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DEVELOPING COMPUTATIONAL TOOLS FOR PREDICTING CHEMICAL FATE, METABOLISM, AND TOXICITY PATHWAYS

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http://cfpub.epa.gov/si/si_public_comments.cfm

Impact/Purpose:

This task is divided into four major research areas: (1) Development of computational tools and databases for screening-level modeling of the environmental fate of organic chemicals; (2) Metabolism of xenobiotics: Enhancing the development of a metabolic simulator; (3) Metabonomics: The use of advanced analytical tools to identify toxicity pathways; and (4) Software infrastructure to support development and application of transformation/metabolic simulators.

For many chemicals, multiple transformation/metabolic pathways can exist. Consequently, transformation/metabolic simulators must utilize transformation rate data for prioritization of competing pathways. The prioritization process thus requires the integration of reliable rate data. When this data is absent, it is necessary to generate a database with metabolic and transformation rate constants based on: (1) experimentally measured values, including those requiring the use of advanced analytical techniques for measuring metabolic rate constants in vivo and in vitro; (2) rate constants derived from SPARC and mechanistic-based QSAR models; and (3) data mined from the literature and Program Office CBI. A long-term goal of this project is to build this database. This information will be used to enhance the predictive capabilities of the transformation/metabolic simulators. As indicated previously, exposure genomics, which provide early signs of chemical exposure based on changes in gene expression, will be used to guide chemical fate and metabolism studies. The incorporation of exposure genomics into fate studies will provide information concerning (1) the minimal concentrations at which biological events occur; and (2) the identification of biologically relevant chemicals(s) in mixtures.

The capability of categorizing chemicals and their metabolites based on toxicity pathway is imperative to the success of the CompTox Research Program. Metabonomics, which is the multi-parametric measurement of metabolites in living systems due to physiological stimuli and/or genetic modification, provides such a capability. The application of metabonomics to toxicity testing involves the elucidation of changes in metabolic patterns associated with chemical toxicity based on the measurement of component profiles in biofluids, and enables the generation of spectral profiles for a wide range of endogenous metabolites. Metabolic profiles can provide a measure of the real outcome of potential changes as the result of xenobiotic exposure.

Description:

ORD's research program in Computational Toxicology (CompTox) will enable EPA Program Offices and other regulators to prioritize and reduce toxicity-testing requirements for potentially hazardous chemicals. The CompTox program defines the "toxicity process" as follows : 1) a stressor source, 2) the environmental concentration of the stressor, 3) the level of exposure of the stressor to a vulnerable organism, 4) the effective dose inside the organism, 5) a biological event triggered by the stressor, and 6) a toxic outcome. At several points in this process, it is critical to accurately model the fate of chemical stressors and predict toxicity pathways. For example, one must model the fate and transport of a chemical after it is released into the environment to determine the level of exposure to organisms of concern. Also, one must model the metabolism of the chemical inside the target organisms, because it is often a metabolite of the original stressor that induces a biological event. Unique to this research will be the application of exposure genomics (evaluating gene expression profiles) to guide the chemical fate and metabolism studies. Finally, the development of the software infrastructure to house the science and knowledge required for the transformation simulators is required. ERD has designed this research task to meet these critical needs of the ORD CompTox Research Program.

Record Details:

Record Type:PROJECT
Start Date:01/01/2003
Projected Completion Date:01/01/2007
OMB Category:Other
Record ID: 56124