ORDs Computational Toxicology Research Program

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ORDs Computational Toxicology Research
Program Robert J. Kavlock, U.S. Environmental
Protection Agency, Office of Research and
Development, NCCT
Research Progress
Science Questions
Given the need to become more efficient and
effective in the use of animals in screening and
testing programs, what role can computational
approaches play in characterizing endocrine
disruption? How can omic approaches be used in
the context of quantitative risk assessements
New Start Projects within the Computational
Toxicology project awards were announced in
October, 2004
Research Goals
Impact. Outcomes and Future Directions
Computational Toxicology is defined in the
Framework for a Computational Toxicology
Research Program as the application of
mathematical and computer models and molecular
biological approaches to improve the Agencys
prioritization of data requirements and risk
assessments. Initiated by a Congressional
reprogramming action in FY02, the computational
toxicology program has undertaken several proof
of concept studies for endocrine disruption, as
it was felt that EPA already had a strong
research presence in the area, and that
considerable information was known about the
relevant toxicity pathways. Therefore, several
projects were launched that will provide both
short term and long term products to the
Endocrine Disruptor Screening Program. In FY03,
ORD developed and had peer reviewed its Framework
document that is intended to guide the increasing
level of resources being dedicated to the
program. In FY04, and Implementation and
Steering Committee (CTISC) was formed to begin to
translate the Framework into action. The CTISC
awarded 10 Augmentation projects funding to
immediately expand omic research across ORD,
and later awarded 7 New Start projects that
represented significant investments over a three
year funding period. In FY05, ORD
institutionalized the computational effort by
creating the National Center for Computational
Toxicology Research Center. The Center is
staffed with systems biologists, computational
chemists and bioinformaticians, and will be focal
point for computational toxicology efforts across
ORD. One of the main early challenges of the
program will be to developed approaches for
priortizing chemical lists of concern to the
Agency for screening and testing purposes.
Ideally this will lead to tailored testing
schemes for chemicals, and to more effective and
efficient use of animals in research. This, in
turn, will lead to improved risk assessment
methodologies and outcomes.
The CT program will continue developing tools and
approaches for the prioritization of screening
and testing needs in the areas of endocrine
disruptors, pesticidal inerts, and non-food use
anti-microbial agents. Application of these
approaches to the screening and testing needs of
EPA program offices (e.g., the Prevention,
Pesticides, and Toxic Substances program and the
Air program) will also be evaluated. The program
also expects to deliver the first alternative
assay for animal testing of environmental
toxicants in FY06. This will be accomplished
with an in-vitro cell line to study the potential
of chemicals to stimulate the excessive
production of steroids within living systems.
This assay could be a replacement for a currently
used animal-based assay in the Tier 1 screening
battery of compounds that may disrupt the bodys
endocrine or hormonal systems. In addition, the
CT program will add a number of new toxicological
databases to the Distributed Structure-Searchable
Toxicity (DSSTox) system, expand the breadth of
chemicals evaluated through computational models
of nuclear receptor-ligand docking preferences,
provide an expanded list of chemicals tested
through the androgen and estrogen cell lines
developed by EPA, and communicate the results of
two conferences on the application of genomic
technologies to eco-toxicological and human
health risk assessment processes. It will also be
working to establish the STAR funded Center for
Environmental Bioinformatics in order to help
ensure that the data emanating from ORD research
projects in omics will be appropriately mined
for information
The mission of the NCCT is to provide scientific
expertise and leadership related to the
application of mathematical and computational
tools and models to high priority Agency needs,
including data reporting requirements, priority
setting, and understanding toxicities and risks
associated posed by environmental agents. The
scientific staff works closely with other Labs
and Centers to establish stronger linkages
between individual components of the source to
outcome paradigm, to develop strategies for
prioritizing chemicals for screening and testing,
and to improve quantitative risk assessments. It
also serves as a think tank within ORD for the
evaluation and potentially adaptation of new
technologies in computational chemistry,
molecular biology, and informattion technology
.
Other Activities of Note - Evaluation of
commercial predictive model of hepatoxicity via
toxicogenomic analysis (ICONIX - Support for
NSF/WTEC assessment of state of the science of
systems biology research in the US, Europe and
Japan - Support for SETAC-Pellston workshop for
the use of toxicgenomic information in ecological
risk assessemnts - Significant expansion of the
numbers of chemicals assayed in ORD developed
transcriptional activation assays for ER and AR
activity
References
The H295R cell based assay for steroidogenesis
is being developed by J Geisy at MSU
US EPA (2004). A Framework for a Computational
Toxicology Program Research Program.
EPA/600/R-03/065