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Profiling Bioactivity of the ToxCast Chemical Library Using BioMAP Primary Human Cell Systems
Citation:
HOUCK, K. A., D. J. DIX, R. JUDSON, R. J. KAVLOCK, J. YANG, AND E. L. BERG. Profiling Bioactivity of the ToxCast Chemical Library Using BioMAP Primary Human Cell Systems. Journal of Biomolecular Screening. SAGE Publications USA, Thousand Oaks, CA, 14(9):1054-1066, (2009).
Impact/Purpose:
Alternatives to whole animal testing of environmental and industrial chemicals are needed for understanding the toxicity potential of the many thousands of chemicals and materials in commercial use. Cost, animal welfare concerns, and relevance to human risk are the major issues driving this need. The U.S. Environmental Protection Agency (EPA) has initiated a large-scale effort, ToxCast, which is investigating high-throughput, in vitro assays as a means to develop predictive toxicology models. The goal of the project is to compose broad bioactivity profiles characterizing the in vitro biological activity of a reference set of chemicals.
Description:
The complexity of human biology has made prediction of health effects as a consequence of exposure to environmental chemicals especially challenging. Complex cell systems, such as the Biologically Multiplexed Activity Profiling (BioMAP) primary, human, cell-based disease models, leverage cellular regulatory networks to detect and distinguish chemicals with a broad range of target mechanisms and biological processes relevant to human toxicity. Here we utilize the BioMAP human cell systems to characterize effects relevant to human tissue and inflammatory disease biology following exposure to the 320 environmental chemicals in the Environmental Protection Agency’s (EPA) ToxCast phase I library. The ToxCast chemicals were assayed at four concentrations in eight BioMap cell systems, with a total of 87 assay endpoints resulting in over 100,000 datapoints. This dataset is being combined with all the other ToxCast datasets for development of predictive toxicity models at EPA. Within the context of the BioMap database, ToxCast compounds could be classified based on their ability to cause overt cytotoxicity in primary human cell types, or according to toxicity mechanism class derived from comparisons to activity profiles of BioMap reference compounds. ToxCast chemicals with similarity to inducers of mitochondrial dysfunction, cAMP elevators, inhibitors of tubulin function, inducers of endoplasmic reticulum stress or NF B pathway inhibitors were identified based on this BioMap analysis.
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Profiling Bioactivity of the ToxCast Chemical Library Using BioMAP Primary Human Cell Systems