The Toxicologist - Society of Toxicology

samples, OPN levels were significantly influenced by diet with DHA exhibiting
62% and 80% that of SAF and CRN, respectively. Thus, DHA suppression of
OPN is a potential critical early event in the downregulation of aberrant humoral
autoimmunity in murine lupus nephritis.
1785 MODULATION OF BODY FAT MASS AND LEAN
WEIGHT IN DEOXYNIVALENOL-INDUCED BODY
WEIGHT REDUCTION IN THE OBESE MOUSE.
K. Hattori 1, 2 , B. Flannery 1 , C. Amuzie 1 and J. J. Pestka 1 . 1 Food Science and
Human Nutrition, Michigan State University, East Lansing, MI and 2 Nutritional
Science, Tokyo University of Agriculture, Setagaya-ku, Tokyo, Japan.
Our laboratory has observed that deoxynivalenol (DON) can both prevent and
ameliorate weight gain in the diet-induced obese (DIO) mouse model. Here we related
DON’s therapeutic effects in DIO mice to food intake, body fat mass and
lean weight. B6C3F1 mice (female, 11-week-old) were divided into 3 groups and
fed each diet (10 kcal%, 45 kcal% and 60 kcal% from fat, Research Diets, Inc.) for
94 days. After inducing obesity, the mice were divided into 5 groups (n=8) and fed
control diet (10 kcal%) or high-fat diets (45 kcal% or 60 kcal%) with or without
DON (10 ppm) from Day 94 to 147. Body weights of the 45 kcal% + DON and
60 kcal% + DON groups rapidly decreased after DON intake and reached that of
the 10 kcal% control by Day 105. As compared to the 45 and 60 kcal% groups,
food intake by DON-fed groups significantly decreased at Day 98 and 101, which
corresponded to the period in which DON-fed groups exhibited robust body
weight decreases. As determined with MRI (EchoMRI-100), body fat mass and
body fat percentages of the 45 and 60 kcal% with DON-fed mice gradually reduced
to those of control. Lean weights of the DON-fed groups were significantly
lower than those of the 45 and 60 kcal% groups after Day 122. We conclude that
DON-induced reduction in body weight in the DIO mice results from decreased
food intake, and this corresponds to decreases in both body fat mass and lean
weight.
1786 NORMAL RANGE AND FORMS OF DIETARY
SELENIUM PREVENTS METHYLMERCURY TOXICITY
IN LONG EVANS RATS.
N. V. Ralston. Energy & Environmental Research Center, University of North
Dakota, Grand Forks, ND. Sponsor: M. Aschner.
Methylmercury (MeHg) is a highly specific irreversible inhibitor of selenium (Se)-
dependent enzymes (Se-enzymes). Over 30 genetically unique Se-enzymes are expressed
in mammals, many with roles in preventing and reversing oxidative damage
in the brain. The Se-enzymes employ selenocysteine (Sec) at their active sites and
MeHg intoxication inhibits Se-enzyme activities in brain and neuroendocrine tissues.
Supplemental Se has been known to counteract Hg toxicity since 1967, but
mechanisms have only recently become clear. Since dietary Se must be reduced to
inorganic forms before it can be incorporated into Sec, it was not known whether
dietary Se from ocean fish would be as effective as inorganic Se provided in the diet.
In the current study, 120 weanling male Long Evans rats were fed diets containing
either low or high MeHg (0.5 or 50 nmol MeHg/g) with Se as inorganic Se
(sodium selenite) at low, normal, or rich (0.1, 1.0, or 10 nmol Se/g) in diets prepared
with torula yeast protein (as~30% of nutritionally complete AIN-93G diet).
or Se from delipidated protein isolated from bigeye tuna, swordfish, or mako shark
added as 10% of the total diet in place of an equivalent amount of torula yeast protein;
(2 Hg levels x 6 Se diets = 12 dietary treatments). Contributions of additional
MeHg in the fish supplemented diets were between 1.6 and 3.6 nmol MeHg/g, and
Se ranged between 2.1 and 3.5 nmol Se/g. Rats were randomly assigned to each of
the 12 diets (10 rats per group). After 5 weeks on low Se diets (without added
MeHg) to deplete their Se reserves, all rats were switched to their assigned dietary
treatments. Rats maintained on high MeHg, low Se diets showed growth inhibition
after 4 weeks, and hind limb crossing after 9 weeks on the dietary treatment, but all
other dietary treatment groups grew normally and were protected against neurofunctional
defects. The MeHg from fish did not contribute to worsening MeHg
toxicity, but the Se from fish was absorbed and utilized as readily as inorganic Se,
and was equally effective in preventing MeHg toxicity.
1787 PRECLINCAL SAFETY EVALUATION OF U.S. FDA-
APPROVED ONCOLOGY DRUGS: RECENT TRENDS IN
CONCURRENCE WITH DRAFT ICH S9 GUIDELINE.
M. Z. Dieter, S. L. Ralston, L. A. Gallenberg and J. E. Burkhardt. Abbott
Laboratories, Abbott Park, IL.
The approval packages of oncology compounds recently approved by the United
States Food and Drug Administration (FDA) were evaluated in order to gauge
trends in preclinical toxicology studies performed to support development of anticancer
compounds, as outlined in the draft International Conference on
Harmonisation (ICH) S9 guideline on Nonclinical Evaluation for Anticancer
Pharmaceuticals. Analysis was limited to original applications approved from July
1999 through July 2009. Data was collected from Summary Basis of Approval
(SBA) documents via the PharmaPendium database current as of July 2009.
SBA’s for 28 oncology-indicated small molecule or biotherapeutic compounds were
evaluated for the scope of toxicology studies conducted. ICH S7A “core battery”
safety pharmacology studies were conducted for 12 compounds; however, 6 compounds
were approved with no safety pharmacology studies performed. Acute single
dose and repeat dose range-finding studies were conducted in at least one
species for the majority of compounds. Pivotal repeat-dose studies were variable in
length from 1 month to 1 year, but generally conducted for at least 6 months in two
species. ICH S2 “standard battery” genotoxicity assays were performed for 17 compounds,
including 5 with expected mechanism-based genotoxity. Genotoxicity assays
were not conducted for two monoclonal antibodies. Carcinogenicity studies
were conducted for 5 compounds. Embryofetal toxicity (Seg II) studies were conducted
in both rodent and non-rodent species for 18 of the compounds; for each of
the 8 compounds evaluated in only one species, the compound was considered a selective
developmental toxicant. Fertility (Seg I) studies were conducted for the majority
of compounds, whereas neonatal and postnatal development (Seg III) studies
were conducted for only 4 compounds. The results signify that many recommendations
contained in the draft ICH S9 guideline are already being adopted, and that
this guideline, once finalized, should expedite development of oncology agents for
advanced cancer patients.
1788 IMPACT OF DATA AVAILABILITY ON THE
CALCULATION OF REACH DNELS FOR WORKER AND
CONSUMER POPULATIONS.
R. Roy, N. Pechacek, L. Milchak and R. Skoglund. 3M Company, St. Paul, MN.
Under the European Union’s Registration, Evaluation, Authorization, and restriction
of CHemicals (REACH) regulation, the Derived No-Effect Level (DNEL)
represents a level of exposure above which humans should not be exposed.
Chemical-specific DNELs for worker (W-DNEL) and consumer (C-DNEL) populations
are often derived as part of the chemical safety assessment. The European
Chemicals Agency (ECHA) has developed guidance for the calculation of DNELs
for both workers and consumers. Steps in DNEL calculation include establishing
study “dose descriptor(s)” such as NOAEL, LOAEL, etc. and their modification for
bioavailability, route-to-route extrapolation and exposure conditions; and, lastly,
application of Assessment Factors (AFs) for intra-and inter-species differences, duration
of exposure, etc. While it is preferable to use chemical-specific modifiers/factors
in DNEL calculations, many are not [readily] available and, thus, ECHA provides
default factors for use in these calculations.
The impact of both chemical- and use-specific data (vs. defaults) is illustrated by
calculating W-DNEL and C-DNEL for: (1) long-term inhalation exposure based
on rat inhalation data and (2) long-term dermal exposure based on oral rat data.
Significant differences in W-DNEL and C-DNEL values can be observed depending
on the use of chemical-specific data (e.g. dermal and oral absorption data for
route-to-route extrapolation) and consumer use data (e.g. number of hours/day of
exposure). For example, if both dermal and oral % absorption of a chemical is
known, the use of these data can provide a significantly different DNEL vs. the
DNEL calculated using ECHA defaults. As an example of case (2), above, the
DNEL for a chemical with 100% and 10% absorption via oral and dermal routes,
respectively, will be 10-fold greater than that calculated using the ECHA defaults.
This exercise shows the importance of using reliable, available, chemical-specific
data for calculation of DNELs for use in REACH compliance.
1789 ICCVAM RECOMMENDATIONS FOR USE OF THE
LLNA FOR EVALUATING THE ALLERGIC CONTACT
DERMATITIS POTENTIAL OF PESTICIDE
FORMULATIONS.
J. Matheson 1 , A. Jacobs 2 , M. Wind 1 , J. Chen 3 , M. Hashim 3 , M. Lewis 3 , E.
Margosches 3 , D. McCall 3 , T. McMahon 3 , J. Redden 3 , R. Ward 3 and W. Stokes 4 .
1
CPSC, Bethesda, MD, 2 U.S. FDA, Silver Spring, MD, 3 U.S. EPA, Washington,
DC and 4 NICEATM, NIEHS, Research Triangle Park, NC.
ICCVAM has updated its 1999 validation report on the LLNA based on a recent
evaluation of the usefulness and limitations of the LLNA for assessing the skin sensitizing
potential of pesticide formulations. This review was initiated because the
original report did not include an analysis of the LLNA for these types of substances,
and there were growing regulatory concerns that the LLNA might not
identify sensitizing pesticide formulations. LLNA data from 104 formulations were
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