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

By Judson, Richard S.; Houck, Keith A. et al. | Environmental Health Perspectives, April 2010 | Go to article overview

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


Judson, Richard S., Houck, Keith A., Kavlock, Robert J., Knudsen, Thomas B., Martin, Matthew T., Mortensen, Holly M., Reif, David M., Rotroff, Daniel M., Shah, Imran, Richard, Ann M., Dix, David J., Environmental Health Perspectives


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.

KEY WORDS: in vitro screening, liver proliferative lesions, liver tumors, pathways, ToxCast. Environ Health Perspect 118:485-492 (2010). doi:10.1289/ehp.0901392 [Online 14 December 2009]

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There are thousands of environmental chemicals, including many industrial chemicals and pesticidal active and inert ingredients, with the potential for significant human exposures but for which toxicity information is either limited or nonexistent (Judson et al. 2009). This data gap is due largely to the high cost and length of time required to conduct animal testing in rodents and other species. A complete set of regulatory tests for a single chemical (including those for carcinogenicity and for chronic, reproductive, and development toxicity) uses thousands of animals and costs millions of dollars. In addition, traditional animal tests often yield limited information on mechanism of action, and hence on the cellular pathways that could lead to toxicity in humans. Such mechanistic information is key to moving beyond default approaches for extrapolating from high-dose animal toxicity tests to estimation of human risk at realistic exposure levels.

There is a pressing need to screen the large backlog of chemicals for their potential toxicity and, ultimately, their contribution to human diseases. The National Research Council (2007) advocated the use of mechanistically informative in vitro assays based on human cells or human cell constituents that measure effects on "toxicity pathways" leading to human disease. The U.S. Environmental Protection Agency (EPA), through its ToxCast program (Dix et al. 2007) and the Tox21 collaboration with the National Toxicology Program and the National Institutes of Health Chemical Genomics Center, is pursuing similar objectives and applying many of the ideas represented in the National Research Council report (Collins et al. 2008; Kavlock et al. 2009).

ToxCast is a large-scale experiment using a battery of in vitro, high-throughput screening (HTS) assays, applied to a relatively large and diverse chemical space, to develop methods to predict potential toxicity of environmental chemicals at a fraction of the cost of full-scale animal testing. …

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