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EPA SCIENCE FORUM - EPA'S TOXICOGENOMICS PARTNERSHIPS ACROSS GOVERNMENT, ACADEMIA AND INDUSTRY
DIX, D. J., W. BAO, H. REN, D. R. EKMAN, AND R. J. KAVLOCK. EPA SCIENCE FORUM - EPA'S TOXICOGENOMICS PARTNERSHIPS ACROSS GOVERNMENT, ACADEMIA AND INDUSTRY. Presented at EPA Science Forum 2005, Washington, DC, May 16 - 18, 2005.
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.
Over the past decade genomics, proteomics and metabonomics technologies have transformed the science of toxicology, and concurrent advances in computing and informatics have provided management and analysis solutions for this onslaught of toxicogenomic data. EPA has been actively developing an intramural research program in genomics, proteomics and metabonomics through a series of strategic alliances between the Office of Research and Development (ORD) and external organizations. The National Health and Environmental Effects Research Laboratory (NHEERL), National Center for Computational Toxicology (NCCT), and the National Exposure Research Laboratory (NERL) have initiated a series of integrated studies wherein genomic, proteomic and metabonomic data are being generated from both in vivo and in vitro experiments.
Record Details:Record Type: DOCUMENT (PRESENTATION/ABSTRACT)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL EXPOSURE RESEARCH LABORATORY
ECOSYSTEMS RESEARCH DIVISION
PROCESSES & MODELING BRANCH