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The US EPAs ToxCast Program for the Prioritization and Prediction of Environmental Chemical Toxicity
Citation:
HOUCK, K. A. The US EPAs ToxCast Program for the Prioritization and Prediction of Environmental Chemical Toxicity. Presented at Workshop on 21st Century Toxicology, Committee on Toxicity, Meriden, UK, February 11, 2009.
Impact/Purpose:
The goal at this stage of the ToxCast project is the development of computational models or signatures of toxicity that will subsequently be tested with additional chemicals run though the appropriate in vitro assays.
Description:
To meet the need for evaluating large numbers of chemicals for potential toxicity, the U.S. Environmental Protection Agency has initiated a research project call ToxCast that makes use of recent advances in molecular biology and high-throughput screening. These technologies have been employed to generate bioactivity profiles of a reference set of environmental chemicals, for which an extensive in vivo toxicity database was also developed. The bioactivity profiles for ToxCast chemicals include determination of activity against a broad array of specific molecular targets such as GPCRs, kinases, phosphatases, nuclear receptors and ion channels. In addition, cellular assays were used to measure activity of the chemical library against both specific molecular targets in the context of the cell and against important cell signaling pathways, as well as measuring activity in phenotypic assays. In recognition of a major limitation of most in vitro assays, efforts were also made to incorporate biotransformation capacity in several ways, including the use of primary rat and human hepatocytes. Profiles or signatures of activity in these assays were combined with computed physicochemical parameters for the compounds, and statistical and machine learning approaches used to correlate results with in vivo toxicity data. The goal at this stage of the ToxCast project is the development of computational models or signatures of toxicity that will subsequently be tested with additional chemicals run though the appropriate in vitro assays.