The Toxicologist - Society of Toxicology

target organs, and the fullerene existed in the blood was possibly excreted rapidly
into the urine through kidney. But there is possibility fullerene might be metabolized
to metabolites by metabolic enzymes.
1195 AIRWAY INFLAMMATION IN MICE EXPOSED TO
OVALBUMIN ALLERGEN AND MULTI-WALLED
CARBON NANOTUBES (MWCNT) IS REGULATED BY
CYCLOOXYGENASE-2 (COX-2).
B. C. Sayers 1 , E.E.Glista 1 , A. J. Taylor 1 , R. Langenbach 2 and J. C. Bonner 1 .
1 Environmental and Molecular Toxicology, North Carolina State University, Raleigh,
NC and 2 Laboratory of Molecular Carcinogenesis, NIEHS, Research Triangle Park, NC.
Growing evidence suggests inhalation exposure to multi-walled carbon nanotubes
(MWCNT) pose a significant human health risk by causing lung injury, inflammation,
and fibrosis. We previously showed that inhaled MWCNT cause airway fibrosis
in mice that were pre-exposed to ovalbumin (OVA) allergen challenge.
Cyclooxygenase-2 (COX-2) is an important mediator of pulmonary fibrosis and
asthma. This study was designed to test the hypothesis that COX-2 plays a protective
role in airway inflammation and fibrosis in mice exposed to OVA and
MWCNT. COX-2-deficient (COX-2-/-) mice or wild-type (COX-2+/+) mice were
pre-exposed to saline or OVA prior to oropharyngeal aspiration (OPA) of
MWCNT (4 mg/kg) or vehicle (0.1% pluronic in saline). Lungs were collected at 1
and 14 days after MWCNT exposure for histopathology, RNA, protein, and collection
of bronchoalveolar lavage fluid (BALF). MWCNT delivered by the OPA
method were evenly distributed throughout the lung and contained mainly within
alveolar macrophages. Differential counts of BALF cells at 1 day showed that OVA
alone, but not MWCNT alone, caused a significant increase in inflammatory cells
from either COX-2+/+ or COX-2-/- mice. Combined OVA/MWCNT exposure
increased total cell counts in COX-2+/+ above that seen with OVA alone. BALF
cell counts were elevated even more in COX-2-/- mice exposed to OVA/MWCNT
as compared to COX-2+/+ mice. OVA alone increased IL-13 protein in BALF to a
similar level in either COX-2+/+ and COX-2-/- mice (~25 pg/ml) whereas IL-13
was not detectable in saline or MWCNT groups. Combined OVA/MWCNT also
increased IL-13 to ~25 pg/ml in COX-2+/+ mice, yet OVA/MWCNT caused a significant
increase in IL-13 in COX-2-/- mice (~75 pg/ml). These findings suggest
that COX-2 plays an important role in reducing MWCNT-induced airway inflammation
in individuals with pre-existing asthma.
(Funded by NIEHS RC2-ES018772-01 and NIEHS T32-ES007046)
1196 RESPIRATORY EFFECTS OF INHALED SINGLE-
WALLED CARBON NANOTUBES: THE ROLE OF IRON
AND PARTICLE MORPHOLOGY.
A. K. Madl, A. Tsumura, K. Johnson, V. Seshachellam, P. C. Edwards, S. V.
Teague, T. Guo, L. S. Van Winkle, J. E. Evans and K. E. Pinkerton. University of
California, Davis, Davis, CA.
With worldwide production of carbon nanotubes (CNTs) exceeding over 500 metric
tons annually and industry growth expecting to double over the next 5 yr, there
are concerns our understanding of the hazards of these nanomaterials may not be
keeping pace with market demand. The physicochemical properties of CNTs may
delineate the key features that determine either toxicity or biocompatibility and assist
in evaluating the potential health risks posed in industrial and consumer product
settings. We hypothesized that the iron content and morphology of inhaled single-walled
carbon nanotubes (SWCNTs) influences the extent of cellular injury and
alters homeostasis in the lung. Rats (SD) were exposed (1 mg/m3) to either
aerosolized SWCNTs (raw FeSWCNT or purified cSWCNT), carbon black (CB),
crocidolite, or fresh air via nose-only inhalation for 6 hr/d for 10 d. Markers of inflammation
and cytotoxicity in lung lavage and mucin in different airway generations
were used to assess immediate and persistent effects. The oxidant and inflammatory
capacity of microdissected airways of exposed animals was used to assess the
ability to withstand an additional oxidant insult. Results showed different timing
and extent of responses resulting from exposure to SWCNTs containing varied
amounts of iron. Depending on the endpoint of interest, responses of SWCNTs
sometimes followed that of CB while in other circumstances matched that of crocidolite.
Notably, FeSWCNTs exposed animals were unable to respond to an additional
oxidant challenge and cSWCNTs exposed animals had a latent and persistent
development of mucous cells in the distal airways. In conclusion, while some toxicity
endpoints follow patterns comparable to CB or crocidolite, the respiratory effects
of inhaled FeSWCNTs and cSWCNTs appear to be unique. Further research
is needed to evaluate whether these changes are suggestive of precursor events to
pathologic changes that might develop under more severe or prolonged exposure
conditions. UC TSRT&P and RC1ES018232
256 SOT 2011 ANNUAL MEETING
1197 IN VIVO TOXICITY STUDY OF QUANTUM DOT
NANOPARTICLES FOLLOWING INTRAVENOUS
ADMINISTRATION IN MICE.
J. Treadway 2 , J. Bartel 2 , J. Schatz 3 and S. Kim 1 . 1 Design-for-Environment, Life
Technologies, Foster City, CA, 2 Life Technologies, Eugene, OR and 3 Design-for-
Environment, Life Technologies, Madison, WI.
Quantum dots provide the revolutionary fluorescence performance inherent in the
nanocrystal structure with a highly customizable surface for directing the bioactivity
of the nanocrystals or for conjugating them to a wide range of biomolecules of
interest, and hence are increasingly used in a wide variety of biomedical research. In
this study, we have evaluated various Qdot® nanocrystals (Qdot® 655 Carboxyl
and PEGylated amine-functionalized variant) for in vivo toxicity in mice (CD-1/female;
12 or 18 / group; intravenous via tail vein; 0.333 -33.3 nM/Kg, 5 ml/Kg).
LD50 values could not be estimated as maximally concentrated dosages were found
to be non-lethal in all cases, but limiting values will be described. Additionally, no
physiological, behavioral, or histological evidence of toxicological impact was observed
within a wide range of practical working dosages, even following repeated
dosing. Nevertheless, at very high doses, some toxicity was seen in the liver as determined
by elevated liver enzymes (AST and ALT) after exposure to Qdot® 655
Carboxyl nanoparticles. Interestingly, studies on related test materials showed no
toxic effect on the liver even at the highest dose strongly suggesting that particle
composition is a strong determinant of toxicological behavior at these high dosages.
These physiological changes were further evidenced by subtle histological changes
found in the liver at the higher doses. Inflammatory changes were seen, predominantly
around the portal veins. There was an increase in inflammation with some
areas showing necrosis and changes suggesting early granuloma formation. In conclusion,
clinical chemistry and histological changes were observed only for the
highest doses, which are significantly higher than practical concentration for imaging
in vivo in mice and the results of this study suggests that the Qdot® nanocrystals
used in this study are not toxic at a useful concentration for in vivo imaging applications
(approx. 20 pmol/animal).
1198 EXPOSURE AND DISEASE SUSCEPTIBILITY
DIFFERENCES IN U.S. AND SWEDISH POPULATIONS:
IMPLICATIONS FOR ASSESSMENT OF RISKS FROM
USE OF TOBACCO PRODUCTS.
C. Ward, G. Mariano and A. Santamaria. Environ International, Arlington, VA.
As the US looks to the Swedish experience with the smokeless tobacco product,
snus, as a possible model for reducing harm from smoked tobacco, researchers have
asked questions about the applicability of health effects data generated on the
Swedish population to US populations. Numerous epidemiology and clinical studies
exist on the potential population harms from snus in the Swedish population.
We sought to understand whether the findings from these health studies can be expected
in the US, even under the same or similar tobacco exposure scenarios, in
terms of comparability of populations, on several levels of disease-related factors.
First, standardized rates of tobacco-related diseases from the two countries were
identified and compared. We also identified and compared rates of demographic,
behavioral, and lifestyle factors that may influence susceptibility and disease risk.
These include differences in diets, exercise and other lifestyle factors, and differences
in potential influences from other environmental exposures, such as metals
and persistent chemicals. A specific example is given for cadmium, a known
nephrotoxicant. Cadmium exposures for smokers are known to be higher than
those of nonsmokers, and the body burdens of cadmium in the Swedish population
have decreased measurably over several decades, attributed to reductions in smoking
rates. We discuss whether similar reductions in cadmium body burdens can be
expected in the US from similar declines in smoking, and the implications for disease
risk. In addition, we summarize known population differences between the US
and Sweden in specific genetic polymorphisms and the potential influence of these
differences on disease risk.
1199 PULMONARY FUNCTION TESTING IN BOAT
MANUFACTURER WORKERS.
G. T. Johnson, S. C. Harbison, J. D. McCluskey, P. Xu, L. Thomas, S.
Goldman and R. D. Harbison. Environmental and Occupational Health, University
of South Florida, Tampa, FL.
Styrene is widely used in boat manufacturing and uncontrolled exposure may lead
to pulmonary function (PF) impairment in workers. This investigation used occupational
health monitoring examination data to characterize PF in a population
currently employed as boat manufacturer workers. PF tests for workers (n = 105)
who required health examinations to ensure fitness for continued respirator use
were compared to NHANES III Raw Spirometry subjects (n = 8,873) to determine