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Basic Information
Introduction
EPA’s Computational Toxicology Research Program is intended to provide innovative solutions to a number of persistent and pervasive issues facing EPAs regulatory programs. The vision of the program is an EPA that efficiently characterizes exposure, hazard, and risk
through the broad use of modern biological tools, information technologies, and computational models.
To facilitate this EPA formed the National Center for Computational Toxicology (NCCT) in 2005. The center is staffed with systems biologists, computational chemists, and bioinformaticians, all focused on solving the Agency’s environmental science questions.
Mission
- Provide scientific expertise and leadership related to the application of mathematical and computational tools and models
- Improve the predictive capabilities of the methods, models, and measurements that constitute input
materials to the computational models
- Conduct and sponsor research to develop
system-level models that can describe biological processes ranging from cellular levels to ecosystems
- Maintain a strong emphasis on the development of partnerships with other government and private organizations
Research Activities
ToxCast™ has been developed as a cost-effective approach for prioritizing the toxicity testing of large numbers of chemicals in a short period of time. Using data from state-of-the-art high-throughput screening bioassays developed in the pharmaceutical industry, ToxCast™ is building computational models to forecast the potential human toxicity of chemicals. These hazard predictions will provide EPA regulatory programs with science-based information helpful in prioritizing chemicals for more detailed toxicological evaluations and lead to more efficient use of animal testing.
NCCT scientists are leading the development of a "Virtual Liver," which is a large-scale biologically based computer model of the organ. The liver plays a key role in removing chemicals from the body and frequently shows the earliest signs of their harmful effects. Animal testing gives useful information about the effects of environmental chemicals; however, the relevance of these findings to humans is not always clear. Human risk assessment will be more effective, efficient, and humane if the biological phenomena involved in the fate of chemicals through the body and the liver could be predicted accurately. The Virtual Liver aims to simulate these phenomena using large-scale computational models.
A sophisticated computer model of a human embryo called the "Virtual Embryo" also is being developed. Many developmental tissues are critically sensitive to many chemicals at levels below those that adversely affect the pregnant mother. Reproductive-developmental studies are among the largest consumer of animal resources in toxicity testing, and the number of chemicals requiring evaluation for developmental toxicity far exceeds what has and can be delivered through traditional methods. Through computer simulations that are biologically based and mathematically driven, the Virtual Embryo aims to advance the long-term goal of understanding and predicting the developmental risks posed by environmental chemicals to the embryo, fetus, or newborn.
Goals
Databases and Models
ACToR (Aggregated Computational Toxicology Resource) is a tool being developed to manage large scale sets of assay and toxicology data on chemicals of interest to the EPA. These include pesticide active and inert ingredients, high production volume chemicals, drinking water contaminants and other environmental chemicals. Currently ACToR is only available to EPA users on the Agency intranet. The ACToR project is compiling both quantitative and qualitative data from a large number of sources and data collections, including EPA databases, PubChem, other NIH and FDA databases, state and other national sources, and academic groups.
Database of Physiological Parameters of Early Life Rats and Mice is designed to be a useful tool for biologically based modelers by providing access to age-specific parameter values and the scientific literature from which they were extracted. One use will be to help estimate values for physiologically
based pharmacokinetic (PBPK) models for rodents. PBPK models are valuable tools for estimating internal measures of dose for application in research and risk assessment of potential effects of exposures to chemicals. A focus of these modeling efforts is to describe growing and aging individuals and the resulting changes in internal dose during these life stages. Modeling life stage requires age- specific information for the model parameters describing physiology. These parameters include body weight, tissue volumes, blood flows, and inhalation rates among others. Data have been compiled from the scientific literature into an electronic database to provide modelers with access to the information. The database currently contains information compiled on Sprague-Dawley, Wistar, and Fisher 344 rats and mice of
any strain.
DSSTox (Distributed Structure-Searchable Toxicity Database Network) is a chemical data foundation for improved structure-activity and predictive toxicology capabilities across and outside of EPA. The DSSTox Web site publishes downloadable, standardized chemical structure files associated with toxicity data in a variety of formats, along with documention and links to source information. In addition, the Web site hosts a large amount of additional information on the DSSTox project, as well as information on data standards, EPA and outside collaborations, quality review procedures, guidance for users, etc.
ToxRefDB (Toxicity Reference Database) is a relational database of standard toxicity test results for pesticides and other environmental chemicals, making it possible to link toxicity information with the HTS and genomic data of ToxCast™ within the ACToR system. ToxRefDB uses a controlled vocabulary and standardized data field structure, aligned with other public data model efforts, to capture toxicological end points, critical effects, and relevant dose-response data from EPA's Office of
Pesticide Programs and other sources.
Though not currently
available publicly, ToxRefDB
and the data it contains will
be available on EPA Web
sites in the near future.
Collaboration and Partnerships
NCCT actively seeks opportunities to partner and collaborate on environmental research and development projects with outside entities, industry, consortia, academia, trade associations, and state and local agencies to facilitate the development of a national approach to the use of computational procedures in toxicology. A current listing of our partners is available on our Web site, http://www.epa.gov/comptox/.
Communities of Practice (CoP) are associations of individuals interested in promoting the utilization of advancements in specific areas of computational toxicology. Each one that is established has a charter and an open membership policy and is co-chaired by a member of NCCT. By bringing together members from different parts of Office of Research and Development (ORD), EPA, and the outside scientific community, CoPs help promote the adoption of common practices and ontologies, guide development of common databases and software usage, aid in construction of training materials, provide recommendations on efficiencies of relevant operations, and act as a public outreach mechanism for ORD activities. To date, three CoPs have been established: (1) Chemoinformatics, (2) Chemical Prioritization, and (3) Biological Modeling.
NCCT encourages cooperative research and development partnerships with nonfederal entities under the Federal Technology Transfer Act. Cooperative Research and Development Agreements (CRADAs) and Materials Transfer Agreements are negotiated agreements between NCCT and nonfederal partners that outline the terms and conditions under which cooperative work will be performed. Although NCCT cannot transfer funds to the cooperating partner under a CRADA, they can exchange personnel, equipment, or services. NCCT can accept funds and in-kind resources from CRADA partners, that go to support the work outlined in the agreement.
Memoranda of Understanding (MOU) are unfunded agreements between NCCT and other outside entities. These agreements, establish a nonbinding general framework for cooperation, including planning for collaboration. NCCT has several MOUs, including a tripartite agreement with two institutes of the NIH, which implements the long-range vision outlined in the 2007 National Research Council report, Toxicity Testing in the 21st Century: A Vision and a Strategy. This report calls for a collaborative effort across the toxicology community to rely less on animal studies and more on in vitro tests using human cells and cellular components to identify chemicals with toxic effects.