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Index Potential Risks of Nanomaterials
and How to Safely Handle Materials of Uncertain Toxicity
“It is a mistake for someone to say
nanoparticles are safe, and it is a mistake to say nanoparticles
are dangerous. They are probably going to be somewhere in the middle.
And it will depend very much on the specifics.”
V. Colvin, Director of Center for Biological
and Environmental Nanotechnolgy at Rice University, quoted in Technology
Review
Summary
In the last year and a half, there have been a number of research
articles on the toxicity of different types of nanomaterials. These
studies have suggested effects at the cellular level and in short-term
animal tests. The effects seen depend on the base material of the
nanoparticle, its size and structure, and its substituents and coatings.
Additional toxicology testing is being funded or planned by the
National Science Foundation (NSF), the National Toxicology Program,
and other research organizations in the US and in Europe. Nanomaterials
of uncertain toxicity can be handled using the same precautions
currently used at MIT to handle toxic materials: use of exhaust
ventilation (such as fume hoods and vented enclosures) to prevent
inhalation exposure during procedures that may release aerosols
or fibers and use of gloves to prevent dermal exposure. The EHS
Office will continue to review health and safety information about
nanomaterials as it becomes available and distribute it to the MIT
community.
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What are
nanomaterials?
The ASTM Committee on Nanotechnology has defined a nanoparticle
as a particle with lengths in 2 or 3 dimensions between 1 to 100
nm that may or may not have a size related intensive properties.
Nanomaterials are generally in the 1-100 nm range and can be composed
of many different base materials (carbon, silicon, and metals such
as gold, cadmium, and selenium). Nanomaterials also have different
shapes: referred to by terms such as nanotubes, nanowires, crystalline
structures such as quantum dots, and fullerenes. Nanomaterials often
exhibit very different properties from their respective bulk materials:
greater strength, conductivity, and fluorescence, among other properties.
For many types of nanoparticles, 50-100% of the atoms may be on
the surface, resulting in greater reactivity than bulk materials.
Particles in the nanometer size range do occur both in nature
and as an incidental byproduct of existing industrial processes.
Nanosized particles are part of the range of atmospheric particles
generated by natural events such as volcanic eruptions and forest
fires. They also form part of the fumes generated during welding,
metal smelting, automobile exhaust, and other industrial processes.
One concern about small particles that are less than 10 um is that
they are respirable and reach the alveolar spaces of the lungs
The current nanotechnology revolution differs from past industrial
processes because nanomaterials are being engineered and fabricated
from the “bottom up”, rather than occurring as a byproduct
of other activities. The nanomaterials being engineered have different
and unexpected properties compared to those of the parent compounds.
Since their properties are different when they are small, it is
expected that they will have different effects on the body and will
need to be evaluated separately from the parent compounds for toxicity.
Currently nanomaterials have a limited commercial market. Some nanmoaterials
are used as catalyst supports in catalytic converters; nanosized
titanium dioxide particles are used as a component of sunscreens;
carbon nanotubes have been used to strengthen tennis rackets; components
in silicon chips are reaching the 45 to 65 nm range. Research and
industrial labs are working at the intersection of engineering and
biology to extend uses to medicine as well as all areas of engineering.
The impact is expected to revolutionize these areas. Government
agencies in the US and Europe are beginning to fund toxicology research
to understand the hazards of these materials before they become
widely available.
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What are
the toxic effects of nanomaterials tested to date?
This article will give a overview of the testing done to date.
A list of review articles and research citations are given at the
end for further information.
Any toxic effects of nanomaterials will be very specific to the
type of base material, size, ligands, and coatings. One of the earliest
observations was that nanomaterials, also called ultrafine particles
(<100 nm), showed greater toxicity than fine particulates (<2.5
um) of the same material on a mass basis. This has been observed
with different types of nanomaterials, including titanium dioxide,
aluminum trioxide, carbon black, cobalt, and nickel. For example,
Oberdorster et al. (1994) found that 21 nm titanium dioxide particles
produced 43 fold more inflammation (as measured by the influx of
polymorphonuclear leucocytes, a type of white blood cell, into the
lung) than 250 nm particles based on the same mass instilled into
animal lungs. The increase in inflammation is believed to due to
the much greater surface area of the small particles for the same
mass of material. Though multiple studies have shown that nano-sized
particles may be more toxic than micro-sized particles, this is
not always the case. Intrinsic surface reactivity may also be as
important as surface area. Warheit et al. (2007) found that the
toxicity for cytotoxic crystalline quartz did not relate to particle
size, but did relate to surface reactivity as measured by hemoglobin
release from cells in vitro. Warheit et al. (2006) also found that
other types of crystalline anatase titanium dioxide did not show
size intensive toxicity for nano sized particles.
Nanoparticles (<0.1 um) are
generally similar in size to proteins in the body. They are considerably
smaller than many cells in the body. Human alveolar macrophages
are 24 um in diameter and red blood cells are 7-8 um in diameter.
Cells growing in tissue culture will pick up most nanoparticles.
The ability to be taken up by cells is being used to develop nanosized
drug delivery systems and does not inherently indicate toxicity.
One study by Goodman et al. (2004) found that cellular toxicity
depended upon cationic charge of side chains substituted onto nanoparticles
with a 2 nm gold core. Gold nanoparticles are being investigated
as transfection agents, DNA-binding agents, protein inhibitors and
other biomedical applications. Goldman et al. found that positively
charged gold particles with quaternary ammonium substituted side
chains were toxic to two types of mammalian cells (red blood cells
and Cos-1 cells) and E coli. bacteria, causing 50% of the cell to
die at 1-3 uM concentrations. Negatively charged cells with carboxylate
substituted side chains did not show cellular toxicity even when
tested at much higher concentrations. The researchers attributed
the cell lysis to binding by cationic particles to negatively charged
cell membranes and subsequent membrane leakage. They are currently
designing nanoparticles with different properties to prevent this
type of toxicity.
Once in the body, some types of nanoparticles may have the ability
to translocate and be distributed to other organs, including the
central nervous system. Silver, albumin, and carbon nanoparticles
all showed systemic availability after inhalation exposure. Significant
amounts of 13C labeled carbon particles (22-30 nm in diameter) were
found in the livers of rats after 6 hours of inhalation exposure
to 80 or 180 ug/m3 (Oberdorster et al. 2002). In contrast, only
very small amounts of 192Ir particles (15 nm) were found systemically.
Oberdorster et al. (2004) also found that inhaled 13 C labeled carbon
particles reached the olfactory bulb and also the cerebrum and cerebellum,
suggesting that translocation to the brain occurred through the
nasal mucosa along the olfactory nerve to the brain. The ability
of nanomaterials to move about the body may depend on their chemical
reactivity, surface characteristics, and ability to bind to body
proteins.
There is currently no consensus about the ability of nanoparticles
to penetrate through the skin. Particles in the micrometer range
are generally thought to be unable to penetrate through the skin.
The outer skin consists of a 10 um thick, tough layer of dead keratinized
cells (stratum corneum) that is difficult to pass for particles,
ionic compounds, and water soluble compounds. Tinkle et al. (2003)
found that 0.5 and 1 um dextran spheres penetrated “flexed”
human skin in an in vitro experiment. Particles penetrated into
the epidermis and a few entered the dermis only during flexing of
the skin. Particles 2 and 4 um in diameter did not penetrate. Rymen-Rasmussen
et al. (2006) also found that quantum dots penetrated through pig
skin and into living dermis using an in vitro pig skin bioassay
which is considered a good model for human skin.
Micronized titanium dioxide (40 nm) is currently being used in
sunscreens and cosmetics as sun protection. The nm particles are
transparent and do not give the cosmetics the white, chalky appearance
that coarser preparations did. The nm particles have been found
to penetrate into the stratum corneum and more deeply into hair
follicles and sweat glands than um particles though they did not
reach the epidermis layer and dermis layers (Laddeman et al., 1999).
There is also a concern that nm titanium dioxide particles have
higher photo-reactivity than coarser particles and may generate
free radicals that can cause cell damage. Some manufacturers have
addressed this issue by coating the particles to prevent free radical
formation. The FDA has reviewed available information and determined
that nm titanium dioxide particles are not a new ingredient but
a specific grade of the original product (Luther, 2004).
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Quantum dots (QD) are nanocrystals
containing 1000 to 100,000 atoms and exhibiting unusual “quantum
effects” such as prolonged fluorescence. They are being investigated
for use in immunostaining as alternatives to fluorescent dyes. The
most commonly used material for the core crystal is cadmium-selenium,
which exhibits bright fluorescence and high photostability. Both
bulk cadmium and selenium are toxic to cells. One of the primary
sites of cadmium toxicity in vivo is the liver.
Early studies found that Cd-Se quantum dots were not toxic to
immortalized cell lines used for these studies. Recently Shiohara
et al. (2004) found that three types mercapto-undecanoic acid (MUA)
substituted Cd-Se quantum dots decrease viability in three types
of cells in vitro (monkey kidney, HeLA cells, and human hepatocytes)
and caused cell death after 4-6 hours of incubation. One type of
MUA-QD was less toxic than the other two. Derfus et al. (2004) also
found that Cd-Se QDs were toxic to liver hepatocytes if exposed
to air or UV light, as a result of oxygen combining with Se and
releasing free Cd+2 from the crystal lattice. They found that coating
the Cd-Se QDs with ZnS, polyethylene glycol, or other coatings prevented
toxicity during a two week incubation with hepatocytes. They concluded
that Cd-Se QDs can be made nontoxic with appropriate surface coatings
but future use in vivo must be carefully evaluated to rule out release
of Cd+2 over time.
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Carbon nanotubes (CNT) can have
either single or multiple layers of carbon atoms arranged in a cylinder.
The dimensions of typical single wall carbon nanotubes (SWCNT) are
about 1-2 nm in diameter by 0.1 um in length. Multiple wall carbon
nanotubes (MWCNT) are 20 nm in diameter and 1 mm long. CNT may behave
like fibers in the lung. They have properties very different from
bulk carbon or graphite. They have great tensile strength and are
potentially the strongest, smallest fibers known. CNT have been
tested in short term animal tests of pulmonary toxicity and the
results suggest the potential for lung toxicity though there are
questions about the nature of the toxicity observed and the doses
used.
Lam et al. (2004) instilled three types of SWCNT into rat lungs
and found granulomas, a type of cellular accumulation in the lung
in which clumps of fibers were surrounded by mononuclear macrophages.
Quartz, a dust known to be very toxic to human lungs, also produced
lung damagebut carbon black did not. Warheit et al. (2004), using
a different type of SWCNT, also found granulomas but did not see
increases in other markers of pulmonary inflammation whereas quartz
produced both macrophage accumulation and increased pulmonary inflammation.
Warheit et al. interpreted their SWCNT results as possibly of limited
physiological relevance but requiring further inhalation studies.
Shvedova et al. (2005) using more physiologically relevant doses,
found granulomas, fibrosis, and increased markers of inflammation
from both SWCNT. SWCNT also affected lung function: breathing rate
and the ability to clear bacteria were decreased. More extensive
inhalation studies are currently underway in several research centers.
One mitigating factor regarding lung toxicity is that CNTs have
a tendency to clump together to form nanoropes, which are large,
non-respirable clumps, and may prevent inhalation exposure in many
instances (see discussion below Maynard et al. [2004] study).
The addition of functional groups such as phenyl-sulfite and phenyl-carboxylic
acid onto CNTs can decrease toxicity, as demonstrated using in vitro
tests by Sayes et al. (2006). Other in vitro tests have found inhibited
cell growth and viability. Good recent reviews of CNT toxicity which
cover pulmonary toxicity and also in vitro testing and environmental
considerations are provided by Donaldson et al. (2006) and Helland
et al. (2007). A recent report by Zheng Li et al. (2007) found that
instillation of CNTs produced cardiovascular effects in transgenic
artherogenesis prone mice; the mice developed accelerated plaque
formation after four doses of CNTs over an 8 week period.
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Fullerenes are another category
of carbon based nanoparticles. The most common type has a molecular
structure of C60 which take the shape of a ball shaped cage of carbon
particles arranged in pentagons and hexagons. Fullerenes have many
potential medical applications as well as applications in industrial
coatings and fuel cells, so a number of preliminary toxicology studies
have been done with them. In cell culture, different types of fullerenes
produced cell death at concentrations of 1 to 15 ppm in different
mammalian cells when activated by light (as discussed in Colvin,
2003). Sayes et al. (2004) found that toxicity could be eliminated
when carboxyl groups were substituted on the fullerene surface to
increase water solubility. Cell death in this study appeared to
be a function of damage to the cell membranes. In an in vivo study,
Chen et al. (2004) found that water soluble polyalkylsulfonated
C60 produced no deaths in rats when given orally but was moderately
toxic when administered intraperitoneally (LD50=600 mg/kg). Doses
of 100 to 600 mg/kg also produced an unusual form of kidney toxicity.
Finally, in the first study investigating aquatic toxicology, Oberdorster
(2004) found that 48 hours of exposure to 0.5 and 1.0 ppm of uncoated
pure C60 produced cell membrane lipid peroxidation in the brains
of fish (juvenile large mouth bass). The changes in the brain as
a result of the short exposure did not appear to affect the behavior
of the fish but were an indication of oxidative stress. An additional
concern generated by this study is the effects of release of durable
carbon nanomaterials into the environment.
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How
to Work Safely with Nanomaterials
The preliminary conclusions to be drawn from the toxicology studies
to date is that some types of nanomaterials can be toxic, if they
are not bound up in a substrate and they are available to the body.
Multiple government organizations are working to fund and assemble
toxicology information on these materials. In the interim, MIT researchers
must use procedures that prevent inhalation and dermal exposures
because at this time nanotoxicology information is limited.
Based on particles physics and studies of fine atmospheric pollutants,
nanoparticles are in the size range that remains suspended for days
to weeks if released into air. Nanoparticles can be inhaled and
will be collected in all regions of the respiratory tract; about
35% will deposit in the deep alveolar region of the lungs.
Because they are so small, nanoparticles follow airstreams more
easily than larger particles, so they will be easily collected and
retained in standard ventilated enclosures such as fume hoods. In
addition, nanoparticles are readily collected by HEPA filters. Respirators
with HEPA filters will be adequate protection for nanoparticles
in case of spills of large amounts of material.
Working safely with nanomaterials involves following standard
procedures that would be followed for any particulate material with
known or uncertain toxicity: preventing inhalation, dermal, and
ingestion exposure. Many nanomaterials are synthesized in enclosed
reactors or glove boxes. The enclosures are under vacuum or exhaust
ventilation, which prevent exposure during the actual synthesis.
Inhalation exposure can occur during additional processing of materials
removed from reactors, and this processing should be done in fume
hoods. In addition, maintenance on reactor parts that may release
residual particles in the air should be done in fume hoods. Another
process, the synthesis of particles using sol-gel chemistry, should
be carried out in ventilated fume hoods or glove boxes.
The type of surface coating on nanoparticles often causes them
to clump together so that few particles are actually released when
particles are removed from reactors. In one of the few workplace
industrial hygiene studies of nanoparticles, Maynard et al. (2004)
found almost no release of fibers when carbon nanotubes were removed
from a reactor and transferred into a secondary container. The SWCNT
clumped together into nanoropes and remained attached to the substrate
as it was removed from the reactor. Maynard et al. (2004) also found
that it took considerable energy to break up the nanoropes and release
them into air: the highest settings on a fluidized bed vortex shaker
were needed to produce aerosol release. The type of SWCNT investigated
in this study were uncoated with about 30% Fe catalyst remaining
as part of the nanoropes. Researchers are attempting to coat CNT
and other nanoparticles with materials that make them less sticky
and more easily dispersed; if successful, this would make them more
easily aerosolized and require additional care when handling.
Concerning skin contact, Maynard et al. found clumps of nanoropes
on the gloves of workers removing the synthesized materials from
the reactors. Since the ability of nanoparticles to penetrate the
skin is uncertain at this point, gloves should be worn when handling
particulate and solutions containing particles. A glove having good
chemical resistance to any solution the particles are suspended
in should be used. If working with dry particulate, a sturdy glove
with good integrity should be used. Disposable nitrile gloves commonly
used in many labs would provide good protection from nanoparticles
for most procedures that don’t involve extensive skin contact.
Two pairs of gloves can be worn if extensive skin contact is anticipated,
as well as gloves with gauntlets or extended sleeve nitrile gloves,
to prevent contamination of lab coats or clothing.
One potential safety concern with nanoparticles is fires and explosions
if large quantities of dust are generated during reactions or production.
This is expected to become more of a concern when reactions are
scaled up to pilot plant or production levels. Both carbonaceous
and metal dusts can burn and explode if an oxidant such as air and
an ignition source are present. Nanodusts can be anticipated to
have a greater potential for explosivity than larger particles.
Determination of lower flammability limits using standard test bomb
protocols is being planned in Europe.
There are currently no government occupational exposure standards
for nanomaterials. When they are eventually developed, different
standards for different types of nanomaterials will be needed. One
should also be aware that Material Safety Data Sheets (MSDS) may
not have accurate information at this point in time. For example,
the MSDSs that are accompanying some commercially available carbon
nanotubes are referring to the graphite Permissible Exposure Limit
as a relevant exposure standard. Both graphite and carbon nanotubes
are composed of carbon arranged in a honeycomb pattern. However
CNTs have very different tensile and conductive properties than
graphite. Additionally CNTs are much more toxic in the short-term
animal tests that have been performed to date. Consequently, the
graphite PEL and toxicity information is not appropriate for MSDSs
of CNTs. CNTs should be treated as potentially toxic fibers, if
capable of being released into the air and not bound up in a substrate,
and should be handled with appropriate controls as described previously.
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Nanomaterial
Waste Management
As nanotechnology emerges and evolves, potential environmental
applications and human health and environmental implications are
under consideration by the EPA and local regulators.
EPA has a number of different offices coordinating their review
of this rapidly evolving technology. The EPA is currently trying
a voluntary approach to testing and developing a stewardship program.
There are currently no guidelines from the EPA specifically addressing
disposal of waste nanomaterials. It seems that regulation at some
level is inevitable. Some political subdivisions, including the
City of Cambridge, are already evaluating local regulation.
MIT is taking a cautious approach to nano waste management. It
is our belief that regulation is inevitable. In order to better
understand the potential volumes and characteristics of these waste
streams we are advising that all waste materials potentially contaminated
with nano materials be identified and evaluated or collected for
special waste disposal. On the content section note that it contains
nano sized particles and indicate what they are.
The following waste management guidance applies to nanomaterial-bearing
waste streams consisting of:
- Pure nanomaterials (e.g., carbon nanotubes)
- Items contaminated with nanomaterials (e.g., wipes/PPE)
- Liquid suspensions containing nanomaterials
- Solid matrixes with nanomaterials that are friable or have a
nanostructure loosely attached to the surface such that they can
reasonably be expected to break free or leach out when in contact
with air or water, or when subjected to reasonably foreseeable
mechanical forces.
The guidance does not apply to nanomaterials embedded in a solid
matrix that cannot reasonably be expected to break free or leach
out when they contact air or water, but would apply to dusts and
fines generated when cuttting or milling such materials.
DO NOT put material from nanomaterial – bearing waste streams
into the regular trash or down the drain. Before disposal of any
waste contaminated with nanomaterial, call the EHS Office (452-3477)
for a waste determination.
Collect paper, wipes, PPE and other items with loose contamination
in a plastic bag or other sealing container stored in the laboratory
hood. When the bag is full, close it, take it out of the hood and
place it into a second plastic bag or other sealing container. Label
the outer bag with the laboratory’s proper waste label. On
the content section note that it contains nano sized particles and
indicate what they are.
Currently the disposal requirements for the base materials should
be considered first when characterizing these materials. If the
base material is toxic, such as silver or cadmium, or the carrier
is a hazardous waste, such as a flammable solvent or acid, clearly
they should carry those identifiers. Many nanoparticles may also
be otherwise joined with toxic metals of chemicals. Bulk carbon
is considered a flammable solid, so even carbon based nanomaterials
should be collected for determination as hazardous waste characteristics.
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Additional
Sources of Information
Below are additional information sources for nanomaterials (web
sites, review articles, and individual research articles). The EHS
Office plans to screen new information regularly and alert the MIT
community about additional toxicology studies as they become available.
We also request that MIT researchers alert us about studies that
they learn of so we can distribute them to the MIT community. We
would like to observe handling procedures in different labs so we
can share good practice information within the MIT community. Many
of the articles listed below can be accessed electronically through
the MIT Libraries if an electronic subscription is available. Web
sites are also provided where available.
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Web Sites that Post Current Information about
Nanotoxicology
Gradient Corp. Monthly EH&S Nano News at www.gradient.com
International Council on Nanotechnology at: http://icon.rice.edu.
Up-to-date postings on nanotoxicology worldwide.
National Institute for Occupational Safety and Health (NIOSH) Nanotechnology
Topic Page at www.cdc.gov/niosh/topics/nanotech
National Nanotechnology Infrastructure Network (NNIN) at: http://www.nnin.org/
National Center for Biotechnology Information (NCBI) Pub Med at:
http://www.ncbi.nlm.nih.gov/entrez.
[Can search for articles on nanoparticle toxicity.]
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Review
Articles or Reports About Nanotoxicology
Borm P JA, Robbins D, Haubold S et al. The potential risks of nanomaterials:
a review carried out for ECETOC. Part Fiber Toxicol 3:11-35 2006.
Colvin VL. The potential environmental impact of engineered nanmoaterials.
Nature Biotechnology 21:1166-1170 2003. [Note: Excellent and succinct
overview of nanotoxicology.
Oberdorster G, Oberdorster E, Oberdorster J. Nanotoxicology: An
Emrging Discipline Evolving from Studies of Ultrafine Particles.
Environmental Health Perspectives 113:823-839 2005.
Health and Safety Executive (UK). Health effects of particles produced
for nanotechnologies. Document EH75/6. 35 pp. December 2004. Available
at: www.hse.gov.uk. [Search
for EH75/6]
Health and Safety Executive (UK). Nanoparticles: an occupational
hygiene review. Research Report 274. 100 pp. 2004. Available at:
www.hse.gov.uk. [Search for
RR274]
BIA. Workshop on ultrafine aerosols at workplaces. Held August
2002 in Germany. 208 pp. Available at: http://www.cdc.gov/niosh/topics/nanotech.
[Go to Nanotechnology Topic Page. Report is listed in section Non-US
Governmental Resources]
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Research
Articles on Nanotoxicology
[Many articles are available electronically through MIT
Libraries]
Chen HH, Yu C, Ueng TH, Chen S et al. Acute and subacute toxicity
study of water soluble polyalkylsulfonated C60 in rats. Toxicol
Pathol 26:143-151 1998.
Cui D, Tian F, Ozkan CS, Wang M, Gao H. Effect of single wall carbon
nanotubes on human HEK293 cells. Toxicol Lett 155:73-85 2005.
Derfus AM, Chan WC, Bhatia SN. Probing the cytotoxicity of semiconductor
quantum dots. Nano Lett 4:11-18 2004.
Donaldson K, Aitken R, Tran L, et al. Carbon nanotubes: a review
of their properties in relation to pulmonary toxicology and workplace
safety. Toxicol Sci 92:5-22 2006.
Goodman CM, McCusker CD, Yilmaz T, Rotello VM. Toxicity of gold
nanoparticles functionalized with cationic and anionic side chains.
Bioconjugate Chem 15:897-900 2004.
Helland A, Wick, P, Koehler A, Schmid K, Som, C. Reviewing the
Environmental and Human Health Knowledge Base of Carbon Nanotubes.
Env Hlth Perspec 115:1125-1131 2007
Lademann J, Weigmann HJ, Rickmeyer C, Barthelmes H et al. Penetration
of titanium dioxide microparticles in a sunscreen formulation into
the horny layer and the follicular orifice. Skin Parmacol Appl Skin
Physiol 12:247-256 1999.
Lam CW, James JT, McCluskey R, Hunter RL Pulmonary toxicity of
single-wall carbon nanotubes in mice 7 and 90 days after intratracheal
instillation. Toxicol Sci 77:126-134 2004.
Li Z, Hulderman T, Salmen R, Chapman R, et al. Cardiovascular effects
of pulmonary exposure to single-wall carbon nanotubes. Environ Hlth
Perspec 115:377-382 2007.
Maynard AD, Baron PA, Foley M, Shvedova AA et al. Exposure to carbon
nanotube material: aerosol release during the handling of unrefined
single-walled carbon nanotube material. J Toxicol Environ Hlth,
Part A, 67:87-107 2004.
Monteiro-Riviere NA, Nemanich RJ, Inman AO, Wang YY et al. Multi-walled
carbon nanotube interactions with human epidermal keratinocytes.
Toxicol Lett 155:377-384 2005.
Oberdorster E. Manufactured nanomaterials (fullerenes) induce oxidative
stress in the brain of juvenile largemouth bass. Enn Hlth Perspec
112:1058-1062 2004.
Oberdorster G, Ferin J, Lehnert BE. Correlation between particle
size, in vivo particle persistence and lung injury. Env Hlth Perspec
102 (suppl 5):173-179 2004a.
Oberdorster G, Sharp Z, Atudorei V, Elder A et al. Extrapulmonary
translocation of ultrafine carbon particles following whole-body
inhalation exposure of rats. J Toxicol Environ Hlth Part A 65:1531-1543
2002.
Oberdorster G, Sharp Z, Atudonrei V, Elder A et al. Translocation
of inhaled ultrafine particles to the brain. Inhal Toxicol 16:453-459
2004b.
Rymen-Rasmussen JP, Riviere JE, Monteiro-Riviere NA. Penetration
of intact skin by quantum dots with diverse physicochemical properties.
Toxicol Sci 91:159-165 2006.
Sayes CM, Fortner JD, Guo W, Lyon D et al. The differential cytotoxicity
of water-soluble fullerenes. Nano Lett 4:1881-1887 2004
Sayes CM, Liang F, Hudson JL et al. Functionalization density dependence
of single-walled carbon nanotubes cytotoxicity in vitro. Toxicol
Lett 161:135-142 2006
Shvedova AA, Kisin ER, Mercer R, Murray AR, et al. Unusual inflammatory
and fibrogenic pulmonary responses to single-walled carbon nanotubes
in mice. Am J Physiol Lung Cell Mol Physiol 289:L698-L708 2005.
Shiohara A, Hshino A, Hanaki K, Suzuki K, et al. On the cyto-toxicity
caused by quantum dots. Microbiol Immunol 48:669-675 2004.
Tinkle SS, Antonini JM, Rich BA, Roberts JR et al. Skin as a route
of exposure and sensitization in chronic beryllium disease. Env
Hlth Perspec 111:1202-1208 2003.
Warheit DB, Laurence BR, Reed KL, Roach DH, et al. Comparative
pulmonary toxicity assessment of single-wall carbon nanotubes in
rats. Toxicol Sci 77:117-125 (2004)
Warheit DB, Webb TR, Colvin VC, et al. Pulmonary bioassay studies
with nanoscale and fine-quartz particles in rats: toxicity is not
dependent upon particle size but on surface characteristics. Toxicol
Sci 95:270-280 2007.
Warheit DB, Webb TR, Sayes CM et al. Pulmonary instillation studies
with nanoscale TiO2 rods and dots in rats: toxicity is not dependent
upon particle size and surface area. Toxicol Sci 91:227-236 2006.
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