NANOSCIENCE AND NANOTECHNOLOGIES - Nanotoxicology: Toxicological and Biological Activities of Nanomaterials Yuliang Zhao, Bing Wang, Weiyue Feng, Chunli Bai

NANOTOXICOLOGY: TOXICOLOGICALACTIVITIES OF NANOMATERIALSANDBIOLOGICAL

Yuliang Zhao,
CAS Key Lab for Biomedical Effects of Nanomaterials and Nanosafety, Institute of HighEnergy Physics, The Chinese Academy of Sciences, Beijing 100049, & National Center
for Nanoscience and Technology of China, Beijing 100190, China
Bing Wang,
CAS Key Lab for Biomedical Effects of Nanomaterials and Nanosafety, Institute of HighEnergy Physics, The Chinese Academy of Sciences, Beijing 100049

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Weiyue Feng,
CAS Key Lab for Biomedical Effects of Nanomaterials and Nanosafety, Institute of HighEnergy Physics, The Chinese Academy of Sciences, Beijing 100049
Chunli Bai
National Center for Nanoscience and Technology of China, Beijing 100190, China
The Chinese Academy of Sciences, Beijing 100864, China
Keywords: Nanotoxicology, Nanosafety, Nanomaterials, Nanoparticles,
Contents

1. Introduction
2. Target organ toxicity of nanoparticles
2.1. Respiratory System
2.1.1. Deposition of Nanoparticles in the Respiratory Tract
2.1.2. Clearance of Nanoparticles in the Respiratory Tract
2.1.3. Nanotoxic Response of Respiratory System
2.2. Gastrointestinal System
2.3. Cardiovascular System
2.4. Central Nervous System
2.5. Skin
3. Absorption, distribution, metabolism and excretion of nanoparticles (ADME)
3.1. ADME of Nanoparticle Following Inhalation Exposure
3.1.1. Absorption and Retention of Nanoparticles Following Respiratory Tract Exposure
3.1.2. Translocation and Distribution of Nanoparticles Following Respiratory Tract
Exposure
3.1.3. Metabolism and Excretion of Nanoparticles in the Lung
3.2. ADME of Nanoparticle via Gastrointestinal Tract
3.3. ADME of Nanoparticles via Skin
4. Cytotoxicity of nanoparticles
4.1. The Interaction of Metallic and Metal Oxide Nanoparticles with Cells
4.2. The Cytotoxicity of the Metallic Nanoparticles and the Possible Mechanism
5. Molecular toxicology of nanoparticles
5.1. The Interaction of Nanoparticles with DNA
5.2. The Interaction of Nanoparticles with Proteins©Encyclopedia of Life Support Systems (EOLSS)NANOSCIENCE AND NANOTECHNOLOGIES - Nanotoxicology: Toxicological and Biological Activities of Nanomaterials Yuliang Zhao, Bing Wang, Weiyue Feng, Chunli Bai

Glossary
Bibliography
Biographical Sketches
Summary

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All aspects of our life will benefit from the revolution in nanotechnology. Thisrevolution will necessitate large scale production of nanosize particles/structures, newformulations and novel surface properties to meet demands of novel functions.
Meanwhile, the rapidly development of nanotechnology is likely to become new sourcesof human or environmental hazards through inhalation, ingestion, skin uptake, or
injection of engineered nanomaterials in workplace or the use of consumer products. So
far, research results suggest that nanoparticles may cause adverse effects on humanhealth at their portal of entry, which show difference from the bulk materials of thesame chemical composition. Taking the lung as an example, some nanoparticles canescape the normal defenses and translocate from their portal of entry to induce diverse
impacts in other organs, and in some cases, the nanoparticles stay in the organ for a longtime and be not easily excreted from the body. On interaction at a cellular level, some
nanoparticles easily enter into the cells, etc. In order to gain a sustainable development,
new technology always needs a good balance between the benefit and risk.
Nanotoxicology is intended to address the toxicological activities of nanoparticles andtheir products to determine whether and to what extent they may pose a threat to theenvironment and to human health, and defined as the study of the nature and mechanismof toxic effects of nanoscale materials/particles on living organisms and other biologicalsystems. It also deals with the quantitative assessment of the severity and frequency of
nanotoxic effects in relation to the exposure of the organisms. The knowledge fromnanotoxicological study will be the base for designing safe nanomaterials andnanoproducts, and also direct uses in the nanomedical sciences. This chapter consists offive sections with a brief introduction, the target organ toxicity of nanoparticles indifferent biological systems, the ADME (absorption, distribution, metabolism andexcretion) of nanoparticles in vivo following different exposure routs, the cytotoxicity
and molecular nanotoxicology of nanoparticles.
1. Introduction

With the fast development of nanotechnology, industries are currently involved in
nanotechnology-related activities, among which the manufactured nanoscale materials
or engineering nanoparticles are using in a wide range of products. It is known thatnanostructured materials or nanoscale particles possess many novel properties such as
self-assembly, size effects, large surface area, ultrahigh reactivity and quantum effects
because of their very small size and unique structures. According to data collected by
the National Nanotechnology Initiative (NNI), the quantity of manufactured nanoscalematerial is growing significantly every year. Business Communications Company has
projected a $10 billion global demand for nanoscale materials, tools, and devices in2010 (see website: http://www.nano.gov/). This large increase in demand andproduction could lead to enormous exposures of humans and other organisms tonanomaterials/nanoparticles. What happens with these very small-size materials when

©Encyclopedia of Life Support Systems (EOLSS)NANOSCIENCE AND NANOTECHNOLOGIES - Nanotoxicology: Toxicological and Biological Activities of Nanomaterials Yuliang Zhao, Bing Wang, Weiyue Feng, Chunli Bai

they entered our body, in particular what can be expected with the increased surface
reactivity which may lead to completely different biological effects in vivo as comparedto the bulk material of the identical chemical composition and the same quantity. Of
cause they can either be positive and desirable, or negative and undesirable, or a mix of
both, these mostly depend on how to utilize them.

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Nanotoxicology is defined as the study of the nature and mechanism of toxic effects ofnanoscale materials/particles on living organisms and other biological systems. It also
deals with the quantitative assessment of the severity and frequency of nanotoxic effects
in relation to the exposure of the organisms. In fact, scientists have studied the healthyeffects of exposure to airborne nanoparticles for years and have shown some
unexpectedly adverse health effects of nanosized particles in vivo. For instance, theepidemiological investigations have found the associations of incidence of a disease andmortality with the concentrations and the sizes of the airborne particles in theenvironment. The increase of mortality might result from the abundant increase of
nanoparticles. Recently, the biological/toxicological effects of manufactured
nanomaterials and nanoparticles have attracted much attention and been seriously
discussed (Service, 2003; Kelly, 2004; Brumfiel, 2003; Zhao et al., 2008).
From the fact that the sizes of the nanoparticle and the biological molecule arecomparable (Figure1), one easily bethinks of such a consequence that the nanoparticle
may easily invade the natural defense system of human body or other species and easily
enter the cells to affect cellular functions. The existing knowledge reminds that whenmolecules are small enough, it is possible for them to slip past the guardians in our
respiratory systems, skip through our skin into unsuspecting cells, and (sometimes)
cross through the blood-brain barrier (BBB). More essentially, the life process is mainly
held out by a series of biochemical reactions in vivo. Manufactured nanoparticles
possess ultra huge surface area, ultrahigh reactivity, highly efficient catalysis, andnanostructures, etc., do they interfere the normal biochemical reactions in vivo whenentering the human body? Are these interferences beneficial or harmful to the life
process? How to avoid the harmful effects, and how to utilize the beneficial effects? For
instance, one sees the similarity in geometric structures of manufactured nanocage(fullerene) and the biological protein (clathrin) in Figure 1, they all consist of thepentagon and hexagon rings.
In fact, many knowledge gaps need to be filled in. For instance, the large alteration inphysicochemical properties of nanomaterials as compared to the bulk material of thesame chemical form, and the large alteration in physicochemical characteristics between
different sizes of the same nanomaterials will undoubtedly lead to different biologicaleffects in vivo. So the existing database of safety evaluation for the bulk materials,
including the effects on health and the environment is probably no longer valid when
extrapolating and applying them for the safety assessment of nanomaterials.

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NANOSCIENCE AND NANOTECHNOLOGIES - Nanotoxicology: Toxicological and Biological Activities of Nanomaterials Yuliang Zhao, Bing Wang, Weiyue Feng, Chunli Bai

Figure 1. The similarity between the structures of manufactured nanocages (fullerene)and proteins (coated veside and clathrin).
In any application or even at the initial stages of the research and development, thesenanoparticles easily enter the environment via various routes, and ultimately enterhuman body through direct routes such as dermal and oral exposures, nanodrugs, or
through indirect routes such as the food chain, etc. For nanoparticles, except the verystrong size-effects, other unique properties such as the tremendous surface, anomalousinterface, complicated reactivity, quantum effects, etc. can also lead to changes inphysicochemical properties which naturally alter the biological activities in vivo. These
have been demonstrated by the reported data and will be summarized and discussed in
the following sections of this chapter (Warheit et al., 2004; Lam, 2004; Chen, 2007;
Feng et al., 2009; Fischer et al., 2007; Wang et al., 2005; Zhao et al., 2007; Nel et al.,2009). Thus, in this chapter, the toxicological effects of nanomaterials will be clarified
in detail at whole-animal, cellular and molecular levels based on the experimental
findings from both the in vivo to in vitro models.
2. Target Organ Toxicity of Nanoparticles
As different tissues and organs have different compositions, structures and functions,
toxic responses are mostly different once nanoparticles (NPs) enter different organs.
Human skin, intestinal tract and respiratory tract are always in direct contact with theenvironmental nanoparticles. For instance, skin, as a structural barrier between theenvironment and the body, plays an important role to protect against break-in ofexogenic particles. Respiratory tract, generally divided into three segments, upper©Encyclopedia of Life Support Systems (EOLSS)NANOSCIENCE AND NANOTECHNOLOGIES - Nanotoxicology: Toxicological and Biological Activities of Nanomaterials Yuliang Zhao, Bing Wang, Weiyue Feng, Chunli Bai

respiratory tract, respiratory airways and lung, most of which exists merely as a piping
system for air to travel in the lungs. Gastrointestinal tract, also known as the digestive
tract, can uptake, transport, digest and adsorb various substances such as nutrients,
water and vitamins from food. On the other hand, the gastrointestinal tract is also
designed as a barrier to restrain the entry of pathogens, toxins and undigested
macromolecules. As such, these potential exposure routes are likely to be the first portalof entry for nanoparticles invading into the human body. In addition, other physiologicalsystems such as cardiovascular system and central nervous system may have chances tointeract with exogenous nanoparticles circulated or transported from the above exposure
routes. So, they may also be a specific target for any type of nanoparticle into the human
body.

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2.1. Respiratory System
We may say that we inaugurate our life with an inspiration of air. However, the air webreathe is not so pure as we would desire it to be, usually containing other pollutants
such as by-products of the combustion processes related to fires, heating, industrial andautomotive processes. So, the toxicity research on NPs in vivo has been carried out on
respiratory system of mammalian.
2.1.1. Deposition of Nanoparticles in the Respiratory Tract

Respiratory system can be further divided into different target zones such as
nasopharyngeal, tracheobronchial and alveolar regions. Specific defense mechanisms
may protect the mammalian organism from harmful materials at the portal of entry,
however, these defenses may not always be as effective for NPs. When the NPs areinhaled, their deposition, clearance, and translocation within the respiratory tract will bedifferent from the larger particles.

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NANOSCIENCE AND NANOTECHNOLOGIES - Nanotoxicology: Toxicological and Biological Activities of Nanomaterials Yuliang Zhao, Bing Wang, Weiyue Feng, Chunli Bai

Figure 2. Predicted fractional deposition of inhaled particles in the nasopharyngeal,
tracheobronchial and alveolar region of the human respiratory tract during nosebreathing (ICRP, 1994).

According to the diffusion motion, exposure to airborne NPs via the inhalation route
will deposit throughout the entire respiratory tract, starting from nasopharyngeal andtracheobronchial, down to the alveolar regions. Depending on the particle size, thedeposition fractions of inhaled NPs in these regions show significant difference. For
instance, 90% of inhaled 1 nm particles are deposited in the nasopharyngeal
compartment, only ~10% in the tracheobronchial region, and essentially none in thealveolar region. On the other hand, 5 nm particles show about equal deposition of ~30%of the inhaled particles in all three regions; 20 nm particles have the highest deposition
efficiency in the alveolar region (~50%), whereas in tracheobronchial andnasopharyngeal regions this particle size deposits with ~15% efficiency (Figure2)(ICRP, 1994). These different deposition efficiencies should have consequences forpotential effects induced by inhaled NPs as well as for their translocation beyond therespiratory tract.
2.1.2. Clearance of Nanoparticles in the Respiratory Tract
Pulmonary retention and clearance of microsized particles have been studied for many

©Encyclopedia of Life Support Systems (EOLSS)NANOSCIENCE AND NANOTECHNOLOGIES - Nanotoxicology: Toxicological and Biological Activities of Nanomaterials Yuliang Zhao, Bing Wang, Weiyue Feng, Chunli Bai

years. While, the recent studies on occupational and environmental exposure ofnanoparticles (NPs) generated a considerable amount of new knowledge regarding theclearance of NPs in the respiratory tract. The clearance of deposited particles in the
respiratory tract is mainly by physical translocation to other sites or chemical clearance.
Chemical dissolution in the upper or lower respiratory tract occurs for biosoluble NPs in
the intra-cellular or extra-cellular fluids. The solutes and soluble components can thenundergo absorption and diffusion in other subcellular structures or binding to proteins incells and may be eventually cleared into blood and lymphatic circulation. This clearance
mechanism can happen at any location within the three regions of the respiratory tract,
depending on the pH of local extracellular and intracellular compartments.

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The clearance for insoluble or poorly soluble NPs in the respiratory tract is basically via
physical translocation. The efficiency of this clearance depends highly on the site ofdeposition and particle size. The NPs trapped within the mucocillary escalator from theupper airways (nasopharyngeal and tracheobronchial) is expelled by pushing the mucus
toward the mouth, hence, it is a relatively rapid process (Kreyling and Scheuch, 2000).
For NPs within the alveolar regions, the most prevalent clearance is mediated bymacrophage phagocytosis, which highly depends on the efficiency of alveolar
macrophages to “sense” deposited particles, move to the site of their deposition,
phagocytize them, and then move towards the mucociliary escalator (Kreyling and
Scheuch, 2000).
2.1.3. Nanotoxic Response of Respiratory System

The epidemiological studies have found a correlation between exposure to respirable
airborne particulate matter (PM) and increased mortality and adverse respiratory healtheffects, including the development of emphysema, chronic bronchitis, and asthma(Samet, 2000; Hoet, 2004). As the most toxic component of airborne particulate matter,
nanoparticles have uncontrolled access to the cells of the airway and even intracellularcomponents because of their size. Hence, deposition of NPs in the alveolar spaces of thelung plays a central role to pulmonary toxicity. When inhaled, NPs deposit dispersedly
upon the alveolar surface, which likely leads to a scattered chemoattractant signal,
resulting in lower recognition and alveolar macrophage responses (Kreyling et al.,2006). The biopersistence of inhaled particles is an important characteristic dictating thelevel of inflammation and tissue injury.
The representative studies of pulmonary inflammation and fibrosis induced bynanoparticles in experimental animal was first reported by Lam and Warheit who
demonstrated that intratracheal instillation of single-walled carbon nanotube (SWNTs)
and multi-walled carbon nanotube (MWNTs) under a certain dose induced a pulmonary
granuloma formation and some interstitial inflammation (Figure3) (Lam, 2004; Warheit,2004). Further study indicates both SWNTs and MWNTs could induce the alteration ofcell structures (Jia et al., 2005). For instance, when exposed to 5 μg/mL SWNTs, themacrophage cell exhibited condensed folds, while the nucleus degenerated and thenuclear matrix reduced when treated with MWNTs (Figure4). At a higher dose level of
20 μg/mL, cells exposed to SWNTs became swelled and vacuolar, and presented
phagosomes explicitly; while in those exposed to MWNTs, the chromatin wasconcentrated, selenodont border and vacuole in cytosol were presented. All the above©Encyclopedia of Life Support Systems (EOLSS)NANOSCIENCE AND NANOTECHNOLOGIES - Nanotoxicology: Toxicological and Biological Activities of Nanomaterials Yuliang Zhao, Bing Wang, Weiyue Feng, Chunli Bai

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alterations show signs of cell apoptosis. It is important to note that the cell apoptosis
induced by SWNTs and MWNTs under a certain dose is much different from the cell
necrosis, which was accompanied with inflammation. Recent studies on intratracheal
instillation of nanoparticles in rats showed intratracheally instilled ferric oxide
nanoparticles (20 nm) induced some clinical pathological changes such as follicular
hyperplasia, protein effusion, pulmonary capillary vessel hyperaemia and alveolar
lipoproteinosis in lung （ Figure5 ） . The sustain burden of particles in alveolar
macrophages and epithelium cells has caused lung emphysema and pro-sign of lungfibrosis (Zhu et al., 2008). Most recently, an age-related difference in the pulmonary
response to the inhaled SiO2 nanoparticles has been found, i.e. the same respiratory
exposure caused much severer pulmonary inflammation in old rats than in young or
adult rats.

Figure 3. Lung tissue from mice instilled with 0.5 mg of a test material per mouse andkilled 7 d after the single treatment. (a) Serum control; (b) carbon black (CarboLex
nanotubes); (c) silica quartz; (d) CNT; (e) RNT (raw nanotube); (f) PNT (purified
nanotube).

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NANOSCIENCE AND NANOTECHNOLOGIES - Nanotoxicology: Toxicological and Biological Activities of Nanomaterials Yuliang Zhao, Bing Wang, Weiyue Feng, Chunli Bai

Figure 4. Ultrastructural changes of phagocytes induced by SWNTs and MWNTs (withdiameter of 10-20 nm) particles at different doses (Jia et al., 2005). (a) Control; (b)control; (c) 5 μg/mL SWNTs; (d) 20 μg/mL SWNTs; (e) 5 μg/mL MWNTs; (f) 20
μg/mL MWNTs.

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Figure 5. Histopathology of lung at days 7 and 30 after intratracheal instillation ofparticles or saline (hematoxylin–eosin stain, magnification = 50). Follicular hyperplasiaof the lymph node was formed at trachea forks (dark arrow). (A) Control group; (B)days 7 after instillation of 0.8 mg/kg bw 22 nm-Fe2O3; (C) days 30 after instillation of
0.8 mg/kg bw22 nm-Fe2O3; (D) days 7 after instillation of 0.8 mg/kg bw280 nm-Fe2O3;(E) days 30 after instillation of 0.8 mg/kg bw 280 nm-Fe2O3; (F) days 7 after instillationof 20 mg/kg bw22 nm-Fe2O3; (G) days 30 after instillation of 20 mg/kg bw22 nmFe2O3; (H) days 7 after instillation of 20 mg/kg bw 280 nm-Fe2O3; (I) days 30 after
instillation of 20 mg/kg bw 280 nm-Fe2O3. (Zhu et al., 2008)©Encyclopedia of Life Support Systems (EOLSS)NANOSCIENCE AND NANOTECHNOLOGIES - Nanotoxicology: Toxicological and Biological Activities of Nanomaterials Yuliang Zhao, Bing Wang, Weiyue Feng, Chunli Bai

2.2. Gastrointestinal System

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The gastrointestinal tract is one of the largest immunological organs of the body,containing more lymphocytes and plasma cells than the spleen, bone marrow and lymph
nodes. It is considered that the exogenous sources of ingestion exposure primarily
results from hand-to-mouth contact in the workplace. Alternatively, NPs can be ingested
directly via food, water, drinking, drugs or drug delivery systems. In addition, NPs
cleared from the respiratory tract via the mucociliary escalator can subsequently beingested into the gastrointestinal (GI) tract. Thus, gastrointestinal tract is considered as
an important target for NPs exposure.

Figure 6. The microscopic pictures (×100) show the pathological changes in kidney
tissues of experimental mice of the control (a); 500 mg/kg nano-copper exposed group(b); 1851 mg/kg nano-copper exposed group (c) 5000 mg/kg nano-copper exposedgroup (d). A: renal glomerulus and B: Bowman’s capsule.
So far, our research group has investigated the acute oral toxicity of several types ofnanoparticles with gastrointestinal tract exposure. For instance, we compared the oral
toxicity of copper nanoparticles (23.5 nm) and micro particles (17 μm) in mice (Chen etal. 2006). In 17 μm particles treated mice only few mice exhibited symptoms of poising,
however, all by nano-copper treated mice appeared obviously symptoms of alimentary
canal function disorder, such as loss of appetite, diarrhea and vomiting, etc. Further
pathological examination revealed grave injuries on kidney, liver and spleen in mice
exposed to nano-copper particles, but not found in mice exposed to micro-copper©Encyclopedia of Life Support Systems (EOLSS)NANOSCIENCE AND NANOTECHNOLOGIES - Nanotoxicology: Toxicological and Biological Activities of Nanomaterials Yuliang Zhao, Bing Wang, Weiyue Feng, Chunli Bai

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particles on mass basis (Figure6-Figure8). When mice were orally administrated with 20
nm and 120 nm ZnO NPs at different doses, we found that the liver, spleen, heart,pancreas and bone became the target organs whose damages show different doseresponse relationship (Wang et al., 2008). The 120 nm ZnO treated mice had a positive
dose-effect pathological damage in stomach (inflammation in gastric lamina propria,
submucosa or serosa layer), liver (fatty degeneration of hepatocytes around central veinor portal area), heart (fatty degeneration of cardiovascular cells) and spleen (largementof splenic corpuscle), whereas, 20nm ZnO displayed a negative dose-effect damage in
the above mentioned organs.

Figure 7. The microscopic pictures (×200) show the pathological changes in livertissues of experimental mice of the control (a); 500 mg/kg nano-copper exposed group(b); 1851 mg/kg nano-copper exposed group (c) and 5000 mg/kg nano-copper exposedgroup (d). A: steatosis.

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NANOSCIENCE AND NANOTECHNOLOGIES - Nanotoxicology: Toxicological and Biological Activities of Nanomaterials Yuliang Zhao, Bing Wang, Weiyue Feng, Chunli Bai

Figure 8. The microscopic pictures (×40) show the pathological changes in spleen
tissues of experimental mice of the control (a); 500 mg/kg nano-copper exposed group(b); 1851 mg/kg nano-copper exposed group (c) and 5000 mg/kg nano-copper exposedgroup (d). A: splenic unit and B: lymphocytes.
2.3. Cardiovascular System

The cardiovascular system is composed of the heart, blood vessels, vasculature, the cells
and plasma that make up the blood. The principal function of the heart is tocontinuously pump blood around the cardiovascular system. It receives both
sympathetic and parasympathetic nerve fibres which alter the rate of the beat, but they
do not initiate the contraction. The blood vessels of the body represent a closed delivery
system, which functions to transport blood around the body, circulating substances suchas oxygen, carbon dioxide, nutrients, hormones and waste products.
The epidemiologic investigations have shown a direct credible relationship between
ambient air particulate pollution and a consistent association with increased healtheffects specifically leading to cardiovascular diseases. The concentration response
relationship between PM2.5 and daily deaths was reported to cause 100,000 deaths
annually in the United States (Schwartz et al., 2002). In a recent comprehensive review
of epidemiologic studies it was shown clearly the pathophysiological changes ofcardiovascular diseases had close association with exposure to ultrafine particles (UFPs)
in air.
In the case of manufactured nanoparticles, a single intrapharyngeal instillation of single-©Encyclopedia of Life Support Systems (EOLSS)NANOSCIENCE AND NANOTECHNOLOGIES - Nanotoxicology: Toxicological and Biological Activities of Nanomaterials Yuliang Zhao, Bing Wang, Weiyue Feng, Chunli Bai

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wall carbon nanotubes (SWCNTs) can induce activation of heme oxygenase-1 (HO-1),
a marker of oxidative insults, in lung, aorta, and heart tissue in HO-1 reporter transgenic
mice (Li et al. 2007). Furthermore, the C57BL/6 mice exposed to SWCNT (dose: 10
and 40 μg/mouse) developed some pathophysiological changes related to cardiovasculardiseases such as mitochondria DNA damage, elevation of mitochondrial glutathione andprotein carbonyl levels (Li et al., 2007). In order to study the age-related difference in
cardiovascular responses to SiO2 nanoparticles inhalation exposure, we designed anovel nanoparticles exposure system, a sealed Plexiglas exposure chamber specifically
mimicking natural (physiologic) inhalation, and investigated the toxicity sensitivity ofnanoparticles in different ages (young, adult, old) of rats (Chen et al., 2008). We
measured and analyzed the changes in serum biomarkers, hemorheologic, heart injury,
and pathology in rats of different ages, and found that the SiO2 nanoparticles inhalation
under identical conditions caused severe myocardial ischemia, significant elevation ofblood viscosity and fibrinogen concentration in old rats, yet less change in young andadult rats. The results indicate that old individuals are more sensitive to nanoparticle
exposure than the young and adult rats (Chen et al., 2008) (Figure9).
From above findings about cardiovascular response to nanoparticles exposure, one may
raise a new and significant question: whether the health effects of air particulate isdominated by the nanosized fraction in air. Moreover, besides the factor of size, otherphysicochemical parameters of nanoparticles, such as shape, crystal structure, solubility,
surface area, surface charge, surface coating may also play key roles on the
cardiovascular events,

Figure 9. With identical inhalation of nanoparticles, myocardial ischemic damage wasseen only in older rats.

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Figure10. Changes in whole blood viscosity (ηb) in different-aged rats who inhaled air
containing manufactured SiO2 nanoparticles. ηb (mean ( SD) is plotted against shear rate
at intervals from 1 S1- to 200 S1- and hematocrit at 41%. ηb was significantly elevatedin the exposed group of old rats (a), but no statistical differences were observed between
the exposed and control groups in each of the young (b) and adult (c) groups. Twoasterisks (**) represents p < 0.01 in the one-way ANOVA t-test. Panels d and e show
the changes in fibrinogen and plasma viscosity (ηp) as a function of age. p, A, and B are
defined in Figure 2. A and B are the Duncan class of Duncan’s multiple-range test.
(Chen et al., 2008)
2.4. Central Nervous System
The central nervous system (CNS), consisting of the brain and spinal cord, is
responsible for receiving and interpreting signals from the peripheral nervous system
and also sends out signals to it, either consciously or unconsciously. Althoughrespiratory system is considered to be the main portal of entry for inhaled nanoparticles,
extrapulmonary translocation after respiratory tract deposition is likely to happen via
accidental or occupational acute exposure (Nemmar et al., 2002). It is also possible that

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inhaled UFPs, by virtue of their extremely small size may deposit in the olfactory
mucosa and then translocate in the central nervous system, which in turn might cause
neurotoxicity. Recent studies support the concept that the CNS may be an important
target organ for nanoparticle inhalation or intranasal instillation exposure (Oberdörster
et al., 2004; Elder et al., 2006).

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The inhaled ultrafine carbon (35 nm) and manganese oxide nanoparticles (30 nm) can
translocate in the brain via the olfactory neuronal pathway (Oberdörster et al., 2004;
Elder et al., 2006). In particular, some investigations have indicated that inhaled or
intranasally instilled ultrafine particle may trigger a proinflammatory response innervous tissue. For instance, intranasally instilled ultrafine carbon black (14 nm) can
induce inflammatory changes (interleukin-1β, tumor necrosis factor-α and chemokinesmRNA) in the brain olfactory bulb (Tin-Tin-Win-Shwe et al., 2006). Further, the sizedependent potential damage of nanoparticles on CNS was also demonstrated by thestudy of intranasal instillation of carbon black (CB) nanoparticles in mice. The
proinflammatory responses were observed in brain olfactory bulb of the 14nm CB
treated mice but not in the 95nm CB treated ones. The intranasal instillation of ufCB
may influence the brain immune function depending on their size. (Tin-Tin-Win-Shweet al., 2006). In our recent study, we found a time-dependent translocation pattern andpotential damages of TiO2 nanoparticles on CNS through intranasal instillation. We
collected the brain tissues and measured the accumulation and distribution of TiO2
(Figure11). The tissues were analyzed with histopathology, oxidative stress, andinflammatory markers at post-instillation time points of 2, 10, 20 and 30 days. Results
indicated that the instilled TiO2 directly entered the brain through olfactory bulb in thewhole exposure period, especially deposited in the hippocampus region and induced
pathological changes in the olfactory bulb and hippocampus regions (Wang et al.,2008).

Figure 11. SRXRF mapping of Ti-element distribution in the brain sections at 30 days
after intranasal instillation of the different-sized TiO2 particles. In the control mice, theTi contents are lower than the detection limit of SRXRF and the mapping is notavailable.

©Encyclopedia of Life Support Systems (EOLSS)NANOSCIENCE AND NANOTECHNOLOGIES - Nanotoxicology: Toxicological and Biological Activities of Nanomaterials Yuliang Zhao, Bing Wang, Weiyue Feng, Chunli Bai

2.5. Skin

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The human skin, the largest organ in the body, is composed of three layers - epidermis,
dermis and subcutaneous, protecting against the environment with a surface area ofnearly 18,000 cm2. The outer portion of the epidermis, called stratum corneum is a 10
μm thick keratinized layer of dead cells and is difficult to pass through by ioniccompounds or water soluble molecules. The surface of epidermis is highly
microstructured, having a scaly appearance as well as pores for sweat, sebaceous
glands, and hair follicle sites. Skin is considered to be the barrier between the wellregulated ‘‘milieu interieur’’ and the outside environment. It also has a relative large
surface area for exposure, serving as one of the principal portals of entry by which
nanomaterials can enter the body.
Currently, there is a lack of information on whether nanoparticles can be absorbed
across the skin’s stratum corneum barrier or whether systemically administered particles
can accumulate in dermal tissue. The tendency for nanomaterials to traverse the skin is a
primary determinant of its dermatotoxic potential. That is, the nanomaterials or
nanoparticles must penetrate the uppermost stratum corneum layer in order to gain
entrance to the viable epidermis and exert toxicity in the lower cell layers. Up to now,
nanoparticle dermal penetration is still under controversial. A current area underdiscussion is whether or not TiO2 NPs in commercially available sunscreens canpenetrate the skin to enter the body. Several studies in murine, porcine, or human skinhave confirmed that TiO2 NPs remained on the skin surface or the outer layers of theskin and had not penetrated into or through the living skin (Lademann et al., 1999;
Pflücker et al., 2001; Schulz et al., 2002). However, there is some evidence whichsuggests the NPs may penetrate into the epidermis or dermis. Bennat and MüllerGoymann (2000) applied TiO2 NPs to human skin either as an aqueous suspension oroil-in-water emulsion and evaluated skin penetration using the tape stripping method(Bennat and Müeller-Goymann, 2000). They observed that TiO2 NPs apparently
penetrated deeper into human skin when applied as an oil-in-water emulsion, and thatpenetration was greater when applied to hairy skin, which suggest that TiO2 NPs
penetrate surface through hair follicles or pores.
Nanoparticles caused dermatoxicity was reported by both in vivo or in vitro
experiments. In an animal model study, both 0.5- and 1.0-μm beryllium particles could
penetrate the stratum corneum and develop hapten-specific, cell-mediated immune
responses (Tinkle et al. 2003). In an in vitro study, Shevedova et al. (2003a) reported
that SWCNT caused a significant dose-response reduction of cell viability and oxidative
stress biomarkers (e.g., antioxidant reserve), and a significant increase in lipid peroxides
in human epidermal keratinocytes (0, 0.06, 0.12 and 0.24 mg/mL of SWCNT for 18
hours), suggesting an increase of cutaneous toxicity.
In the recent years, a majority of nanotoxicity research is focusing on in vitro systems.
However, the data from in vitro studies easily mislead the safety assessment efforts. The
data will require verification from in vivo animal experiments. On the other hand, invivo systems are extremely complicated and the interactions of the nanostructures withbiological components, such as proteins and cells, could lead to unique biodistribution,clearance, immune response, and metabolism. Thus, an understanding of the©Encyclopedia of Life Support Systems (EOLSS)NANOSCIENCE AND NANOTECHNOLOGIES - Nanotoxicology: Toxicological and Biological Activities of Nanomaterials Yuliang Zhao, Bing Wang, Weiyue Feng, Chunli Bai

relationship between the physical and chemical properties of the nanostructure and theirin vivo behavior would provide a basis for assessing nanotoxicity and more importantly
may lead to predictive models for nanotoxicity assessment.
-

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©Encyclopedia of Life Support Systems (EOLSS)NANOSCIENCE AND NANOTECHNOLOGIES - Nanotoxicology: Toxicological and Biological Activities of Nanomaterials Yuliang Zhao, Bing Wang, Weiyue Feng, Chunli Bai

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paper’s investigations using optical and electron microscopy proved that neither surface characteristics,
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Shvedova A.A., Castranova V., Kisin E.R, Schwegler-Berry D., Murray A.R., Gandelsman V.Z.,
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nanoparticle]
Tinkle S.S., Antonini J.M., Rich B.A., Roberts J.R., Salmen R., DePree K. (2003). Skin as a route of
exposure and sensitization in chronic beryllium disease. Environ Health Perspect 111, 1202-1208. [Thisarticle used optical scanning laser confocal microscopy and size-selected fluorospheres received data areconsistent with development of a hapten-specific, cell-mediated immune response following topicalapplication of beryllium and suggest a mechanistic link between the persistent rate of beryllium worker
sensitization and skin exposure to fine and ultrafine beryllium particles.]Tin-Tin-Win-Shwe, Yamamoto S., Ahmed S., Kakeyama M., Kobayashi T., Fujimaki H. (2006). Braincytokine and chemokine mRNA expression in mice induced by intranasal instillation with ultrafine
carbon black. Toxicol Lett 163(2), 153-160.[This paper suggests that the intranasal instillation of ultrafine
carbon black (ufCB) may influence the brain immune function depending on their size.]
Videira M.A., Botelho M.F., Santos A.C., Gouveia L.F., De Lima J.J., Almeida A.J. (2002). Lymphatic
uptake of pulmonary delivered radiolabelled solid lipid nanoparticles. J Drug Target 10, 607-613. [Thisarticle investigated Lymphatic uptake of pulmonary delivered radiolabelled solid lipid nanoparticles.]Wang B., Feng W.Y., Wang M., Shi J.W., Zhang F., Ouyang H., Zhao Y.L., Chai Z.F., Huang Y.Y., Xie
Y.N., Wang H.F., Wang J. (2007). Transport of intranasally instilled fine Fe2O3 particles into the brain:
Micro-distribution, chemical states, and histopathological observation. Biol Trace Elem Res 118, 233243. [This work describes the initial observation of the transport of intranasally instilled fine ferric oxide(Fe2O3) particles in animal brain, the iron micro-distribution and chemical state in the mice brain on day
14 after intranasal instillation of fine Fe2O3.]
Wang B., Feng W.Y., Zhao Y.L., Xing G..M., Chai Z.F., Wang H.F., Jia G.. (2005). Status of study on
biological and toxicological effects of nanoscale materials. Sci China Ser B-Chem 48(5), 385-394. (Thisreview paper analyzed and summarized the existing data of the experimental study on the biologicalactivities and adverse effects of nanoscale materials/particles including single wall carbon nanotubes,
multi wall carbon nanotubes, titanium oxide and iron powders.)
Wang B., Feng W.Y., Wang M., Wang T.C., Gu Y.Q., Zhu M.T., Ouyang H., Shi J.W., Zhang F., Zhao
Y.L., Chai Z.F., Wang H.F., Wang J. (2008). Acute toxicological impact of nano- and submicro-scaled
zinc oxide powder on healthy adult mice. J Nanopart Res 10, 263-276. [This article evaluated the acute©Encyclopedia of Life Support Systems (EOLSS)NANOSCIENCE AND NANOTECHNOLOGIES - Nanotoxicology: Toxicological and Biological Activities of Nanomaterials Yuliang Zhao, Bing Wang, Weiyue Feng, Chunli Bai

oral toxicity of nano-sized and submicron-sized ZnO nanoparticles, including the distribution of Zn invivo, serum biochemical, blood viscosity and histopathological damage.]
Wang B., Feng W.Y., Wang M., Wang T.C., Gu Y.Q., Zhu M.T., Ouyang H., Shi J.W., Zhang F., Zhao
Y. L., Chai Z.F., Wang H.F., Wang J. (2008). Acute toxicological impact of nano- and submicro-scaled
zinc oxide powder on healthy adult mice. J Nanopart Res 10(2), 263-276.[This article evaluated the acuteoral toxicity of nano-sized and submicron-sized ZnO nanoparticles, including the distribution of Zn invivo, serum biochemical, blood viscosity and histopathological damage.]
Wang J.X., Zhou G.Q., Chen C.Y., Yu H.W., Wang T.C., Ma Y.M., Jia G., Gao Y.X., Li B., Sun J., Li
Y.F., Jiao F., Zhao Y.L., Chai Z.F. (2007). Acute toxicity and biodistribution of different sized titanium
dioxide particles in mice after oral administration. Toxicol Lett 168(2), 176-185. [This article evaluatedthe acute toxicity of nano-sized TiO2 particles (25 and 80nm), including the changes of serum
biochemical parameters and pathology]

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Wang J.X., Chen C.Y., Liu Y, Jiao F, Li W, Lao F, Li Y.F, Li B, Ge C.C, Zhou G.Q, Gao Y.X, Zhao YL,
Chai Z.F. (2008). Potential neurological lesion after nasal instillation of TiO2 nanoparticles in the anataseand rutile crystal phases. Toxicology Letters 183, 72-80. [This work explored the neurotoxicity after nasal
instillation of different crystaline of TiO2 nanoparticles, and found that a crystal-type dependent
nanotoxicity.]
Wang J.X., Liu Y, Jiao F, Lao F, Li W, Gu Y.Q, Li Y.F, Ge C.C, Zhou G.Q, Li B, Zhao YL, Chai Z.F.,
Chen C.Y (2008). Time-dependent Translocation and Potential Impairment on Central Nervous System
by Intranasally Instilled TiO2 Nanoparticles. Toxicology, 254, 82-90.[The paper studied the neurotoxicity
of intranasally instilled TiO2 nanoparticles, and found a time-dependent translocation of NPs in brain,
which caused impairment on central nervous system.]
Warheit D.B., Laurence B.R., Reed K.L., Roach D.H., Reynolds G. A. M., Webb T. R. (2004).
Comparative Pulmonary Toxicity Assessment of Single-wall Carbon Nanotubes in Rats. Toxicol Sci 77,
117-125. [This article compared the pulmonary toxicity of single-wall carbon nanotubes in rats after
intratracheal instillation in the infant stagy of nanotoxicology research and raised extensive attention inthis field]
Warheit D.B., Laurence B.R., Reed K.L., Roach D.H., Reynolds G.A.M., Webb T.R. (2004).
Comparative pulmonary toxicity assessment of single-wall carbon nanotubes in rats. Toxicol Sci 77, 117125[This paper evaluated the acute lung toxicity of intratracheally instilled single-wall carbon nanotubes(SWCNT) in rats.]
Wichmann H.E., Spix C., Tuch T., Woelke G., Peters A., Heinrich J., Kreyling W.G., Heyder J. (2000).
Daily mortality and fine and ultrafine particles in Erfurt, Germany. Part I: Role of particle number andparticle mass. Res Rep Health Eff Inst 98, 87-94. [This article investigated the association of mortality not
only with ambient particles but also with gaseous pollutants and indicators of sources]
Wichmann H.H., Peters A. (2000). Epidemiological evidence of the effects of ultrafine particle exposure.
Phil Trans R Soc Lond 358, 2751-2769. [The review investigated the Epidemiological evidence of theeffects of ultrafine particle exposure]
Wiebert P., Sanchez-Crespo A., Falk R., Philipson K., Lundin A., Larsson S., Moller W., Kreyling W.G.,
Svartengren M. (2006). No significant translocation of inhaled 35-nm carbon particles to the circulationin humans. Inhal Toxicol 18, 741-747. [This paper investigated translocation of inhaled 35-nm carbon
particles to the circulation in humans.]
Wojciak-Stothard B., Curtis A., Monaghan W., MacDonald K., Wilkinson C. (1996). Guidance andactivation of murine macrophages by nanometric scale topography. Exp Cell Res 223, 426-435. [Thisarticle studied the guidance and activation of macrophages from the P388D1 cell line and rat peritoneumby topographic features on a nanometric scale.]
Yamago S., Tokuyama H., Nakamura E., Kikuchi K., Kananishi S., Sueki K., Nakahara H., Enomoto S.,
Ambe F. (1995). In-vivo biological behavior of a water-miscible fullerene-C-14 labeling, absorption,
distribution, excretion and acute toxicity. Chem Biol 2, 385-389. [This article assessed the in vivo
behavior of fullerenes, including the oral absorption, distribution and excretion of this class ofcompounds]
Yin J.J., Lao F, Fu P, Wamer W, Zhao Y.L, et al (2009). The scavenging of reactive oxygen species and©Encyclopedia of Life Support Systems (EOLSS)NANOSCIENCE AND NANOTECHNOLOGIES - Nanotoxicology: Toxicological and Biological Activities of Nanomaterials Yuliang Zhao, Bing Wang, Weiyue Feng, Chunli Bai

the potential for cell protection by functionalized fullerene nanomaterials, Biomaterials, 30, 611621.[This study shows that the surface modified fullerene nanoparticles can scavenge reactive oxygen
species in cell and hence protect cells from the oxidative damages]
Yin J.J., Lao F, Meng J, Fu P, Zhao Y.L, et al (2008), Inhibition of Tumor Growth by Endohedral
Metallofullerenol Nanoparticles Optimized as Reactive Oxygen Species Scavenger, Molecular
Pharmacology, 74, 1132-1140. [This paper reports that molecular mechanism of the anticancer activity ofmetallofullerenol nanoparticles]
Zhang L.W., Monteiro-Riviere N.A. (2008). Assessment of quantum dot penetration into intact, tapestripped, abraded and flexed rat skin. Skin Pharmacol Phys 21, 166-180. [This article evaluated thepenetration of carboxylic coated quantum dot in flow-through diffusion cells with flexed, tape-stripped
and abraded rat skin]

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Zhao Y.L., Nalwa H.S. (2007). Nanotoxicology. American Scientific Publisher. California, USA. [Thisbook is the first monograph about nanotoxicology and is composed of 16 state-of-the-art review chapterson evaluating the safety of nanotechnology, covering the main aspects dealing with the risks andimplications of exposure to nanomaterials, especially potential dangers of nanoparticles to human healthand safety and the environment. It is a very valuable reference source for nanotechnology industries andpublic as well as for scientists, students and university professors working in the field of nanotoxicology]
Zhao Y.L., Xing G.M., Chai Z.F. (2008). Nanotoxicology: Are Carbon Nanotubes Safe? Nature
Nanotechnology 3, 191-192. [This article reviewed the safety of carbon nanotubes using a small numberof mice]Zhu M.T., Feng W.Y., Wang B., Wang T.C., Gu Y.Q., Wang M., Wang Y., Ouyang H., Zhao Y.L., Chai
Z.F. (2008). Comparative study of pulmonary responses to nano- and submicron-sized ferric oxide in rats.
Toxicology 247(2-3), 102-111. [This paper compared lung injury induced by submicron-sized and nanosized Fe2O3 particle intratracheal exposure, including microvascular permeability, cell lysis in lungepitheliums and blood coagulation parameters etc.]
Zhu M.T., Feng W.Y., Wang Y., Wang B., Wang M., Ouyang H., Zhao Y.L., Chai Z.F. (2009).
Particokinetics and extrapulmonary translocation of intratracheally instilled ferric oxide nanoparticles inrats and the potential health risk assessment. Toxicol Sci 107, 342-351. [This paper investigatedparticokinetics and extrapulmonary translocation intratracheal-instilled nano-59Fe2O3 particles passthrough the alveolar-capillary barrier into systemic circulation within 10 min.]
Biographical Sketches

Professor Yuliang Zhao’s degrees are in Chemistry (1985, Sichuan Univ.), and in Chemistry/Physics(M.D.1996 & Ph.D. 1999, Tokyo, Japan). He moved to Chinese Academy of Sciences (CAS) fromRIKEN (Japan) as a Hundred Elite Professor in 2001. He is the founder of CAS Key Laboratory for
Biomedical Effects of Nanomaterials and Nanosafety, and also the founder of Research Center for Cancer
Nanotechnology which is a joint research center from CAS and Tianjin Cancer Hospital. His current
researches mainly focus on toxicological effects of nanomaterials, biomedical functions ofmultifunctional nanoparticles, and nanosurface chemistry for the purposes of enhancing the biomedical
functions or reducing the potential toxicity. Dr Zhao`s other research interest includes the theoreticalsimulation and modeling the dynamic processes of the interplay between nano-systems and bio-systems
like membrane or biological channels. Prof. Zhao has published more than 120 peer-reviewed journal
articles at International journals, and more than 70 research articles at domestic Chinese journals, one
book “Nanotoxicology” in USA (2007), which is the first textbook in the nanotoxicology field. He is also
the editor-in-chief of 10 books on biological activities and safety assessment of nanoscale materials,
published by China Scientific Press (2009). He serves as editorial board member of 8 international
journals, Associate Editors for Biomedical Microdevices (USA), Particle and Fiber Toxicology (UK), andJournal of Nanoscience and Nanotechnology (USA). He has been invited and given more than 110
Invited Lectures at conferences and universities/institutes worldwide.
Professor Wei-Yue Feng (born in 1967) obtained a B.S. in Chemistry from Fudan University in 1989,
and a Ph.D. from Institute of High Energy Physics, Chinese Academy of Sciences in 1998. Since then,she has been working in the CAS Key Lab for Biomedical Effects of Nanomaterials and Nanosafety of
the institute. Her current primary fields of research include nanotoxicology, proteomics and nuclear©Encyclopedia of Life Support Systems (EOLSS)NANOSCIENCE AND NANOTECHNOLOGIES - Nanotoxicology: Toxicological and Biological Activities of Nanomaterials Yuliang Zhao, Bing Wang, Weiyue Feng, Chunli Bai

analytical techniques application. She has published more than sixty related papers at peer-reviewed
journals. Now she is a professor and a research group leader at Institute of High Energy Physics, Chinese
Academy of Sciences.
Professor Bing Wang (born in 1977) obtained a B.S. in Chemistry from Shandong University in 1999,
and a Ph.D. from Institute of High Energy Physics, Chinese Academy of Sciences in 2007. Since then,she has been working in the CAS Key Lab for Biomedical Effects of Nanomaterials and Nanosafety of
the institute. Her primary fields of research include nanotoxicology and nuclear analytical techniquesapplication. She has published more than ten related papers at peer-reviewed journals. Now she is anassistant professor at Institute of High Energy Physics, Chinese Academy of Sciences.

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Professor Chunli Bai is Professor and Executive Vice President of the Chinese Academy of Sciences(CAS) and President of the Graduate University of CAS with more than 32,000 students, Director of
Division of Chemistry and member of Executive Committee of the Presidium. He graduated from the
Department of Chemistry, Peking University in 1978 and received his MS and Ph.D. degrees from CAS
Institute of Chemistry in 1981 and 1985, respectively. During 1985-1987, he was at Caltech, the US foradvanced study, conducting research work in the field of physical chemistry as a post-doctorate associate
and visiting scholar. After his return home in 1987, he continued his research at CAS Institute ofChemistry. From 1991 to 1992, he was a visiting professor at Tohoku University in Japan. Prof. Bai has along list of scientific publications and has won more than twenty prestigious awards and prizes for hisacademic achievements. Because of his meritorious service, He was elected a member of CAS and afellow of the Academy of Sciences for the Developing World (TWAS) in 1997. He is also foreign
associate of the US National Academy of Sciences, fellow of the Royal Society of Chemistry, foreign
member of the Mongolian National Academy of Sciences and honorary doctor or honorary professor inseveral universities abroad. Prof. Bai now serves as the chief scientist for the National Steering
Committee for Nanoscience. In his social activities, he is president of Chinese Chemical Society,honorary president of Chinese Society of Micro-Nano Technology (CSMNT), The Vice-President of the
China Association for Science and Technology, Vice-President of TWAS, member of Bureau andExecutive Committee of IUPAC. President-Elect of Federation of Asian Chemical Societies. He is themember of the International Editorial Adversary Board of JACS, Angewandte Chemie ， Advanced
Materials and Chemical Physics Letters.

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