates 100-400 nm typical of natural
clay; and environmental silicates 100-700 nm with various morphologies [271]. A diet low in
exogenous particles seems to alleviate the symptoms of Crohn's disease [244].
This analysis is still controversial, with some proposing that an abnormal response to dietary
nanoparticles may be the cause of this disease, and not an excess intake [268]. More precisely, some
members of the population may have a genetic predisposition where they are more affected by the
intake of nanoparticles, and therefore develop Crohns disease [252]. Some evidence suggests that
dietary nanoparticles may exacerbate inflammation in Crohns disease [268]. These studies
measured the intake of dietary particle, but did not analyze the levels of outdoor and indoor
nanoparticle pollution at the subjects residences. As was described previously, significant
quantities of nanoparticles are cleared by the mucociliary escalator and subsequently swallowed,
ultimately reaching the gastro-intestinal tract.
Treatment. The diseases associated with gastro-intestinal uptake of nanoparticles (such as
Crohns disease and ulcerative colitis) have no cure and often requires surgical intervention.
Treatments aim to keep the disease in remission and consist of anti-inflammatory drugs and
specially formulated liquid meals [244]. If dietary nanoparticles are conclusively shown to cause
these chronic diseases, their use in foods should be avoided or strictly regulated.
4.8. Dermal uptake of nanoparticles

4.8.1. Penetration sites
The skin is composed of three layers - epidermis, dermis and subcutaneous (Figure 37 a). The outer
portion of the epidermis, called stratum corneum - is a 10 m thick keratinized layer of dead cells
and is difficult to pass for ionic compounds and water soluble molecules [30]. The surface of
epidermis is highly microstructured, as seen in Figure 37, having a scaly appearance as well as
pores for sweat, sebaceous glands, and hair follicle sites.
As with many subjects involving nanoparticles, dermal penetration is still controversial [18].
Several studies show that nanoparticles are able to penetrate the stratum corneum [18], [20], [8789], [272], [273]. Nanoparticle penetration through the skin typically occurs at hair follicles [272],
and flexed [273] and broken skin [20]. Intracellular nanoparticles penetration is also possible, as
demonstrated by cell culture experiments [274]. MWCNTs are internalized by human epidermal
keratinocytes (the major cell type of the epidermis) in cytoplasmic vacuoles and induce the release
of pro-inflammatory mediators [274]. Spherical particles with diameter between 750 nm and 6
microns selectively penetrate the skin at hair follicles with a maximum penetration depth of more
than 2400 microns (2.4 mm) [272]. Broken skin facilitates the entry of a wide range of larger
particles (500 nm - 7 m) [20]. While stationary unbroken skin has been shown to be impervious to
penetration, nanoparticles have been observed to penetrate when the skin is flexed. Thus
mechanical deformation is capable of transporting particles through the stratum corneum and into
the epidermis and dermis.
A current area under discussion is whether or not nanoparticles of TiO2 found in commercially
available sunscreens penetrate the skin [275]. For example, the application of a sunscreen
containing 8% nanoparticles (10-15nm) onto the skin of humans showed no penetration, while oilin-water emulsions showed penetration, higher penetration being present in hairy skin at the hair
follicles site or pores [275]. The quantity of nanoparticles that penetrate is very small, with less than
1% of the total amount in the applied sunscreen being found in a given hair follicle [276].
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Figure 37. (a) Schematics of cross-section in the skin. (b) The surface of human skin epidermis. Dr.
David M. Phillips/Visuals Unlimited, reproduced with permission from Visuals Unlimited [25].
The dermis has a rich supply of blood and macrophages, lymph vessels, dendritic cells, and
nerve endings [20]. Therefore, the particles that cross through the stratum corneum and into the
epidermis and dermis are potentially available for recognition by the immune system.
Translocation of nanoparticles through skin into the lymphatic system is demonstrated by soil
particles found in lymph nodes of patients with podoconiosis [87-89].
Neuronal transport of small nanoparticles along sensory skin nerves may be possible, in a similar
way to the proven path for herpes virus [20].
4.8.3. Adverse health effects of dermal uptake

Many manufacturing processes pose an occupational health hazard by exposing workers to
nanoparticles and small fibers, as suggested from the intracellular uptake of MWCNTs by human
epidermal keratinocytes [274]. This can explain beryllium sensitization in workers wearing
inhalation protective equipment exposed to nanoparticulate beryllium [273]. Also, this may be
relevant for latex sensitivity and other materials that provoke dermatologic responses.
Soil particles. Lymphatic system uptake of nanoparticles via the dermis is shown to cause
podoconiosis (Figure 12 d) [87-89] and Kaposis sarcoma (Figure 12 f) [81], [90], diseases
discussed in Chapter 3.1.3.
Titanium dioxide. Currently, a controversial subject is the toxicity of titanium dioxide from
cosmetics [139]. There are concerns about the toxicity of titanium dioxide - commonly used as a
physical sunscreen since it reflects and scatters UVB (290-320 nm) and UVA (320-400 nm) light
rays the skin-damaging portion of the solar spectrum. TiO2 also absorbs a substantial amount of
UV radiation, however, which in aqueous media leads to the production of reactive oxygen species,
including superoxide anion radicals, hydrogen peroxide, free hydroxyl radicals, and singlet
oxygens. These reactive oxygen species can cause substantial damage to DNA [142]. Titanium
dioxide particles under UV light irradiation have been shown to suppress tumor growth in cultured
human bladder cancer cells via reactive oxygen species [277]. Sun-illuminated titanium dioxide
73
particles in sunscreen were observed to catalyze DNA damage both in vitro and in vivo [143], [278].
Reports regarding the toxicity of titanium dioxide nanoparticles in the absence of UV radiation are
contradictory. Nanoparticles were seen to have no inflammatory effect or genotoxicity in rats (when
introduced by instillation) [279]. However, several other studies reported that titanium dioxide
caused chronic pulmonary inflammation in rats (again by instillation) [280], and in vitro had a proinflammatory effect in cultured human endothelial cells [281].
Silver. It is known that silver has a beneficial antibacterial effect when used as a wound
dressing, reducing inflammation and facilitating healing in the early phases [282], [283]. However,
there are contradictory studies on silver nanoparticles and ions cytotoxicity from laboratories
around the world. Silver is known to have a lethal effect on bacteria, but the same property that
makes it antibacterial may render it toxic to human cells. Concentrations of silver that are lethal for
bacteria are also lethal for both keratinocytes and fibroblasts [282].
4.9. Nanoparticles uptake via injection

Injection is the administration of a fluid into the subcutaneous tissue, muscle, blood vessels, or
body cavities. Injection of nanoparticles has been studied in drug delivery.
The translocation of nanoparticles following injection depends on the site of injection:
intravenously injected nanoparticles quickly spread throughout the circulatory system, with
subsequent translocation to organs; intradermal injection leads to lymph nodes uptake; while
intramuscular injection is followed by neuronal and lymphatic system uptake [20]. For example, the
injection of magnetic nanoparticles smaller than 100 nm into the tongues and facial muscles of mice
resulted in synaptic uptake [20].
Nanoparticles injected intravenously are retained longer in the body than ingested ones. For
example, 90% of injected functionalized fullerenes are retained after one week of exposure [20].
Intravenously injected nanoparticles (quantum dots, fullerenes, polystyrene, plant virus) with
size ranging from 10-240 nm show localization in different organs, such as liver, spleen, bone
marrow, lymph nodes [20], small intestine, brain, lungs [270]. Talc particles introduced by injection
are found in the liver of intravenous drug users [265]. The distribution of particles in the body is a
function of their surface characteristics and their size. Coating nanoparticles with various types and
concentrations of surfactants before injection significantly affects their distribution in the body
[284]. For example, coating with polyethylene glycol or other substances almost completely
prevents hepatic and splenic localization [20], [284]. Another example is the modification of
nanoparticles surface with cationic compounds that facilitate arterial uptake by up to 10 fold [285].
The adverse health effects of injected nanoparticles are a function of particle chemistry and
charge. A common side effect of injecting nanoparticles intravenously is hypersensitivity, a reaction
that occurs in a large number of recipients and is probably due to the complement activation [286].
4.10. Nanoparticles generation by implants

Nanoparticle debris produced by wear and corrosion of implants is transported to region beyond
the implant [265]. Implants release metal ions and wear particles and, after several years of wear, in
some cases the concentration of metals in blood exceeds the biological exposure indices
recommended for occupational exposure [287].
Materials considered chemically inert in bulk form (like ceramic porcelain and alumina), or in
other terms biocompatible, are used for implants and prostheses [265]. However, nanoparticles with
74
the same composition have been observed in liver and kidneys of diseased patients with implants
and prostheses. It was suggested that the concept of biocompatibility should be revised in view of
these findings [265].
Patients with orthopedic implants have a statistically significant rise in the incidence of
autoimmune diseases, perhaps due to the particulate wear debris generated by the implant, which is
associated with electrochemical processes that may activate the immune system [288].
Immunological responses and aseptic inflammation in patients with total hip replacement are a
response to wear particles [289]. Exposure to orthopedic wear-debris leads to inflammatory initiated
bone resorption, implant failure, dermatitis, urticaria, and vasculitis [288], [290]
4.11. Positive effects of nanoparticles

4.11.1. Nanoparticles as antioxidants
Fullerene derivatives [61] and nanoparticles made of compounds holding oxygen vacancies (CeO2,
and Y2O3) [62] have demonstrated neuroprotective properties and antiapoptotic activity. Fullerene
derivatives have been shown to prevent apoptosis in hepatic, kidney, and neuronal cells, a fact
attributed to their antioxidant properties [61]. The decrease of apoptotic cell death is related to the
neutralization of reactive oxygen species both in vitro and in vivo. Neurodegenerative disorders,
such as Parkinson's and Alzheimer's diseases present hyper-production of oxygen and nitric oxide
radical species [61]. As described previously, oxidative stress by oxygen radicals induces cellular
instability by a cascade of events, leading to cell death. The use of fullerenes as radical sponges (or
scavengers) has been shown to decrease neuronal death [61]. Functionalized fullerenes can react
with oxygen species that attack lipids, proteins, and DNA, conferring neuroprotective properties. In
particular, poly-hydroxylated fullerenes (fullerols) [C60(OH)n] are excellent antioxidants and offer
exceptional neuroprotective properties, having high solubility and ability to cross the blood-brain
barrier [61].
Figure 38. (a) E. Coli bacteria, just after division, showing fimbriae on the cell surface. Dr. Dennis
Kunkel / Visuals Unlimited, reproduced with permission [25]. (b) The HIV Virus. Dr. Hans
Gelderblom/Visuals Unlimited, reproduced with permission [25].
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4.11.2. Anti-microbial activity

Several types of nanoparticle are known to have an antimicrobial effect, such as: silver [14],
titanium dioxide [291], fullerenes [61], zinc oxide [292], and magnesium oxide [286].
Antimicrobial activity of fullerenes was observed on various bacteria, such as E. Coli (Figure 38
b), Salmonella, Streptococcus spp. [61]. The bactericide action is probably due to inhibition of
energy metabolism once the bacteria have internalized the nanoparticles. Zinc oxide nanoparticles
are bactericidal, disrupting membrane permeability and being internalized by Escherichia coli
bacteria [292]. Silver nanoparticles and ions are broad spectrum antimicrobial agents [293]. Their
antibacterial action results from destabilization of the outer membrane of bacteria, and depletion of
the levels of adenosine triphosphate, a molecule that is the principal form of energy immediately
usable by the cell.
Fullerenes have also been shown to have an anti-HIV activity, probably due to a good
geometrical fit of a C60 sphere into the active site (diameter of about 1 nm) on the fundamental
enzyme (HIV protease) necessary for HIV virus (Figure 38 a) survival, leading to strong Van der
Waals interactions between the enzyme and fullerene [61]. It has been demonstrated that silver
nanoparticles undergo a size dependent interaction with HIV-1 virus, with nanoparticles exclusively
in the range of 110 nm attached to the virus [294]. Due to this interaction, silver nanoparticles
inhibit the virus from binding to host cells, as demonstrated in vitro.
5. Physico-chemical characteristics dependent toxicity

From previous knowledge of toxicological properties of fibrous particles (such as asbestos), it is
believed that the most important parameters in determining the adverse health effects of
nanoparticles are dose, dimension, and durability (the three D's) [38]. However, recent studies show
different correlations between various physico-chemical properties of nanoparticles and the
associated health effects, raising some uncertainties as to which are the most important parameters
in deciding their toxicity: mass, number, size, bulk or surface chemistry, aggregation, or all
together. In the following we will emphasize what we believe are the most important nanoparticle
characteristics associated with their toxicity.
5.1. Dose-dependent toxicity

Dose is defined as the amount or quantity of substance that will reach a biological system. The dose
is directly related to exposure or the concentration of substance in the relevant medium (air, food,
water) multiplied by the duration of contact.
Generally, the negative health effects of nanoparticles do not correlate with nanoparticle mass
dose (see Figure 39) [20], [49]. Comparing the health effects of inhaled TiO2 nanoparticles with
different sizes, it is remarkable that the low dose (10 mg/m3) exposure to 20 nm diameter particles
resulted in a greater lung tumor incidence than the high dose (250 mg/m3) exposure of 300 nm
diameter particles [30]. The measure that correlates with the effects is the surface area and not the
mass dose (Figure 39 a) [20], [216], [295].
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Figure 39. (a) Inflammation generated by instillation of low-toxicity particles (carbon black, titanium
dioxide and polystyrene) with the dose expressed as surface area, after [49] (b) Indication of oxidation
induced fluorescence for nanoparticles and microparticles versus mass dose, after [49].
5.2. Size-dependent toxicity

In the last decade, toxicological studies have demonstrated that small nanoparticles (<100 nm)
cause adverse respiratory health effects, typically causing more inflammation than larger particles
made from the same material [20], [49], [142], [216], [242], [296]. Rat inhalation [216] and
instillation [20] of titanium oxide particles with two sizes, 20 nm and 250 nm diameter, having the
same crystalline structure show that smaller particles led to a persistently high inflammatory
reaction in the lungs compared to larger size particles. In the postexposure period (up to 1 year) it
was observed that the smaller particles had (1) a significantly prolonged retention, (2) increased
translocation to the pulmonary interstitium and pulmonary persistence of nanoparticles, (3) greater
epithelial effects (such as type II cell proliferation), (4) impairment of alveolar macrophages
function [216].
5.3. Surface area-dependent toxicity

For the same mass of particles with the same chemical composition and crystalline structure, a
greater toxicity was found from nanoparticles than from their larger counterparts. This led to the
conclusion that the inflammatory effect may be dependent on the surface area of nanoparticles,
suggesting a need for changes in definitions and regulations related to dose and exposure limits.
Indeed, smaller nanoparticles have higher surface area and particle number per unit mass compared
to larger particles. The body will react differently to the same mass dose consisting of billions of
nanoparticles compared to several microparticles. Larger surface area leads to increased reactivity
[27] and is an increased source of reactive oxygen species, as demonstrated by in vitro experiments
[49].
Intratracheal instillation studies on mice with titanium dioxide anatase show that small
nanoparticles (20 nm) induce a much greater inflammatory response than larger nanoparticles (250
nm) for the same mass dose [20]. If instilled at the same surface area dose, they generated similar
toxicity, fitting the same curve [20].
The higher surface area of nanoparticles causes a dose dependent increase in oxidation [49] and
DNA damage [46], much higher than larger particles with the same mass dose [49]. Giving an
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example for the dose, high levels of oxidative DNA have been observed in cell culture experiments
at 25 g per well, with surface area of wells of 9.6 cm2 [46]. In a simplified calculation, for a total
surface area of the human lung alveolar region of 75 m2, from which 3% are type II epithelial cells
(target for cancer development), this dose is equivalent to about 4 years of exposure at the highest
ambient particle concentration [46]. However, mathematical modeling of particle deposition in the
airways indicate that some cells may receive 100-fold more particles depending on their orientation
geometry [297]. Other studies suggested a threshold of 20 cm2 surface area of instilled nanoparticles
below which there is no significant inflammatory response in mice [295]. Extrapolating these
findings to humans and environmental pollution, the critical surface area of nanoparticles becomes
30,000 cm2 [295]. In a busy urban area with nanoparticles concentrations of up to 10 g/m3, with
specific surface area of 110m2/g, deposition efficiency of 70%, the lung burden results in 150
cm2/day. If deposited particles accumulate in the lungs, the surface threshold for significant
inflammatory effects is reached in about half a year [295]. However, subjects with respiratory or
cardiovascular diseases may have a lower threshold. In addition, cardiovascular consequences may
appear at a lower pollution threshold. We must emphasize that epidemiological studies do not
indicate the existence of a threshold below which there are no adverse health effects [295].
Attempts have been made to contradict surface-area dependent toxicity [298]. One study claims
that they tested toxicity of smaller nanoparticles against larger nanoparticles of similar composition
and their findings show that they generate similar cytotoxicity or inflammatory reaction within the
lung [298]. However, they used two different forms of titanium dioxide: rutile and anatase, which
seems to have different toxicity levels regarding generation of oxidative compounds [142]. Similar
composition does not necessary implies similar chemistry, chemical bonds. The best example is
carbon, whose allotropes are: graphite, diamond, carbon nanotubes, and fullerenes, each with
distinct physical and biological characteristics.
5.4. Concentration-dependent toxicity

There are many contradictory results related to the toxic effects of nanoparticles at different
concentrations. Some studies show that certain materials are not as toxic as was observed by other
studies. When comparing the results of different studies one must take into account that there are
differences in the aggregation properties of nanoparticles in air and water, resulting in inherent
discrepancies between inhalation studies and instillation or in vitro experiments. The aggregation
may depend on surface charge, material type, size, among others.
One must stress the fact that aggregation of nanoparticles is essential in determining their
toxicity, due to a more effective macrophage clearance for larger particles compared to smaller ones
(that seem to evade easier this defense mechanism), leading to reduced toxicity of nanoparticle
aggregates larger than 100-200 nm [20], [145]. It has been demonstrated that a high concentration
of nanoparticles would promote particle aggregation [142], [299], and therefore reduce toxic effects
compared to lower concentrations [145]. Most aggregates are observed to be larger than 100 nm, a
size that seems to be a threshold for many of the adverse health effects of small particles. Therefore,
experiments performed with high concentrations of nanoparticles will lead to the formation of
nanoparticle aggregates that may not be as toxic as lower concentrations of the same nanoparticles.
78
Figure 40. (a) Unit cells of rutile, and (b) anatase, both crystalline forms of titanium dioxide; (c) gold
micro- and nanoparticles formed by vacuum evaporation and vapor-phase condensation (Kevin Robbie,
unpublished).
5.5. Particle chemistry and crystalline structure dependent toxicity

Although there have been suggestions that size may be more important than chemical
composition in deciding nanoparticles toxicity [46], one can not generally extrapolate the results of
studies showing similar extent of inflammation for different nanoparticles chemistries. Particle
chemistry is critical in determining nanoparticles toxicity. Particle chemistry is especially relevant
from the point of view of cell molecular chemistry and oxidative stress. Namely, depending on their
chemistry, nanoparticles can show different cellular uptake, subcellular localization, and ability to
catalyze the production of reactive oxygen species [228].
One must make the distinction between composition and chemistry. Though particles may have
the same composition, they may have different chemical or crystalline structure. The toxicity of a
material depends on its type of crystalline form [142]. Lets take for example rutile and anatase,
shown in Figure 40 a, b, both allotropes of titanium dioxide, i.e. polymorphs with the same
chemical composition, but different crystalline structure, and hence different chemical and physical
properties. Rutile nanoparticles (200 nm) were found to induce oxidative DNA damage in the
absence of light, but anatase nanoparticles of the same size did not [142].
Nanoparticles can change crystal structure after interaction with water or liquids. For example, it
is reported that zinc sulphide ZnS nanoparticles (3 nm across containing around 700 atoms)
rearrange their crystal structure in the presence of water and become more ordered, closer to the
structure of a bulk piece of solid ZnS [300]. Nanoparticles often exhibit unexpected crystal
structures due to surface effects (Figure 40 c). The collection of gold nano- and microparticles
shown in Figure 40 c was made by evaporting gold by heating it with an electron beam, and
allowing the vapourized atoms sufficient time and density to condensate into clusters before
collection on a substrate. Condensation dynamics dictate that gold under these conditions will form
these crystalline particles, which form equilibrium-seeking quasi-spheres as the condensing atoms
jostle each other in random walks on the surface towards final resting places within the crystal. The
effects of crystallinity on condensation are clearly observed in the faceting, and fine (nano)
structure of the crystal faces. Incidentally interesting is the dendritic patterns on the (111) faces
where the condensation forms a classic diffusion-limited aggregation structure. These nanoparticles
79
are similar to the engineered nanoparticles produced in many industrial processes - they are
engineered or designed by developing unique recipes that yield materials with beneficial
characteristics. Finally, note the size of the largest gold particle in Figure 40 c, and that of the two
progressively smaller particles stacked one upon the other. The largest is 2.5 m in diameter with
approximately 1011 atoms, the middle is 450 nm with 109 atoms, and the smallest on top is 80 nm
with 107 atoms. The smallest nanoparticle in the image, just below the x arrow, is only 25 nm in
diameter, and contains roughly half a million atoms. Unique behavior emerges from these, and
other nanomaterials, when small clusters of atoms form and manifest quantum effects.
5.6. Aspect ratio dependent toxicity

It was found that the higher the aspect ratio, the more toxic the particle is [201]. More exactly, lung
cancer was associated with the presence of asbestos fibers longer than 10 microns in the lungs,
mesothelioma with fibers longer than 5 microns, asbestosis with fibers longer than 2 microns [201].
All of these fibers had a minimum thickness of about 150 nm [201]. Long fibres (longer than 20
microns for humans) will not be effectively cleared from the respiratory tract due to the inability of
macrophages to phagocytize them [30]. Alveolar macrophages were measured to have average
diameters of 14-21 m [38]. The biopersistence of these long aspect ratio fibers leads to long-term
carcinogenic effects, as shown in Figure 41 [38].
The toxicity of long aspect fibers is closely related to their bio-durability. The bio-durability of a
fiber depends on its dissolution and mechanical properties (breaking). Longer fibers that break
perpendicular to their long axis, become shorter and can be removed by macrophages. Asbestos
fibers break longitudinally, resulting in more fibers with smaller diameter, being harder to clear
[30]. If the lung clearance is slow, the longer the time these fibers will stay in the lung and the
higher the probability of an adverse response. Fibers that are sufficiently soluble in lung fluid can
disappear in a matter of months, while the insoluble fibers are likely to remain in the lungs
indefinitely. Even short insoluble fibers that are efficiently phagocytized by alveolar macrophages
may induce biochemical reactions (release of cytokines, reactive oxygen species, and other
mediators).
Long aspect ratio engineered nanoparticles, such as carbon nanotubes (CNTs), are new materials
of emerging technological relevance and have recently attracted a lot of attention due to their
possible negative health effects [159], [274], [301-308], as suggested by their morphological
similarities with asbestos. However, there is no consensus in the characterization of CNTs toxicity.
Figure 41. Fiber health indices describing diseases associated to fibers of different size, after
[201].
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The contradictory reports on CNTs toxicity could be associated with the multitude of morphologies,
size, and chemical functionalization of their surface or ends. Carbon nanotubes can be single walled
(SWCNTs) or multiple walled (MWCNTs), with varying diameter and length, with closed capped
sections or open ends [309]. In addition to the many forms of nanotubes, they can also be
chemically modified. The diameter of CNTs varies between 0.4 nm and 100 nm. Their lengths can
range between several nanometers to centimeters [309]. Due to their hydrophobicity and tendency
to aggregate, they are harmful to living cells in culture [274], [307]. For many applications, CNTs
are oxidized to create hydroxyl and carboxyl groups, especially in their ends, which makes them
more readily dispersed in aqueous solutions [310].
The conclusions of research on carbon nanotube cytotoxicity are that in general CNTs are very
toxic, inducing cell death at sufficiently high doses of 400 g/ml on human T cells [310], and 3.06
g/cm2 on alveolar macrophages [308]. Cell cultures with added SWCNTs at much lower doses of
3.8 g/ml did not show cytotoxicity [306]. However, dose related inflammation or cell death is not
in agreement between various studies. It was found that cells actively respond to SWCNTs by
secreting proteins to aggregate and wrap them [306]. At the same time, SWCNTs induce upregulation of apoptosis-associated genes [306].
Long-aspect ratio particles (SWCNTs) were reported to produce significant pulmonary toxicity
compared to spherical particles (amorphous carbon black) [301], [303], [310]. Pharyngeal
introduction of SWCNTs resulted in acute inflammation with onset of progressive fibrosis and
granulomas in rats [301], [303]. For comparison, equal doses of carbon black or silica nanoparticles
did not induce granulomas, alveolar wall thickening, causing only a weak inflammation and limited
damage [301]. The enhanced toxicity was attributed to physicochemical properties and fibrous
nature. Carbon nanotubes are not eliminated from the lungs or very slowly eliminated, 81% are
found in rat lungs after 60 days after exposure [159].
5.7. Surface coating and functionalization

Due to the possibility of chemical interactions, the combined effects of inhalation, ingestion, or
dermal application of nanoparticles with other nanoparticles, chemicals, and gases are largely
unknown. The estimated risk of two or more pollutants is not a simple additive process. Particle
surface plays a critical role in toxicity as it makes contact with cells and biological material.
Surfactants can drastically change the physicochemical properties of nanoparticles, such as
magnetic, electric, optical properties and chemical reactivity [20], [311], [312], affecting their
cytotoxicity. Surface coatings can render noxious particles non-toxic while less harmful particles
can be made highly toxic. The presence of oxygen, ozone [46], oxygen radicals [313], and transition
metals [49] on nanoparticle surfaces leads to the creation of reactive oxygen species and the
induction of inflammation. For example, specific cytotoxicity of silica is strongly associated with
the occurrence of surface radicals and reactive oxygen species [30]. Experiments performed on
hamsters showed that the formation of blood clots is more prominent when the surface of
polystyrene nanoparticles is aminated [238]. Diesel exhaust particles interacting with ozone cause
increased inflammation in the lungs of rats compared to diesel particles alone [46]. Nickel ferrite
particles, with and without surface oleic acid, show different cytotoxicity [311]. The cytotoxicity of
C60 molecules systematically correlates with their chemical functionality in human (skin and liver)
carcinoma cells with cell death occurring due to lipid oxidation caused by the generation of oxygen
radicals [313]. Spherical gold nanoparticles with various surface coatings are not toxic to human
cells, despite the fact that they are internalized [58], [59]. Quantum dots of CdSe can be rendered
nontoxic when appropriately coated [60].
81

5.8. Adaptability to nanomaterials inhalation
Recent studies suggest that pre-exposure to lower concentrations of nanoparticles or shorter

exposure times stimulates the phagocytic activity of cells, while high concentration of nanoparticles
impairs this activity [177], [224], [225]. As a result, pulmonary inflammation is drastically reduced
by several previous shorter exposure times to the same nanomaterials [177]. The severe pulmonary
inflammatory response observed after only 15 minutes of rats exposed to 50g/m3 Teflon fume
particles (with diameter of about 16 nm) can be prevented by three preceding daily 5 minutes
exposure to the fumes [177]. During the three days of adaptation, the animals did not show clinical
symptoms of respiratory effects, in contrast to the nonadapted group rats that were severely
affected, showing difficulty breathing starting 1 h after exposure. The number of alveolar
macrophages was significantly lower in nonadapted group.
5.9. Comparison studies

In order to assess the toxicity of various nanomaterials one must compare their toxic effects with
those of known toxic particles. Several studies have pioneered this initiative [113], [159], [302],
[303], [314], [315]. However, the database of studied materials is limited. The conclusions of these
studies indicate that CNTs are extremely toxic, producing more damage to the lungs than carbon
black or silica [159]. Varieties of CNT aggregates, and some carbon blacks, were shown to be as
cytotoxic as asbestos (see Table 4) [113]. Silver nanoparticle aggregates were found to be more
toxic than asbestos, while titanium oxide, alumina, iron oxide, zirconium oxide were found to be
less toxic [113].
Table 4. Nanomaterials, their morphologies, and their relative cytotoxicity index (RCI) on murine
macrophage cells [113].
Material
Ag
Ag
Al2O3
Fe2O3
ZrO2
TiO2 (rutile)
Mean
aggregate size
(m)
1
0.4
0.7
0.7
0.7
1
TiO2 (anatase)
Si3N4
Asbestos
Chrysotile
2.5
1
7
Carbon black
SWCNT
MWCNT
0.5
10
2
Mean particle
size
(nm)
30
30
50
50
20
short fibers
5-15 nm diam.
20 nm
60
Fibers 20 nm
diam., up to
500 aspect
ratio
20
100 nm diam.
15 nm diam.
RCI
(at 5 g/ml)
RCI
(at 10 g/ml)
1.5
1.8
0.7
0.9
0.7
0.3
0.8
0.1
0.4
0.1
0.6
0.05
0.4
0.4
1
0.1
0.06
1
0.8
1.1
0.9
0.6
0.9
0.8
82
6. Applications of nanoparticles
In this chapter we will outline several of the many applications of nanomaterials, both current
and anticipated. To our knowledge, there is no comprehensive review of nanotechnology
applications, likely due to the rapid development of this field. We feel that this chapter is necessary
in order to broaden understanding of the importance that nanomaterials have and will play in our
future, improving the quality of life through nanomedicine, electronics, and other nano-fields.
Among the established applications of nanomaterials, we give as examples: microelectronics,
synthetic rubber, catalytic compounds, photographic supplies, inks and pigments, coatings and
adhesives, ultrafine polishing compounds, UV absorbers for sun screens, synthetic bone, ferrofluids,
optical fiber cladding, and cosmetics. Applications currently entering widespread use include:
fabrics and their treatments, filtration, dental materials, surface disinfectants, diesel and fuel
additives, hazardous chemical neutralizers, automotive components, electronics, scientific
instruments, sports equipment, flat panel displays, drug delivery systems, and pharmaceutics.
The unique properties of nanomaterials encourage belief that they can be applied in a wide range
of fields, from medical applications to environmental sciences. Studies conducted by
nanotechnology experts mapping the risks and opportunities of nanotechnology have revealed
enormous prospects for progress in both life sciences and information technology [19]. Medical
applications are expected to increase our quality of life through early diagnosis and treatment of
diseases, and prosthetics, among others. Ecological applications include removal of persistent
pollutants from soil and water supplies. Nanotechnology has become a top research priority in most
of the industrialized world, including the USA, the EU and Japan. In the U.S.A. nanotechnology is
now at the level of a federal program [316]. Since 2000, around 60 countries have initiated
nanotechnology based initiatives at a national level [317].
6.1. Electronics
Microelectronics. Many of the current microelectronics applications are already at a nanoscale
[318]. During the last four decades, the smallest feature of a transistor shrunk from 10 m down to
30 nm [318]. The ultimate objective of microelectronics fabrication is to make electronic circuit
elements that are nanoscopic. For example, by achieving a significant reduction in the size of circuit
elements, the microprocessors (or better said, nanoprocessors) that contain these components could
run faster and incorporate more logic gates, thereby enabling computations at far higher speeds.
CNTs are exciting alternatives to conventional doped semiconductor crystals due to their varied
electronic properties, ranging from metallic, to semiconducting [319], to superconducting [320].
Displays. The resolution of a television or a monitor improves with reduction of pixel size. The
use of nanocrystalline materials can greatly enhance resolution and may significantly reduce cost.
Also, flat-panel displays constructed with nanomaterials may possess much higher brightness and
contrast than conventional displays owing to the enhanced electrical and optical properties of the
new materials. CNTs are being investigated for low voltage field-emission displays [321]. Their
combination of mechanical and electrical properties makes them potentially very attractive for longlife emitters.
Data storage. Devices, such as computer hard-disks function based on their ability to magnetize
a small area of a spinning disk to record information, are established nano-applications. Discs and
tapes containing engineered nanomaterials can store large amounts of information. Future avenues
for magnetic recording that will drastically increase the capability of data storage include
spintronics and nanowires.
83
High energy density batteries.!New nanomaterials show promising properties as anode and
cathode materials in lithium-ion batteries, having higher capacity and better cycle life than their
larger-particle equivalents [322]. Among them are: aerogel intercalation electrode materials,
nanocrystalline alloys, nanosized composite materials, carbon nanotubes, and nanosized transitionmetal oxides [322].
High-sensitivity sensors. Due to their high surface area and increased reactivity, nanomaterials
could be employed as sensors for detecting various parameters, such as electrical resistivity,
chemical activity, magnetic permeability, thermal conductivity, and capacitance.
6.2. Transportation and telecommunication

Car tires. Nanoparticles of carbon black ranging between 10 nm - 500 nm act as a filler in the
polymer matrix of tires, and are used for mechanical reinforcement.
Car bumpers. Clay particle based composites containing plastics and nano-sized clay are used
to make car exteriors that are lighter and twice as resistant to scratches than usual materials [323].
6.3. Imaging
Scanning microscope imaging. SWCNTs have been used as probe tips for atomic-force
microscopy imaging of antibodies, DNA, etc. [324]. Nanotubes are ideal probe tips for scanning
microscopy due to their small diameter (which maximizes resolution), high aspect ratio, and
stiffness.
Molecular-recognition AFM tips. SWCNTs with attached biomolecules are attached to AFM
tips, and used for molecular-recognition in order to study chemical forces between molecules
[324].
6.4. Biomedical applications

Nanoscaffolds. Nanofiber scaffolds can be used to regenerate central nervous system cells and
possible other organs. Experiments performed on a hamster with severed optic tract demonstrated
the regeneration of axonal tissue initiated by a peptide nanofibers scaffold [325].
Antimicrobial nanopowders and coatings. Certain nanopowders, possess antimicrobial
properties [61], [326]. When these powders contact cells of E. coli, or other bacteria species and
viruses, over 90% are killed within a few minutes. Due to their antimicrobial effect, nanoparticle of
silver and titanium dioxide (<100nm) are assessed as coatings for surgical masks [291].
Bioseparation. Nanotube membranes can act as channels for highly selective transport of
molecules and ions between solutions that are present on both side of the membrane [327]. For
example, membranes containing nanotubes with inside diameters of molecular dimensions (less
than 1 nm) separate small molecules on the basis of molecular size, while nanotubes with larger
inside diameters (2060 nm) can be used to separate proteins [328].
Drug delivery. The ability of nanoparticles to target and penetrate specific organs and cells
contributes to their toxicity, however, this ability may be exploited in nanomedicine. Nanospheres
composed of biodegradable polymers can incorporated drugs, allowing the timed release of the drug
as the polymer degrades [329]. When particles are set to degrade in an acid microenvironment, such
as tumor cells or around inflammation sites, this allows site-specific or targeted drug delivery.
84
Gene transfection. Surface-functionalized nanoparticles can be used to permeate cell

membranes at a much higher level than nanoparticles without a functionalized surface [330]. This
property can be used to deliver genetic material into living cells, a process called transfection. For
example, silica nanospheres labeled on their outer surfaces with cationic ammonium groups can
bind DNA (a polyanion) through electrostatic interactions [331]. Then nanoparticles deliver the
DNA into cells.
Medical imaging. A variety of techniques currently called non-invasive have been used for
more than a quarter of a century in medical imaging, for example superparamagnetic magnetite
particles coated with dextran are used as image-enhancement agents in magnetic resonance imaging
[332]. Intracellular imaging is also possible through attachment of quantum dots to selected
molecules, which allows intracellular processes to be observed directly.
Nasal vaccination. Nanospheres carriers for vaccines are in development. Antigen-coated
polystyrene nanospheres, used as vaccine carriers targeting human dendritic cells, have been
researched for nasal vaccination [333]. Nanospheres had a direct effect on human dendritic cells,
inducing transcription of genes important for, e.g., phagocytosis as well as an immune response.
Nucleic acid sequence and protein detection. Targeting and identifying various diseases could
be made possible by detecting nucleic acid sequences unique to specific bacteria and viruses, or to
specific diseases, or abnormal concentration of certain proteins that signal the presence of various
cancers and diseases [334]. Nanomaterials-based assays are currently evaluated as well as more
sensitive proteins detections methods. Nucleic acid sequences are currently detected with
polymerase chain reaction (PCR) coupled with molecular fluorophore assays. Despite high
sensitivity, PCR has significant drawbacks, such as: complexity, sensitivity to contamination, cost,
and lack of portability [334]. Current protein detection methods, such as enzyme-linked
immunoabsorbent assay (ELISA), allow the detection of proteins concentrations at which the
disease is often advanced. More sensitive methods based on nanomaterials would revolutionize
physical treatment of many cancer types and diseases [334].
Smart nanophase extractors. Differentially functionalized nanotubes are used as smart
nanophase extractors, with molecular-recognition capabilities, to remove specific molecules from
solutions [328].
Treatment for local anesthetic toxicity. Local anesthetic can be sometimes very toxic, ranging
from local neurotoxicity to cardiovascular collapse and coma. In addition to conventional therapies,
drug-scavenging nanoparticles have shown to increase survival rate from no animals in the control
group to all animals in the treated group [335], [336].
6.5. Pollution remediation

Although research on environmental applications of nanoparticles is still a new area, it is growing
rapidly. The potential of nanoparticles to react with pollutants in the air, soil, and water and
transform them into harmless compounds is currently being researched. Nanotechnology could be
applied at both ends of the environmental spectrum, to clean up existing pollution and to decrease
or prevent its generation (see below).
Elimination of pollutants. Due to their enhanced chemical activity, nanomaterials can be used
as catalysts to react with toxic gases (such as carbon monoxide and nitrogen oxide) in automobile
catalytic converters and power generation equipment. This could prevent gaseous environmental
pollution arising from burning gasoline and coal. Paints that absorb noxious gases from vehicle
exhaust have already been developed [337]. They contain 30 nm spherical nanoparticles of titanium
oxide and calcium carbonate mixed in a silicon-based polymer, polysiloxane, and absorb nitrogen
85
oxide gases from vehicle exhausts, a pollution source that can cause smog and respiratory problems.
The porous polysiloxane lets the nitrogen oxide gases diffuse and adhere to the titanium dioxide
particles. UV radiation from sunlight converts nitrogen oxide to nitric acid, which is then
neutralized by the calcium carbonate. The lifetime of the paint is said to be up to 5 years [337].
Water Remediation. Iron nanoparticles with a small content of palladium are tested to
transform harmful products in groundwater into less harmful end products [338]. The nanoparticles
are able to remove organic chlorine (a carcinogen) from water and soil contaminated with the
chlorine-based organic solvents (used in dry cleaners) and convert the solvents to benign
hydrocarbons.
6.6. Cosmetics
Titanium dioxide and zinc oxide become transparent to visible light when formed at the nanoscale,
however are able to absorb and reflect UV light, being currently used in sunscreens and in the
cosmetic industry. More cosmetics products containing nanoparticles are discussed in chapter 3.2.5.
6.7. Coatings
Nanomaterials have been used for very thin coatings for decades, if not centuries. Today thin
coatings are used in a vast range of applications, including architectural glass, microelectronics,
anticounterfeit devices, optoelectronic devices, and catalytically active surfaces. Structured coatings
with nanometer-scale features in more than one dimension promise to be an important foundational
technology for the future.
Self-cleaning windows. Self-cleaning windows have been demonstrated that are coated in
highly hydrophobic titanium dioxide. The titanium dioxide nanoparticles speed up, in the presence
of water and sunlight, the breakdown of dirt and bacteria that can then be washed off the glass more
easily.
Scratch resistant materials. Nanoscale intermediate layers between the hard outer layer and the
substrate material significantly improve wear and scratch resistant coatings. The intermediate layers
are designed to give a good bonding and graded matching of mechanical and thermal properties,
leading to improved adhesion.
Textiles. Nanoparticles have already been used in coating textiles such as nylon, to provide
antimicrobial characteristics [339], Also the control of porosity at the nanoscale and surface
roughness in a variety of polymers and inorganic materials led to ultrahydrophobic - waterproof and
stain resistant fabrics.
6.8. Materials
Insulation materials. Nanocrystalline materials synthesized by the sol-gel technique exhibit a
foam-like structure called an "aerogel" [340]. Aerogels are composed of three-dimensional,
continuous networks of particles and voids. Aerogels are porous, extremely lightweight, and have
low thermal conductivity.
Nanocomposites. Composites are materials that combine two or more components and are
designed to exhibit overall the best properties of each component (mechanical, biological, optical,
electric, or magnetic). Nanocomposites containing CNT and polymers used to control their
conductivity are interesting for a wide range of applications, such as supercapacitors, sensors, solar
cells, etc. [341].
Paints. Nanoparticles confer enhanced desired mechanical properties to composites, such as
86
scratch resistant paints based on encapsulated nanoparticles [342]. The wear resistance of the
coatings is claimed to be ten times greater than that for conventional acrylic paints.
6.9. Mechanical engineering
Cutting tools made of nanocrystalline materials (such as tungsten carbide, WC) are much harder
than their conventional due to the fact that the microhardness of nanosized composites is increased
compared to that of microsized composites [343].
Lubricants. Nanospheres of inorganic materials could be used as lubricants, acting as nanosized
ball bearings [344].
7. Conclusions and future directions

Human exposure to nanoparticles from natural and anthropogenic sources has occurred since
ancient times. Following the invention of combustion engines and the development of industry,
however, significant levels of nanoparticle pollution have arisen in most major cities and even
across large regions of our planet, with climatic and environmental effects that are generally
unknown.
There is heightened concern today that the development of nanotechnology will negatively
impact public health, and it is indisputable that engineered nanomaterials are a source of
nanoparticle pollution when not safely manufactured, handled, and disposed of or recycled. A large
body of research exists regarding nanoparticle toxicity, comprising epidemiological, animal, human,
and cell culture studies. Compelling evidence that relates levels of particulate pollution to
respiratory, cardiovascular disease, and mortality, has shifted attention to particles with smaller and
smaller sizes (nanometer scale). Research on humans and animals indicates that some nanoparticles
are able to enter the body, and rapidly migrate to the organs via the circulatory and lymphatic
systems. Subjects with pre-existing diseases (such as asthma, diabetes, among others) may be more
prone to the toxic effects of nanoparticles. Genetic factors may also play an important role in the
response of an organism to nanoparticles exposure.
As shown in this review, it is clear that workers in nanotechnology related industries may be
potentially exposed to uniquely engineered nanomaterials with new sizes, shapes and
physicochemical properties. Exposure monitoring and control strategies are necessary. Indeed, there
is a need for a new discipline - nanotoxicology - that would evaluate the health threats posed by
nanoparticles, and would enable safe development of the emerging nanotechnology industry [19].
We emphasize that this field of study should include not only newly engineered nanomaterials, but
also those generated by nature and pollution.
The ability of nanoparticles to enter cells and affect their biochemical function makes them
important tools at the molecular level. The toxic properties of nanoparticles can in some instances
be harnessed to improve human health through targeting cancer cells or harmful bacteria and
viruses. These very properties that might be exploited as beneficial may also have secondary
negative effects on health and the environment. For example, nanoparticles used to destroy cancer
cells may cause harmful effects elsewhere in the body, or nanoparticles used for soil remediation
may have an adverse impact upon entering the food chain via microorganisms, such as bacteria and
protozoa.
In the following we highlight important questions and research directions that should be
addressed in the near future by the scientific community involved in the study of nanoparticles
sciences and by government agencies responsible for regulations and funding.
87
Advanced analysis of the physical and chemical characteristics of nanoparticles will continue to
be essential in revealing the relationship between their size, composition, crystallinity, and
morphology and their electromagnetic response properties, reactivity, aggregation, and kinetics. It is
important to note that fundamental properties of nanoparticles are still being discovered, such as
magnetism in nanoparticles made of materials that are non-magnetic in bulk form. A systematic
scientific approach to the study of nanoparticle toxicity requires correlation of the physical and
chemical characteristics of nanoparticles with their toxicity. Existing research on nanotoxicity has
concentrated on empirical evaluation of the toxicity of various nanoparticles, with less regard given
to the relationship between nanoparticle properties (such as exact composition, crystallinity, size,
size dispersion, aggregation, ageing) and toxicity. This approach gives very limited information,
and should not be considered adequate for developing predictions of toxicity of seemingly similar
nanoparticle materials.
Further studies on kinetics and biochemical interactions of nanoparticles within organisms are
imperative. These studies must include, at least, research on nanoparticles translocation pathways,
accumulation, short- and long-term toxicity, their interactions with cells, the receptors and signaling
pathways involved, cytotoxicity, and their surface functionalization for an effective phagocytosis.
Existent knowledge on the effects of nanoparticle exposure on the lymphatic and immune systems,
as well as various organs, is sparse. For example it is known that nanoparticle exposure is able to
modulate the response of the immune system to different diseases, however much research is
needed in order to better understand to what extent this occurs and the full implications of risk
groups (age, genotype). In order to clarify the possible role of nanoparticles in diseases recently
associated with them (such as Crohns disease, neurodegenerative diseases, autoimmune diseases,
and cancer), nanoscale characterization techniques should be used to a larger extent to identify
nanoparticles at disease sites in affected organs or tissues, and to establish pertinent interaction
mechanisms.
Other important research topics to be pursued include nanoparticle ageing, surface
modifications, and change in aggregation state after interaction with bystander substances in the
environment and with biomolecules and other chemicals within the organisms. How do these
interactions modify the toxicity of nanoparticles? Do they render toxic nanoparticles less toxic? Or
can they render benign nanoparticles more toxic? What about the beneficial properties of some
nanoparticles? Do they change in the short- and long-term after undergoing chemical interactions?
Research should also be directed toward finding ways to reduce nanoparticle toxicity (such as
antioxidants provided from dietary sources and supplements, metals chelators, anti-inflammatory
agents).
Understanding and rationally dealing with the potentially toxic effects of nanoparticles requires a
multidisciplinary approach, necessitating a dialogue between those involved in the disparate aspects
of nanoparticle fabrication and their effects, including but not limited to nanomaterial fabrication
scientists, chemists, toxicologists, epidemiologists, environmental scientists, industry, and policy
makers. In order to achieve an interdisciplinary dialogue, systematic summaries should be prepared,
discussing current knowledge in the various nano-fields, and using a common vocabulary. This will
help bring together scientists in different fields, as well as policy makers and society at large. These
summaries should include periodic written reviews, conferences, and accessible databases that
contain the collected knowledge of nanoparticle synthesis, characterization, properties, and toxicity,
in a format easily comprehensible to a wide audience of scientists. A database initiative has already
begun, led by the National Institute for Occupational Safety and Health, as the Nanoparticles
Information Library.
We also suggest several directions for minimizing human exposure to nanoparticles, and thereby
reducing associated adverse health effects. National governments and international organizations
88
should enact stringent air quality policies, with standardized testing methods and low exposure
limits. With such compelling existing evidence of the correlation between particle pollution levels,
mortality, and a wide range of diseases (comprising cardiovascular, respiratory diseases, and
malignant tumors), the primary source of atmospheric nanoparticles in urban areas combustionbased vehicles - should be mandated to have lower nanoparticle emission levels. In the light of their
potential toxicity, the commercialization of dietary and cosmetic nanoparticles, as well as other
consumer products incorporating nanoparticles, must be strictly regulated. In particular they must
be regulated as distinct materials from their bulk constituents. Before using these nanoparticles
several questions should be answered: Are they biocompatible? Do they translocate and accumulate
in the body (including skin)? What are the long-term effects of uptake and accumulation? In
general, consumer products containing nanomaterials should be recycled. A model initiative began
in 2001 in Japan for electrical appliances, where the retailers, manufacturers, and importers are now
responsible for recycling the goods they produce or sell.
There is limited existing research regarding ecological and environmental implications of natural
and anthropogenic nanoparticles pollution, though the role of nanoparticles in some forms of
environmental degradation is well known, e.g. atmospheric nanoparticles play a central role in
ozone depletion. Nanoparticulate pollution is likely to play an important role in global climate
balance, despite the fact that current anthropogenic climate changes are attributed solely to
greenhouse gases. This is dangerous as it encourages the misconception that wood burning does not
contribute to pollution and/or climate change. In a simple calculation of carbon liberation and
fixation, it appears that wood burning, as a so-called renewable source of energy, is benign to the
environment. A proper accounting of nanoparticle pollution in addition to CO2 reveals the naivety
of this analysis.
Advances in nanotechnology are driven by rapid commercialization of products containing
nanostructures and nanoparticles with remarkable properties. This is reflected in the enormous
number of publications on nanotechnology. In comparison, the number of publications on
nanoparticle toxicity is much smaller, as the funding available for toxicity studies are mostly
government related. One way of increasing funding for nanotoxicity research might be via
international regulations requiring that a fraction of the revenues of each company involved in their
production and commercialization to be dedicated to this field of research. Without this level of
commitment it is likely that a current or future industrial nanoparticle product, with non-obvious or
delayed toxicity, will cause significant human suffering and/or environmental damage. The field of
nanotechnology has yet to have a significant public health hazard, but it is a real possibility that can
and should be prevented.
We conclude that the development of nanotechnology and the study of nanotoxicology have
increased our awareness of environmental particulate pollution generated from natural and
anthropogenic sources, and hope that this new awareness will lead to significant reductions in
human exposure to these potentially toxic materials. With increased knowledge, and ongoing study,
we are more likely to find cures for diseases associated with nanoparticle exposure, as we will
understand their causes and mechanisms. We foresee a future with better-informed, and hopefully
more cautious manipulation of engineered nanomaterials, as well as the development of laws and
policies for safely managing all aspects of nanomaterial manufacturing, industrial and commercial
use, and recycling.
89
Acknowledgments
We gratefully acknowledge financial support from the Natural Sciences and Engineering Council of
Canada (NSERC), the Canada Research Chairs Program (CRC), the Canadian Institute for Photonic
Innovations (CIPI), and the Ontario Photonic Consortium (OPC). We also thank Jennifer K. Gregg
and Prof. Alex Braginski for a critical reading of the manuscript.
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Biointerphases vol.

2, issue 4 (2007) pages MR17 - MR172

Nanomaterials and nanoparticles:

Department of Physics, Queen's University, Kingston, Ontario K7L 3N6, Canada

Gastrointestinal Diseases Research Unit & Department of Physiology, Queens

author to whom correspondence should be addressed

Biointerphases vol. 2, issue 4 (2007) pages MR17 - MR172

Biointerphases vol. 2, issue 4 (2007) pages MR17 - MR172

Keywords: nanomaterials, nanoparticles, particulate matter, ultrafine particles, nanoparticle

Biointerphases vol. 2, issue 4 (2007) pages MR17 - MR172

Biointerphases vol. 2, issue 4 (2007) pages MR17 - MR172

Biointerphases vol. 2, issue 4 (2007) pages MR17 - MR172

Biointerphases vol. 2, issue 4 (2007) pages MR17 - MR172

Biointerphases vol. 2, issue 4 (2007) pages MR17 - MR172

the group of phagocytes, and mature into various macrophages in tissue.

Biointerphases vol. 2, issue 4 (2007) pages MR17 - MR172

Translocation the process of transit of particles or substances within an organism.

Biointerphases vol. 2, issue 4 (2007) pages MR17 - MR172

Biointerphases vol. 2, issue 4 (2007) pages MR17 - MR172

1.1. Nano* etymology

Biointerphases vol. 2, issue 4 (2007) pages MR17 - MR172

Biointerphases vol. 2, issue 4 (2007) pages MR17 - MR172

Biointerphases vol. 2, issue 4 (2007) pages MR17 - MR172

Biointerphases vol. 2, issue 4 (2007) pages MR17 - MR172

either nanoparticles NP (any dimension smaller than 1 micron) or microparticles MP (all

Biointerphases vol. 2, issue 4 (2007) pages MR17 - MR172

Figure. 4. ( a ) TEM image of CdSe semiconductor nanoparticles, and ( b ) photograph of CdSe

Biointerphases vol. 2, issue 4 (2007) pages MR17 - MR172

1.3. Nanomaterials and nanotoxicology publications statistics

Biointerphases vol. 2, issue 4 (2007) pages MR17 - MR172

1.4. Introduction to nanoparticles toxicity

Biointerphases vol. 2, issue 4 (2007) pages MR17 - MR172

Biointerphases vol. 2, issue 4 (2007) pages MR17 - MR172

Biointerphases vol. 2, issue 4 (2007) pages MR17 - MR172

3. Sources of nanoparticles and their health effects

Biointerphases vol. 2, issue 4 (2007) pages MR17 - MR172

3.1.1. Dust storms and health effects

Biointerphases vol. 2, issue 4 (2007) pages MR17 - MR172

Biointerphases vol. 2, issue 4 (2007) pages MR17 - MR172

Biointerphases vol. 2, issue 4 (2007) pages MR17 - MR172

3.1.2. Forest fires and health effects

Biointerphases vol. 2, issue 4 (2007) pages MR17 - MR172

3.1.3. Volcanoes and health effects

Biointerphases vol. 2, issue 4 (2007) pages MR17 - MR172

Biointerphases vol. 2, issue 4 (2007) pages MR17 - MR172

3.1.4. Ocean and water evaporation and health effects

Biointerphases vol. 2, issue 4 (2007) pages MR17 - MR172

3.1.5. Organisms and health effects

Biointerphases vol. 2, issue 4 (2007) pages MR17 - MR172

Biointerphases vol. 2, issue 4 (2007) pages MR17 - MR172

3.2. Anthropogenic nanomaterials

3.2.1. Diesel and engine exhaust nanoparticles and health effects

Biointerphases vol. 2, issue 4 (2007) pages MR17 - MR172

Biointerphases vol. 2, issue 4 (2007) pages MR17 - MR172

Estimated source strength (particles/min x 1011)

Biointerphases vol. 2, issue 4 (2007) pages MR17 - MR172

3.2.3. Cigarette smoke and health effects

3.2.4. Buildings demolition and health effects

Biointerphases vol. 2, issue 4 (2007) pages MR17 - MR172