The Toxicologist - Society of Toxicology

genotoxic effects in the lung (Comet Assay) and bone marrow (Micronucleus Test)
were examined along with the general toxicity (e.g. inflammation of the lung). The
comparison of the in vitro and in vivo methods revealed that some genotoxic effects
observed in vitro could not be observed in the in vivo studies.
1470 COMPARATIVE GENE EXPRESSION PROFILE IN
TISSUES OF RATS INTRATRACHEALLY EXPOSED TO
CADMIUM-DOPED NANOPARTICLES.
T. Coccini 1 , E. Roda 2 , M. Fabbri 3 , M. Sacco 3 , L. Manzo 1, 2 and L. Gribaldo 3 .
1 Toxicology Division, Maugeri Foundation IRCCS, Institute of Pavia, Pavia, Italy,
2 European Centre for Nanomedicine, University of Pavia, Pavia, Italy and 3 IHCP,
European Commission, Joint Research Centre, Ispra, Italy.
The development of novel nanopharmaceuticals have potential for revolutionizing
medical treatment. Engineered cadmium-containing silica nanoparticles (CdNPs)
show great promise for targeted drug delivery. However, risk associated with new
nanotechnology needs to be assessed, further Cd accumulates in tissues, particularly
in kidney, the main target organ, while, when inhaled, it causes several lung
pathologies. This in vivo study investigated pulmonary and renal molecular effects
of NPCd (1mg/rat) versus CdCl2 (400μg/rat) 7 and 30 days after intratracheal administration.
Cd-containing Silica NPs were prepared from commercial nano-size
silica powder (20nm average pore size and 240m2/g surface area). Toxicogenomic
analysis was performed by the DNA microarray technology to evaluate changes in
gene expression of the entire genome. In lung, the total number of modulated genes
was: (i) higher after 30 days compared to 7 days post administration for both
CdCl2 (229 and 83 genes modulated at 30 and 7 days, respectively) and NPCd
(318 genes at 30 days and 180 genes at 7 days, (ii) higher after NPCd vs CdCl2 at
both time points considered (318 vs 229 genes at 30 days; and 180 vs 83 genes at 7
days). Most of the genes modulated by NPCd were different than those modulated
by CdCl2: at 30 days, NPCd altered several chemokines, calmodulin-like3, cathepsin,
whereas CdCl2 prevalently induced changes in albumin, cytochrome P450, coagulation
factor. In kidney, the modulating gene effects were already pronounced at
the early time point for both Cd and NPCd (373 vs 268 genes, respectively) with a
lasting marked effect until 30 days for NPCd compared to Cd (268 vs 140 genes,
respectively).
These outcomes support that whole genome analysis represents a valuable approach
to assess the whole spectrum of biological responses to Cd-containing nanomaterials
(Supp. Italian Ministries of Health, Research, Education-PRIN2007).
1471 NANOPARTICLES ALTER CYCLOOXYGENASE
ACTIVITY IN MICROVASCULAR DYSFUNCTION.
T. L. Knuckles 1 , J. Yi 1 , D. Frazer 2 , J. Cumpston 2 , B. Chen 2 , V. Castranova 2 and
T. R. Nurkiewicz 1 . 1 Physiology and Pharmacology, West Virginia University,
Morgantown, WV and 2 National Institute of Occupational Safety and Health,
Morgantown, WV.
The widespread increase in the production and use of nanomaterials has increased
the potential for nanoparticle exposure; however, little is known about the biologic
effects of nanoparticle inhalation. We have shown that blunted nitric oxide (NO)
production significantly contributes to nanoparticle induced microvascular dysfunction.
However, it cannot account for all of the microvascular effects of
nanoparticle exposure. The purpose of this study was to evaluate alternative mechanisms
of microvascular dysfunction. Rats were exposed to nano-TiO 2 (primary
particle size ~21 nm) aerosols in our Inhalation Facility at a concentration of 4-5
mg/m 3 with a count median aerodynamic diameter of ~145 nm for 4-6 hours yielding
a total calculated lung burden of 30 μg. 24 h post-exposure, the spinotrapezius
muscle was prepared for intravital microscopy. We assessed arteriolar function via
perivascular nerve stimulation and active hyperemia with or without inhibitors for
endogenous NO production or cyclooxygenase (COX) products. NO inhibition
increased vasoconstriction and decreased vasodilation in control but not in exposed
animals. COX inhibition had no effect on vasoconstriction in either group but
overtly blunted vasodilation in exposed animals. Based on these results, we then determined
if exposure altered sensitivity to COX products. Suffusion of the muscle
with U46619 (1-100 nM), a thromboxane A 2 mimetic, led to a significantly greater
vasoconstriction in exposed animals compared to control (max % of control -22 ±
3.4% sham, -31 ± 4.0% exposed). Furthermore, suffusion of iloprost (2.8-28 nM),
a prostacyclin mimetic, led to a slight increase in vasodilation in the exposed animals
compared to control (max % of control 177 ± 25% sham, 214 ± 41% exposed).
Hence, the compensatory mechanism for the NO deficit appears to be
COX mediated, through enhanced sensitivity and possibly increased endogenous
production. Support: NIH RO1-ES015022, RC1-ES018274 (TRN).
316 SOT 2011 ANNUAL MEETING
1472 HUMAN CLINICAL STUDIES OF DIESEL EXHAUST
PARTICULATE AND IMPLICATION FOR
NANOPARTICLE EXPOSURES.
P. A. Valberg 2 , T. W. Hesterberg 1 , C. M. Long 2 , C. A. Lapin 3 and A. K.
Hamade 2 . 1 Navistar, Inc., Chicago, IL, 2 Gradient, Inc., Cambridge, MA and 3 Lapin
and Associates, Glendale, CA.
While there is a lack of health effects data for humans exposed to engineered
nanoparticles (ENPs), there are human data for another source of nanoparticle
(NP) exposure, notably for the NPs contained in diesel exhaust particulate (DEP).
Studies of human volunteers exposed to diesel exhaust (DE) in research settings
have been conducted at DEP-NP number concentrations (i.e., greater than 10 6 particles/cm
3 ) that exceed number concentrations reported for worst-case exposure
conditions for workers manufacturing and handling ENPs. These human DE exposure
studies, using sensitive physiological instrumentation and well-characterized
exposure concentrations and durations, suggest that elevated DE exposures from
pre-2007 engines may trigger short-term changes in, for example, lung and systemic
inflammation, thrombogenesis, vascular function, and brain activity. Considerable
uncertainty remains both as to which DE constituents produce the observed responses
(i.e., DEP NPs, DEP mass, DE gases), and as to the implications of the observed
short-term changes for the development of disease. Even so, these DE
human clinical data do not give evidence of a unique toxicity for NPs as compared
to other small particles. Of course, physicochemical properties of toxicological relevance
may differ between DEP NPs and other NPs, yet overall, the DE human clinical
data do not support the idea that elevated levels of NPs per se (at least in the
DEP context) must be acutely toxic by virtue of their nano-sized nature alone.
1473 PULMONARY AND HEMATOLOGICAL EFFECTS IN
RATS FOLLOWING A SINGLE INHALATION
EXPOSURE TO CEO2 NANOPARTICLES.
K. Dreher, A. Ledbetter, R. Jaskot, M. Odegaard, R. Snyder, J. Richards and
N. Coates. ORD, NHEERL, U.S. EPA, Research Triangle Park, NC.
Engineered nanomaterials have unknown environmental and health implications
due to their novel properties and/or by-products associated with their applications.
Combustion studies have shown nanoCe-enabled fuel additives alter the physicochemical
properties of diesel emissions (DE) resulting in increased levels of
nanoscale particles containing aggregates of CeO2 NPs. The health effects associated
with exposure to CeO2 NPs, or DE produced using nanoCeO2 additives, are
unknown. To examine the health effects of CeO2 NP exposure, a low consumption
generating system was developed capable of producing CeO2 NPs displaying similar
1 o size and aggregate size ranges observed in DE produced with a nanoCeO2 additive.
Rats were exposed to a single 6h inhalation to either air or CeO2 NPs with a
primary diameter of 4 – 6 nm in the 14 – 300 nm size range having a CMD 47 –
69 nm, GSD 1.89 – 2.0 at either: 0.25, 0.5, or 1.9 mg/m 3 . Pulmonary
toxicity/physiology and hematological effects were examined in control and exposed
rats at various post-exposure time points up to 1 month. Pulmonary edema,
cytotoxicity and inflammation were evaluated by alterations in bronchoalveolar
lavage fluid (BALF): protein, albumin, LDH and cellular differential levels, respectively,
while hematological effects were assessed by alterations in blood: WBC,
RBC, lymphocyte and hematocrit. Exposure to 1.8 mg/m 3 CeO2 NPs produced no
alterations in pulmonary physiology. Significant increase in all BALF endpoints was
detected as early as 12 – 24hr post-exposure and remained elevated over control levels
at 1 mon post-exposure. Significant decrease in WBC and lymphocytes was observed
only at 24h post-exposure. Similar pulmonary effects were observed in rats
exposed to 0.5 mg/m 3 CeO2 NPs while no pulmonary effects were seen in rats exposed
to 0.25 mg/m 3 CeO2 NPs. The data provide the first evidence that a single
acute exposure to low concentrations of CeO2 NPs can induce a transient hematological
effect and persistent lung injury. This abstract does not reflect EPA policy.
1474 EFFECTS OF COPPER NANOPARTICLE EXPOSURE ON
HOST DEFENSE IN MURINE PULMONARY
INFECTION MODEL OF KLEBSIELLA PNEUMONIAE.
J. Kim 1 , A. Adamcakova-Dodd 2 , P. T. O’Shaughnessy 2 , V. H. Grassian 1 and P. S.
Thorne 1, 2 . 1 Interdisciplinary Graduate Program in Human Toxicology, University of
Iowa, Iowa City, IA and 2 Occupational and Environmental Health, University of
Iowa, Iowa City, IA.
Human exposure to nanoparticles (NPs) and environmental bacteria can occur simultaneously.
NPs induce inflammatory responses and oxidative stress but may
also have immune-suppressive effects, impairing macrophage function and altering
epithelial barrier functions. The purpose of this study was to assess the potential effects
associated with the exposure of commercial copper (Cu) NPs using a murine