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U.S. ENVIRONMENTAL PROTECTION AGENCY'S COMPUTATIONAL TOXCIOLOGY PROGRAM - METABOLISM AND METABONOMICS
Kenneke, J F. U.S. ENVIRONMENTAL PROTECTION AGENCY'S COMPUTATIONAL TOXCIOLOGY PROGRAM - METABOLISM AND METABONOMICS. Presented at Imperial College, London, United Kingdom, July 26, 2004.
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.
The mission of the U. S. Environmental Protection Agency (EPA) is to safeguard public health and the environment from adverse effects that may be caused by exposure to pollutants in the air, water, soil and food. Protecting human health and the environment carries with it the challenge of assessing hundreds of possible hazardous effects for thousands of chemicals. In assessing risk associated with exposure to a chemical or other environmental stressor, there are a number of uncertainties that lie along a continuum beginning with the presence of the chemical in the environment, the uptake and distribution of the chemical in the organism or human or environment, the presence of the active chemical at a target site, and the series of biological events that lead to the manifestation of an adverse outcome that can be used for risk assessment. The large number of chemicals that the Agency must consider under many different regulations together with the large cost of test batteries limits the full use of these test methods to only a small number of chemicals. The end result is that the Agency is being forced to prioritize and reduce toxicity-testing requirements for potentially hazardous chemicals - including chemicals for which little if any data exists.
In a response to these issues, the EPA's Office of Research and Development (ORD) has implemented a Computational Toxicology Program (CompTox) to apply novel technologies derived from computational chemistry, molecular biology and systems biology to toxicological risk assessment. The overall goal of the program is to use emerging technologies to improve quantitative risk assessment and reduce uncertainties in the source to adverse outcome continuum. A predominant theme of CompTox is on the use of "omic" tools as early indicators of exposure and effects due to anthropogenic chemicals.