The Toxicologist - Society of Toxicology

platform. This novel type of visualization allows not yet-seen insights and interpretations
on how certain ADRs are connected in chemical space. Several examples
and extensions of the method will be discussed.
858 INNOVATIONS IN TOXICITY TESTING – AN
INTEGRATED APPROACH TO TESTING OF A NEW
AGROCHEMICAL BASED ON SOUND SCIENCE AND
THE “3RS” PRINCIPLES ON ANIMAL RESEARCH.
C. Terry 1 , R. J. Rasoulpour 2 , B. Gollapudi 2 and R. Billington 1 . 1 Dow
AgroSciences LLC, Oxfordshire, United Kingdom and 2 The Dow Chemical Company,
Midland, MI.
The toxicology development program for a new agricultural molecule
(X11422208) provided an opportunity to modify standard testing strategies and
study designs by undertaking, for the first time, an integrated approach to 1) applying
3Rs (Replacement, Refinement and Reduction) principles, 2) generating
toxicokinetic (TK) data across studies, and 3) including mode-of-action (MoA)
end-points to facilitate early, informed decision-making.
Approaches to the 3Rs included modifying standard palatability studies to provide
additional information, performing toxicokinetic analysis without using satellite
animals, and obtaining MoA data from regulatory studies. For example, the 90-day
rat study included many integrated components such as immunotoxicity based on
OPPTS guideline 870.7800, neurotoxicity following OECD and OPPTS guidelines
and tissue sampling to aid MoA investigations.
Performing TK in all toxicity studies generated comparative blood and urine
TK/metabolism data across dose levels, sexes, study durations, species, strains and
life stages. These data may also be useful to provide perspective on biomonitoring
data where human blood levels could be compared to NOAEL/LOAEL blood concentrations
from animal studies, to inform human health risk assessment and to
draw meaningful animal to human correlations.
Finally, decision-making was facilitated by providing early information, including
MoA data (versus retrospective investigations at the end of the program) to predict
potential effects in longer-term studies (e.g., carcinogenesis), to provide clues on
potential human relevance, to aid study design and dose selection (e.g., kineticallyderived
maximum dose levels) and to optimize the collection of desirable information
from a minimum number of animals. These innovative approaches are introducing
a new paradigm in pesticide regulatory toxicology testing with primary
drivers being animal welfare and sound science potentially leading to more informed
human risk assessment.
859 CROSS-SPECIES GENE EXPRESSION CHANGES IN
PRIMARY HEPATOCYTES EXPOSED TO 2, 3, 7, 8-
TETRACHLORODIBENZO-P-DIOXIN.
J. Rowlands 1 , R. A. Budinsky 1 , A. A. Dombkowski 2 and R. S. Thomas 3 .
1 Toxicology and Environmental Research & Consulting, The Dow Chemical
Company, Midland, MI, 2 Department of Pediatrics, Wayne State University School of
Medicine, Detroit, MI and 3 Center for Genomic Biology and Bioinformatics, The
Hamner Institutes for Health Sciences, Research Triangle Park, NC.
Human and rat primary hepatocytes were used to explore species-specific differences
in gene expression profiles after treatment with 2,3,7,8-tetrachlorodibenzo-pdioxin
(TCDD). Hepatocytes from five adult women and five female Sprague-
Dawley adult rats were exposed for 24 hours to eleven concentrations of TCDD
spanning 7-log concentrations (0.00001 nM to 100 nM) and the mRNA expression
changes measured on whole genome arrays. Comparison of the orthologous
genes with a minimum 1.5 fold change revealed that only a very small number of
genes were upregulated in rat and human cells with 11 genes and 12 genes affected,
respectively. Of these, 7 genes were in common between rats and humans and these
were largely AHR core battery genes. Pathway enrichment analysis was performed
on the most positively and most negatively correlated orthologous genes (r > 0.7).
For genes with positive dose response correlation, cross-species comparison showed
enrichment in AHR signaling and xenobiotic metabolizing enzyme pathways. A
cross-species comparison of genes with a negative dose response correlation showed
enrichment in immune system pathways. Benchmark dose (BMD) analysis was
conducted on AHR core genes CYP1A1, CYP1A2, CYP1B1 and NQO1 and on
AHR regulated signaling pathways. The median human to rat BMD ratio was 7.1
for individual genes and 6.5 for pathways. On both a gene- and pathway-basis, the
results indicate significant differences exist in the response of rats vs. humans to
TCDD and the data support cross-species adjustment factor of 1.0 or less for risk
assessment of TCDD.
184 SOT 2011 ANNUAL MEETING
860 COMPARATIVE QSAR STUDIES OF MONO-
HYDROXYLATED POLYCHLORINATED BIPHENYLS
AND THEIR POTENTIAL ESTROGENIC EFFECTS.
P. Ruiz, O. Faroon, B. Fowler and M. Mumtaz. Department of Toxicology and
Environmental Medicine, ATSDR, Atlanta, GA.
Mono-hydroxylated Polychlorinated Biphenyls (OH-PCBs) represent a new health
and environmental concern because they have been shown to have agonist or antagonist
interactions with hormone receptors (HRs) or hormone-receptor mediated
responses. Preliminary comparative Quantitative Structure Activity
Relationship (QSAR) analyses have been performed with 71OH-PCBs for estrogenic
activity (human estrogen receptor ERalpha) using two-dimensional (topological
and structural) and three-dimensional (spatial) descriptors. The chemometric
tools used for the analyses are stepwise multiple linear regression, partial least
squares, and recursive partitioning. The data set was divided into a training set and
test set, and models were developed from the training set compounds. The best
model was selected based on the highest external predictive q2 (cross-validation)
value (0.932) and the lowest standard error of prediction value (0.64). The developed
QSAR equations suggest the importance of the position of hydroxyl substitution
on the phenyl ring, polarizability and the contribution of adjacent unsubstituted
carbon pairs towards greater activity of these chemicals. When fully
developed this model may be used for prediction of toxicity and for identification
of potential adverse health consequences of untested OH-PCBs and serve as a useful
tool for the safety and risk assessment of these chemicals. Further development
of the model and evaluation of findings could enable mechanistic insight into the
estrogenicity effects of OH-PCBs.
861 MOLECULAR FIELD TOPOLOGY ANALYSIS OF
STRUCTURAL DETERMINANTS FOR ACUTE AND
DELAYED NEUROTOXICITY OF O-
PHOSPHORYLATED OXIMES.
G. F. Makhaeva 1 , E. V. Radchenko 2 , V. B. Sokolov 1 , V. A. Palyulin 2 , N. S.
Zefirov 1, 2 and R. J. Richardson 3 . 1 Institute of Physiologically Active Compounds,
Russian Academy of Sciences, Chernogolovka, Russian Federation, 2 Chemistry
Department, M.V. Lomonosov Moscow State University, Moscow, Russian Federation
and 3 Toxicology Program, Department of Environmental Health Sciences, University
of Michigan, Ann Arbor, MI.
We used Molecular Field Topology Analysis (MFTA), a 2D QSAR approach based
on local molecular properties (e.g., atomic charges, group van der Waals radii and
group lipophilicities), to create QSAR models for anti-acetylcholinesterase (AChE)
and anti-neuropathy target esterase (NTE) activity and selectivity for a series of Ophosphorylated
oximes. MFTA produces a molecular supergraph providing a common
frame of reference for the set of structures under study, partial least squares
(PLS)-based regression models, and graphical maps summarizing the influence of
local properties on activity or selectivity. Data on inhibitor activity were represented
as logk i (AChE)and logk i (NTE) [k i , M -1 min -1 ]; and selectivity for NTE vs AChE as
log[k i (NTE)/k i (AChE)]. Three models were obtained: (1) logk i (AChE): N=58,
N F =6, R 2 =0.91, RMSE=0.33, Q 2 =0.73, RMSEcv=0.58; (2) logk i (NTE): N=35, N F =6,
R 2 =0.96, RMSE=0.26, Q 2 =0.82, RMSEcv=0.55; and (3) log[k i (NTE)/k i (AChE)]:
N=35, N F =2, R 2 =0.80, RMSE=0.61, Q 2 =0.70, RMSEcv=0.77, where N = number
of compounds; N F = number of factors in the PLS model; R 2 = squared correlation
coefficient; RMSE = root-mean-square error; Q 2 = cross-validation parameter; and
RMSEcv = root-mean-square error for cross validation. In addition to the predictive
PLS regression models, maps of local descriptor influence on the anti-AChE and
anti-NTE activity of the compounds as well as on the selectivity of compounds to
NTE vs AChE (neuropathicity maps) were obtained. The predictive value of the
models for acute and delayed neurotoxicity remains to be validated by experimental
tests. Supported by ISTC project #3130 and RAS Program “Biomolecular &
Medicinal Chemistry”.
862 FRAMEWORK FOR INTEGRATION OF HUMAN AND
ANIMAL DATA FOR RISK ASSESSMENT PURPOSES:
CHLORPYRIFOS NEUROBEHAVIORAL DATA AS
CASE-STUDY.
A. A. Li 1 , K. Lowe 1 , L. McIntosh 1 and P. Mink 2 . 1 Health Sciences, Exponent Inc.,
San Francisco, CA and 2 Epidemiology, Emory University, Atlanta, GA.
Both analytical epidemiology and animal research data from the published literature
are important for a comprehensive assessment of risks due to pesticide exposure
to humans. Currently, risk assessments (RA) for food-use pesticides are based
primarily on guideline animal toxicity studies required for registration. Approaches