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TOXCAST, A TOOL FOR CATEGORIZATION AND PRIORITIZATION OF CHEMICAL HAZARD BASED ON MULTI-DIMENSIONAL INFORMATION DOMAINS
Modern computational chemistry and molecular biology tools bring enabling technologies forward that can provide information about the physical and biological properties of large numbers of chemicals. The essence of the proposal is to conduct a demonstration project based upon a rich toxicological database (e.g., registered pesticides, or the chemicals tested in the NTP bioassay program), select a fairly large number (50-100 or more chemicals) representative of a number of differing structural classes and phenotypic outcomes (e.g., carcinogens, reproductive toxicants, neurotoxicants), and evaluate them across a broad spectrum of information domains that modern technology has provided (i.e., physical-chemical properties, predicted biological activities based on existing structure-activity models, biochemical properties based on high throughput screening assays, cell based organotypic assays, and genomic analysis of cells or organisms). These domains represent increasing biological relevance, as well as increasing resource requirements. The ultimate goal of the project would be to mine the resulting data for association between and among the various domains and the known toxicological properties of the base set of chemicals in order to provide a structured strategy to identify potential toxicity pathways, and to prioritize chemicals them for subsequent testing based on that information. The underlying hypothesis is that whether is concerned with the off target effects of drugs, as desired to be understood by the pharmaceutical industry, or toxicity in case of environmental agents of interest to the EPA, the response is driven by interactions with biomolecular targets of one form or another. One needs only to identify those receptors of concern and identify tools for assessing the likelihood of interaction with the chemicals of concern. In moving from the drug development arena (which can be compared to working along one or just a few vectors) to the environmental toxicology arena (which can be likened to working on a matrix instead of a vector), one needs to shift from a specific screening target to a more global agenda, and it becomes necessary to vastly expand the number of potential biomolecular targets, be these obtained from in silico assays, biochemical assays, cell based in vitro assays, surrogate animal models, or short term studies in traditional species. Hence, a wider net of endpoints and information sources will be applied, at least initially, as the concept transgresses from a concept to a reality.
Across several EPA Program Offices (e.g., OPPTS, OW, OAR), there is a clear need to develop strategies and methods to screen large numbers of chemicals for potential toxicity, and to use the resulting information to prioritize the use of testing resources towards those entities and endpoints that present the greatest likelihood of risk to human health and the environment. This need could be addressed using the experience of the pharmaceutical industry in the use of advanced modern molecular biology and computational chemistry tools for the development of new drugs, with appropriate adjustment to the needs and desires of environmental toxicology. A conceptual approach named ToxCast has been developed to address the needs of EPA Program Offices in the area of prioritization and screening.