In Vitro Screening of Environmental Chemicals for Targeted Testing Prioritization: The ToxCast Project.

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Bibliographic Details
Title:	In Vitro Screening of Environmental Chemicals for Targeted Testing Prioritization: The ToxCast Project.
Authors:	Judson, Richard S.¹ judson.richard@epa.gov, Houck, Keith A.¹, Kavlock, Robert J.¹, Knudsen, Thomas B.¹, Martin, Matthew T.¹, Mortensen, Holly M.¹, Reif, David M.¹, Rotroff, Daniel M.¹, Shah, Imran¹, Richard, Ann M.¹, Dix, David J.¹
Source:	Environmental Health Perspectives. Apr2010, Vol. 118 Issue 4, p485-492. 8p. 2 Diagrams, 1 Chart, 4 Graphs.
Subject Terms:	Poisons, Ecological disturbances, *Pollution, Biological research, In vivo toxicity testing, Liver cells, Xenobiotics, Enzyme promiscuity
Geographic Terms:	United States
Company/Entity:	United States. Environmental Protection Agency. Office of Environmental Justice
Abstract:	Background: Chemical toxicity testing is being transformed by advances in biology and computer modeling, concerns over animal use, and the thousands of environmental chemicals lacking toxicity data. The U.S. Environmental Protection Agency's ToxCast program aims to address these concerns by screening and prioritizing chemicals for potential human toxicity using in vitro assays and in silico approaches. Objectives: This project aims to evaluate the use of in vitro assays for understanding the types of molecular and pathway perturbations caused by environmental chemicals and to build initial prioritization models of in vivo toxicity. Methods: We tested 309 mostly pesticide active chemicals in 467 assays across nine technologies, including high-throughput cell-free assays and cell-based assays, in multiple human primary cells and cell lines plus rat primary hepatocytes. Both individual and composite scores for effects on genes and pathways were analyzed. Results: Chemicals displayed a broad spectrum of activity at the molecular and pathway levels. We saw many expected interactions, including endocrine and xenobiotic metabolism enzyme activity. Chemicals ranged in promiscuity across pathways, from no activity to affecting dozens of pathways. We found a statistically significant inverse association between the number of pathways perturbed by a chemical at low in vitro concentrations and the lowest in vivo dose at which a chemical causes toxicity. We also found associations between a small set of in vitro assays and rodent liver lesion formation. Conclusions: This approach promises to provide meaningful data on the thousands of untested environmental chemicals and to guide targeted testing of environmental contaminants. [ABSTRACT FROM AUTHOR]
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Database:	GreenFILE

Description
Abstract:	Background: Chemical toxicity testing is being transformed by advances in biology and computer modeling, concerns over animal use, and the thousands of environmental chemicals lacking toxicity data. The U.S. Environmental Protection Agency's ToxCast program aims to address these concerns by screening and prioritizing chemicals for potential human toxicity using in vitro assays and in silico approaches. Objectives: This project aims to evaluate the use of in vitro assays for understanding the types of molecular and pathway perturbations caused by environmental chemicals and to build initial prioritization models of in vivo toxicity. Methods: We tested 309 mostly pesticide active chemicals in 467 assays across nine technologies, including high-throughput cell-free assays and cell-based assays, in multiple human primary cells and cell lines plus rat primary hepatocytes. Both individual and composite scores for effects on genes and pathways were analyzed. Results: Chemicals displayed a broad spectrum of activity at the molecular and pathway levels. We saw many expected interactions, including endocrine and xenobiotic metabolism enzyme activity. Chemicals ranged in promiscuity across pathways, from no activity to affecting dozens of pathways. We found a statistically significant inverse association between the number of pathways perturbed by a chemical at low in vitro concentrations and the lowest in vivo dose at which a chemical causes toxicity. We also found associations between a small set of in vitro assays and rodent liver lesion formation. Conclusions: This approach promises to provide meaningful data on the thousands of untested environmental chemicals and to guide targeted testing of environmental contaminants. [ABSTRACT FROM AUTHOR]
ISSN:	00916765
DOI:	10.1289/ehp.0901392