Citation:

PROTZEL, A., G. DANNAN, R. C. KOLANCZYK, O. MEKENYAN, S. ABEL, P. K. SCHMIEDER, AND W. J. JONES. DEVELOPMENT OF A STRUCTURE-SEARCHABLE DATABASE FOR PESTICIDE METABOLITES AND ENVIRONMENTAL DEGRADATES. Presented at Society for Toxicology Annual Meeting, San Diego, CA, March 05 - 09, 2006.

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:

USEPA is modifying and enhancing existing software for the depiction of metabolic maps to provide access via structures to metabolism information and associated data in EPA's Office of Pesticide Programs (OPP). The database includes information submitted to EPA in support of pesticide registration such as pesticide metabolism in laboratory animals, plants, livestock, in addition to environmental degradates. The database will be used by OPP risk assessors to increase efficiency of data access and performance of risk assessments. The system includes the ability to: depict hierarchical connection sequences of parent chemical and all listed metabolites; track radiolabel within a pathway and combine/separate maps from associated radiolabel studies; identify all maps (and the parent chemical structure) that contain a specific metabolite of concern; search for specific sub-structures of toxicological concern and indicate its presence across chemicals; and, compare complete maps across chemicals and species. Associated chemical identifiers and tracking information is included, as well as bioassay and analytical chemistry. In its simplest mode, the database will furnish curated structures of pesticides and their metabolites suitable for searches in other databases, provide metabolic maps plus tabulations of amounts of metabolites, and other parameters. In a more advanced mode, the database may be used by risk assessors to perform substructure searches for types of compounds and toxicophores, and to identify metabolism commonalities and differences across pesticides and species. At present, some of these questions are answered manually and the results may vary among individual risk assessors. The database is expected to make this process more efficient, to furnish more reliable results, and to serve as a tool for hypothesis formulation by EPA researchers.

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