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The Second Phase of ToxCast and Initial Applications to Chemical Prioritization
Citation:
DIX, D. J., K. A. HOUCK, R. JUDSON, T. B. KNUDSEN, S. LITTLE, M. T. MARTIN, H. M. MORTENSEN, D. REIF, A. M. RICHARD, R. W. SETZER, J. F. WAMBAUGH, A. BEAM, D. ROTROFF, M. WOLF, AND R. J. KAVLOCK. The Second Phase of ToxCast and Initial Applications to Chemical Prioritization. Presented at Computational Toxicology Board of Scientific Counselors Review, RTP, NC, September 29 - 30, 2009.
Impact/Purpose:
ToxCast is focused on closing this data gap and improving the management of chemical risk through a high throughput screening (HTS) system providing bioactivity profiles in a broad range of pathways relevant to carcinogenic, mutagenic, reproductive and chronic toxicity.
Description:
Tens of thousands of chemicals and other contaminants exist in our environment, but only a fraction of these have been characterized for their potential hazard to humans. ToxCast is focused on closing this data gap and improving the management of chemical risk through a high throughput screening (HTS) system providing bioactivity profiles in a broad range of pathways relevant to carcinogenic, mutagenic, reproductive and chronic toxicity. In Phase II of ToxCast 700 additional chemicals will be screened in many of same 467 assays of Phase I, as well as additional HTS assays being added to the program. These include cell-free assays, cell-based assays in a variety of human and rodent primary cells and cell lines, and assays in zebrafish and other non-mammalian species. The 700 chemicals being prepared for Phase II of ToxCastTM are a subset of the 10,000 chemical library being assembled for Tox21 HTS testing by NTP-NCGC-EPA. Approximately 400 Phase II chemicals are pesticidal actives, inerts or antimicrobials, or industrial chemicals rich in existing animal toxicity data and thus useful for verifying and expanding predictive toxicity signatures and pathways from Phase I screening. Approximately 150 Phase II chemicals are pesticidal inerts, antimicrobials, or industrial chemicals with limited toxicity data and in need of chemical categorization and prioritization. Another 150 Phase II chemicals are failed pharmaceutical compounds with animal and human toxicity data for direct confirmation of human toxicity pathways and predictors. ToxCast HTS assays will provide an in vitro threshold concentration for specific biological targets, genes, pathways or predictors, which in combination with high throughput pharmacokinetic modeling can provide an estimated dose at which a similar in vivo activity is expected. This estimated in vivo equivalent dose can then be used in combination with chemical structures from DSSTox, and existing in vitro and in vivo toxicity data from ToxRefDB for predictive modeling and chemical prioritization. Upon successful completion of Phase II, the ToxCast program will be prepared to conduct rapid, quantitative and high-quality hazard characterizations and subsequent prioritizations on thousands of chemicals. In combination with ExpoCast profiling of exposure potential, these chemical prioritizations can eventually be based upon both hazard and exposure characterizations, providing ranking of chemicals for entry into targeted testing specific to carcinogenic, mutagenic, developmental and reproductive, or chronic toxicity. Decision support software for chemical prioritizations is being provided by ToxMiner, an integrated database and interface for ToxCast data analysis, visualization and uncertainty assessment. ToxMiner is user-friendly and will be freely available, facilitating widespread implementation. ToxCast data will also be available through ACToR, other EPA websites, and PubChem. ToxCast provides a means to generating meaningful data on the thousands of untested environmental chemicals, and with associated tools a way to use this data to guide more intelligent, targeted testing of environmental chemicals in the future. This abstract was reviewed by EPA and approved for publication, but may not necessarily reflect official Agency policy.
URLs/Downloads:
The Second Phase of ToxCast and Initial Applications to Chemical Prioritization (abs) (PDF, NA pp, 11 KB, about PDF)The Second Phase of ToxCast and Initial Applications to Chemical Prioritization (poster) (PDF, NA pp, 1322 KB, about PDF)