The Toxicologist - Society of Toxicology

1484 NANOTOXICOLOGY AND NANOHEALTH
BIBLIOMETRY FROM 2000 TO 2009.
W. Waissmann 1 , M. M. Alencar 2 , M. Moura 1 , A. B. Veggi 1 , T. Pastorello 1 and
R. B. Santana 1 . 1 Sergio Arouca National School of Public Health, Oswaldo Cruz
Foundation, Rio de Janeiro, Rio de Janeiro, Brazil and 2 Institute of Scientific and
Technological Communication and Information in Health, Oswaldo Cruz
Foundation, Rio de Janeiro, Rio de Janeiro, Brazil. Sponsor: E. Silbergeld.
a) Scope: To know the number of published articles in the field of nanoscience and
nanotechnology (NN) and what proportion of them are devoted to health and toxicology.
b) Research approach: Initially, we looked for the total number of articles
published in the field of NN, from January 1, 2000 to December 31, 2009. To this,
we used a technique based on a complex strategy of keywords combination which
could identified almost 530,000 articles. After known the total, we focused on three
scopes of interest to public health, related to the journal categories of Web of
Science (WoS). This database classifies journals in 232 categories. For the subject
Food/Nutrition, 8 categories were selected, for Health, 61 categories, and for
Toxicology, 1 category. c) Results: We identified 2229 articles from 87 countries
and 268 different periodicals, which correspond to the combined scopes NN +
Food / Nutrition, and 33083 articles, from 116 countries, attending the combination
of NN + Health. For toxicological purposes, 1240 articles were identified that
matched the scopes of NN + Toxicology, 33 that matched scopes NN +
Food/Nutrition + Toxicology, and 514 articles that matched scopes NN + Health +
Toxicology. The analysis of the annual profiles for all scopes shows rising number of
published articles, in particular since 2007. The big difference between the total
number of articles published in the area devoted to NN + Toxicology has been
changing slowly if compared to the total number of articles published. From 2000
to 2003, the NN + Toxicology scope accounted for 0.16% of the total and in 2009
to 0.41% (in general, 0.23% for the period). d) Conclusions: The challenges that
nanotechnology and nanomaterials bring to toxicology and their potential environmental
and social impacts cannot be adequately addressed with the maintenance of
the differences between NN and NN + Toxicology.
1485 DISRUPTION OF MUSCARINIC RECEPTOR
MEDIATED SIGNAL TRANSDUCTION BY OXIDATIVE
STRESS.
C. Wu, J. Erickson, H. Wang, Y. Huang and R. S. Aronstam. Biological Sciences,
Missouri University of Science and Technology, Rolla, MO.
The ability of metal oxide nanoparticles (20-60 nm) to alter muscarinic receptor
signaling was studied in CHO cells stably transfected with the gene for human M3
muscarinic acetylcholine receptor. Activation of M3 muscarinic receptors induced a
biphasic increase in [Ca2+]i: an initial, IP3-mediated release of Ca2+ from endoplasmic
reticulum (ER) stores followed by a sustained phase of Ca2+ entry (i.e.,
store operated calcium entry, SOCE). The cells were exposed to the nanoparticles
(0 – 100 μg/ml) 2.5 or 24 hours. Little toxicity was evident after the 2.5 hour exposure.
Following a 24 hour exposure, however, the following order of toxic potency
was obtained: CuO > ZnO = CoO > Cr2O3>NiO >>SiO2, TiO, Fe2O3.
The different particles had multiple effects on calcium metabolism and muscarinic
signaling: 1) resting calcium concentration was increased; 2) thapsigargin-induced
release of calcium from the ER was depressed; 3) IP3 receptor-mediated release of
calcium from the ER was inhibited; and 4) SOCE entry was decreased. Only ZnO,
CuO, CoO and NiO particles consistently increased resting ([Ca2+]i. Thapsigargin
induced depletion of ER calcium was diminished by exposure to ZnO, CoO and
Mn2O3 particles. The initial (IP3 receptor-mediated) increase in [Ca2+]i induced
by muscarinic stimulation was depressed only by exposure to ZnO. However,
SOCE was depressed by several metal oxide particles, with the following order of
potency (2.5 hour exposure): ZnO > CoO > NiO > Fe2O3. Thus, ZnO, CuO,
CoO nanoparticles possessed the most cytotoxicity, and this toxicity was most
closely related to changes in [Ca2+]i. ZnO depressed most aspects of calcium signaling
in response to muscarinic stimulation. While several metal oxide nanoparticles
interfered with SOCE, this effect did not correlate highly with nanoparticle
toxicity. In previous studies, we related ZnO cytotoxic and signaling effects to induction
of oxidative stress. The present findings raise the possibility that the two
sets of action have different origins.
1486 SYSTEMATIC EVALUATION OF THE TOXICITY OF
CARBON-COATED AND NON-COATED COPPER AND
NICKEL NANOPARTICLES.
S. Minocha, A. Sarangi, A. Tropsha and R. J. Mumper. UNC Eshelman School of
Pharmacy, Chapel Hill, NC. Sponsor: A. Ghio.
Manufactured Nanoparticles (MNPs) offer unique advantages of small size and
high surface area and are consequently applicable in a variety of areas ranging from
the medical, agricultural to the electronics industry. In light of the paucity of infor-
mation on the toxicity of these MNPs and their immense applicability, there is a
current need to systematically study the toxicity profiles of MNPs. In this direction,
we have evaluated the effect of carbon coating on the toxicity profiles of matched
pairs of carbon-coated (C-Cu and C-Ni) and non-coated copper and nickel (Cu
and Ni) MNPs in cell-based assays using the A549 alveolar epithelial cell line.
MNPs were characterized for their size, zeta potential, morphology, surface composition,
cellular localization and quantitative cell uptake. Dose dependent toxicity of
MNPs was evaluated using the mitochondrial function and membrane integrity assays
at 24 hr. A kinetic analysis to further investigate the mechanism of cell death
was also performed using Annexin V/ PI staining assay. Average particle size measured
by dynamic light scattering showed that all MNP sizes were on an average 20fold
higher than provided by the manufacturer. The TEM results confirmed the
presence of MNP agglomerates. XPS analysis revealed oxidation of bare metal noncarbon-coated
MNPs. Protection against oxidation is conferred by the carbon coating
in C-Cu and C-Ni MNPs. Ni MNPs appear to be benign under the tested conditions
and C-Ni MNPs altered the mitochondrial function. Cu and C-Cu MNPs
showed altered mitochondrial function and perturbed membrane integrity.
Annexin V/PI staining assay for Cu and C-Cu MNPs suggest that cell death may
occur through a necrotic pathway. In Conclusion the Cu and C-Cu MNPs were
found to be more toxic than Ni and C-Ni MNPs. Currently we are investigating
the physicochemical characteristics responsible for differential toxicity of Cu and
C-Cu MNPs. This research is supported by a grant to RJM and AT from SRC/SE-
MATECH Engineering Research Center for Environmentally Benign
Semiconductor Manufacturing.
1487 THE OCCUPATIONAL HEALTH SURVEY ON WORKERS
AND NANOPARTICLE NUMBERS IN THE FACTORY
HANDLING NANO-TITANIUM DIOXIDE.
S. Ichihara 1 , W. Li 2 , T. Kobayashi 3 , S. Omura 3 , Y. Hiraku 5 , X. Ding 2 and G.
Ichihara 4 . 1 Life Science Research Center, Mie University, Tsu, Japan, 2 Shanghai
Institute of Planned Parenthood Research, Shanghai, China, 3 Tokyo Institute of
Technology, Yokohama, Japan, 4 Nagoya University Graduate School of Medicine,
Nagoya, Japan and 5 Mie University Graduate School of Medicine, Tsu, Japan.
Background: Nano-titanium dioxide is widely used as pigment, sunscreen, and
photocatalyst. Although several epidemiological studies were reported, there was no
information on the particle size. Past epidemiological studies were on the workers
producing titanium dioxide, but there are no studies on workers handling them.
The present study investigated possible respiratory and cardiovascular effects of titanium
dioxide on the workers in Shanghai and the number of particles using condensation
particle counter (CPC) and optical particle counter (OPC). Methods
and results: The diameter of the individual particles before and during working was
measured by electron microscopy. Whereas the first quarter of the primary particle
size was bigger than 100 nm before working, the value was less than 100 nm during
working at the first and second days. Size dependent particle number concentration
was measured by a combined CPC-OPC instrument. The number concentration
of particles with a dimension more than 10 or 5 μm was correlated with the number
concentration of particles with a dimension less than 100 nm, suggesting that
the particle aggregation occurred in the workplace. The mobile ECG was attached
to eight workers and heart rate was monitored during work. In some workers heart
rate was correlated with the number concentration of particles with a dimension
with a dimension less than 100nm. Conclusion: Given that the aggregation of
nano- titanium dioxide plays an important role in the environmental effects of
nanoparticles, it is essential to analyze the status of particles in workplace to consider
the risk for the workers.
1488 QUANTITATIVE PROTEOMICS ANALYSIS OF
ADSORBED PLASMA PROTEINS CLASSIFIES
NANOPARTICLES WITH DIFFERENT SURFACE
PROPERTIES AND SIZE.
H. Zhang, K. E. Burnum, M. L. Luna, B. O. Petritis, J. Kim, W. Qian, R. J.
Moore, B. Webb-Robertson, R. D. Smith, B. D. Thrall, J. G. Pounds and T. Liu.
Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA.
The biological activity, biocompatibility, disposition and fate of engineered nanomaterials
can be directly affected by layers adsorbed proteins or “protein corona”.
We on the interactions between human blood plasma proteins and nanoparticles
with a controlled systematic variation of properties using stable isotope labeling and
liquid chromatography-mass spectrometry (LC-MS) based quantitative proteomics.
We developed a novel protocol to both simplify isolation of nanoparticle
bound proteins and improve reproducibility. LC-MS analysis identified and quantified
plasma proteins associated with polystyrene nanoparticles consisting of three
different surface chemistries and two sizes, as well as, for four different exposure
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