The Toxicologist - Society of Toxicology

tant source of n-3 fatty acids such as decosahexaenoic acid (DHA) which has neuroprotective
effects, and which plays an important role during the prenatal development
of the central nervous system. The aim of the present study was to study
the effects of DHA on developmental MeHg toxicity using behavioural endpoints
in a mammalian model. A battery of neurobehavioural analyses were performed on
15d-old mice which had been exposed to varying levels of DHA and MeHg
throughout development via the maternal diet. There were six exposure groups:
Control; MeHg (as its naturally-occurring cysteinate form; ~ 4 mg/kg); low DHA
(~ 9.5 mg/kg); high DHA (~ 29 mg/kg); MeHg + low DHA and MeHg + high
DHA. Supplementation of the maternal diet with DHA reduced MeHg accumulation
in brains of mice offspring. This effect was unrelated to the level of DHA
supplementation. DHA accelerated the development of grasping reflex in a dosedependent
manner in mice offspring. Effects were also noted on grip strength, a
measure of both physical and behavioral development. Pups from dams fed with
‘MeHg + low DHA’ showed lower grip strength. This effect seemed to disappear in
pups from dams fed with ‘low DHA’. A significant interaction between ‘MeHg’ and
‘low DHA’ was also observed. Development of physical markers and some of the
early pup behavioral parameters (righting, rooting, clasp and auditory startle) did
not seem to be impacted by the exposure groups. The results from the present study
show the potential of DHA in alleviating toxicity caused by MeHg, contributing
towards refining risk/benefit assessments and towards a better understanding of
neurodevelopmental discrepancies found between epidemiological studies.
1026 IN UTERO AND LACTATIONAL EXPOSURE TO 2, 3, 7,
8-TETRACHLORODIBENZO-P-DIOXIN (TCDD)
INDUCES DISRUPTION OF THE PROSTATE GLANDS
AND FIBROSIS IN RHESUS MONKEYS.
H. Kato, R. Ise, T. Hara, H. Wakamatsu, K. Matsushita, A. Matsushita, Y.
Ooshima, R. Nagata and A. Arima. Drug Safety Research Laboratories, Shin
Nippon Biomedical Laboratories Ltd., (SNBL), Kagoshima, Japan.
We investigated the effects of TCDD exposure on the prostate in rhesus monkey
offspring. Dams received 0, 30 or 300 ng/kg TCDD subcutaneously on Day 20 of
gestation, and then 5% of the initial dose was injected every 30 days until Day 90
after delivery. The offspring were maintained until reaching sexual maturity, and
examined histopathologically. Dose-dependent decreases in the prostate glands and
widespread fibrosis were observed in offspring. It is noteworthy that 7 years from
the final lactational TCDD exposure, inflammatory cell infiltration and disruption
of the glandular epithelium were also observed, and indicated these changes were
considered to be ongoing. Furthermore, we conducted global gene expression
analysis by microarray analysis. As a result, the number of genes with a greater than
1.5-fold change and statistically significant differences in mRNA expression was
1502. Among these differentially expressed genes, we classified 5 categories
(Fibrogenesis, Inflammatory response, Disruption of cell component,
Tumorigenesis and Antitumorigenesis) that were considered to be associated with
histopathological changes. We also selected four genes (TGM4, TGFB1, COL1A1
and MMP2), which are associated with fibrosis, inflammatory response and disruption
of cell components, and confirmed quantitatively with real-time quantitative
PCR. Then, all four selected genes were confirmed to have increased expression levels
when compared with the control values, and the expression patterns were similar
between microarray analysis and real-time quantitative PCR. These results indicated
that fibrosis in the prostate were ongoing changes in offspring and had caused
prostatic dysfunction. This prostatic dysfunction caused by TCDD exposure is considered
associated with the findings in our previous reports, i.e., reductions in
sperm and semen quality in second-generation rhesus monkeys.
1027 EVALUATION OF ORGAN WEIGHT DATA FOR
RODENT TOXICITY STUDIES.
S. Jana, M. A. Mulla, S. K. Pandey, A. Govindarajan, V. Goyal, S. Ingle and R.
Nirogi. Toxicology, Suven Life Sciences Limited, Hyderabad, Andhra Pradesh, India.
Sponsor: V. Reddy.
Comparison of organ weights between control and treatment groups is indeed an
important quantitative endpoint in toxicity studies and has conventionally been
used to evaluate the toxic effect of the test article. A statistical analysis is performed
to estimate a treatment effect on the organ weight. The objective of this work is to
understand the relationship between organ weight, body weight and brain weight
as well as to identify parameter which best predict a true effect of chemical on organ
weights. Materials for the present evaluation are comprised of control animal data
collected from short-term repeated dose oral toxicity studies conducted in Wistar
and Sprague-Dawley rats at Suven Life Sciences. All the organ weight data were
subjected to linear regression and correlation was established with body weight and
brain weight. Degree of correlation was determined on the basis of ratio between
correlation coefficient (r) and probable error (PE). If the ratio (r/PE) was more than
6, correlation was considered significant. Significant correlation between body
weights and weights of liver, kidneys and heart was noticed in the present data set.
Correlation with brain weight was also evident for these organs but it was more in
Wistar than Sprague-Dawley rats. Similarly, spleen weights were also correlated
with body weights only in Wistar rats. Thyroid-parathyroid weights were more correlated
with brain weights than body weights. Sex biasness in weights of adrenals
was observed where females only revealed a significant correlation with body
weights in either strain. Other organs did not show any correlation neither with
body weights nor with brain weights. In conclusion, liver, kidneys, heart, spleen
and adrenals weights relative to body weight could be considered for toxicity prediction
whereas in case of thyroid-parathyroid weights, relation to brain weight
should be used. For organs like testes/ovaries, pituitary gland and brain, either absolute
weight or other alternative statistical methods should be identified.
1028 PROVISIONAL ADVISORY LEVEL (PAL)
DEVELOPMENT FOR FENAMIPHOS.
P. B. Selby 1 , C. Weese 2 , P. McGinnis 3 and F. Adeshina 4 . 1 Oak Ridge National
Laboratory, Oak Ridge, TN, 2 U.S. Army Center for Health Promotion and
Preventive Medicine, Aberdeen Proving Ground, MD, 3 Syracuse Research
Corporation, North Syracuse, NY and 4 U.S. EPA, Washington, DC.
PAL values developed for hazardous materials by the U.S. EPA represent general
public emergency exposure limits for oral and inhalation exposures corresponding
to three different severity levels (1, 2, and 3) for 24-hour, 30-day, 90-day, and 2-
year durations. PAL 1 represents the threshold for mild effects; PAL 2 represents the
threshold for serious, irreversible or escape-impairing effects; PAL 3 represents the
threshold for lethal effects. PALs have not been promulgated nor have they been
formally issued as regulatory guidance. They are intended to be used at the discretion
of risk managers in emergency situations when site-specific risk assessments are
not available. Application of PAL protocols has been performed for fenamiphos to
the degree supported by the available data. Fenamiphos is an organophosphate nematicide
and insecticide, for which all registrations in the United States were cancelled
on or before May 31, 2007. Fenamiphos inhibits cholinesterase activity in
humans and other mammals, and, as a result, it can overstimulate the nervous system
to cause nausea, dizziness, confusion, and, at very high exposures, respiratory
paralysis and death. It is readily absorbed from the gastrointestinal tract and is also
absorbed through inhalation and through intact skin. Oral PAL values were derived
from feeding studies on dogs and rats and from gavage studies on rats. Data were
available to support derivation of oral PAL values at all durations for PAL 1,
through 90 days for PAL 2, and only for 24 hours for PAL 3. Inhalation PAL values
were derived from inhalation studies on rats that involved either a single 4-hour exposure
or repeated 6-hour exposures spread over three weeks. These data supported
derivations of all three PAL values for 24 hours and a PAL 1 for 30 days. PAL estimates
for fenamiphos were approved by the Expert Consultation Panel for
Provisional Advisory Levels in July 2008 and will be presented.
1029 ATSDR’S ACUTE- AND INTERMEDIATE-DURATION
ORAL MINIMAL RISK LEVELS (MRLS) FOR
ACRYLAMIDE.
O. Faroon 1 , P. Ruiz 1 , D. Wholers 2 and M. Mumtaz 1 . 1 ATSDR, Atlanta, GA and
2
SRC Inc., North Syracuse, NY.
In 2008, about 141,000 metric tons of acrylamide were produced in the USA.
Human exposed to acrylamide via oral route mainly ATSDR has derived acute- and
intermediate-duration oral MRLs of 0.02 mg/kg/day and 0.002 mg/kg/day, respectively,
for acrylamide during the development of a new Toxicological Profile for
Acrylamide. The MRLs are based on results of animal studies because adequate
dose-response human data are not presently available. Male-mediated decreased fertility
and increased pre- and post-implantation losses are considered to represent
the most sensitive adverse nonneoplastic effects of acute-duration oral exposure to
acrylamide. These effects were elicited in Long-Evans rats following oral dosing of
males for 5 days and subsequent matings with untreated females. Benchmark dose
(BMD) analysis was performed on the dichotomous fertility data using a benchmark
response of 10% to determine a point of departure for deriving the MRL.
Default uncertainty factors for extrapolation from animals to humans and for
human variability were applied. Results of available animal studies identify malemediated
reproductive effects and neurological effects in orally-exposed rats as the
most sensitive nonneoplastic effects of intermediate-duration oral exposure to acrylamide.
Ultrastructural degenerative peripheral nerve changes have been detected at
lower exposure levels than those eliciting male-mediated reproductive effects.
Therefore, the intermediate-duration oral MRL for acrylamide is based on degenerative
nerve changes in orally-exposed rats as the critical effect. A NOAEL/LOAEL
SOT 2010 ANNUAL MEETING 219