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Chem Res Toxicol. 2016 Aug 15;29(8):1225-51. doi: 10.1021/acs.chemrestox.6b00135. Epub 2016 Jul 20.

ToxCast Chemical Landscape: Paving the Road to 21st Century Toxicology.

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National Center for Computational Toxicology, Office of Research & Development, U.S. Environmental Protection Agency , Mail Code B205-01, Research Triangle Park, Durham, North Carolina 27711, United States.
Center for Food Safety and Nutrition, U.S. Food and Drug Administration , 5100 Paint Branch Parkway, College Park, Maryland 20740, United States.
Senior Environmental Employment Program, U.S. Environmental Protection Agency , Research Triangle Park, Durham, North Carolina 27711, United States.
Molecular Networks GmbH , Henkestra├če 91, 91052 Erlangen, Germany.
Altamira, LLC , 1455 Candlewood Drive, Columbus, Ohio 43235, United States.
Department of Chemical and Biomolecular Engineering, The Ohio State University , 151 W. Woodruff Avenue, Columbus, Ohio 43210, United States.
ORISE Fellow, U.S. Environmental Protection Agency, Research Triangle Park, Durham, North Carolina 27711, United States.


The U.S. Environmental Protection Agency's (EPA) ToxCast program is testing a large library of Agency-relevant chemicals using in vitro high-throughput screening (HTS) approaches to support the development of improved toxicity prediction models. Launched in 2007, Phase I of the program screened 310 chemicals, mostly pesticides, across hundreds of ToxCast assay end points. In Phase II, the ToxCast library was expanded to 1878 chemicals, culminating in the public release of screening data at the end of 2013. Subsequent expansion in Phase III has resulted in more than 3800 chemicals actively undergoing ToxCast screening, 96% of which are also being screened in the multi-Agency Tox21 project. The chemical library unpinning these efforts plays a central role in defining the scope and potential application of ToxCast HTS results. The history of the phased construction of EPA's ToxCast library is reviewed, followed by a survey of the library contents from several different vantage points. CAS Registry Numbers are used to assess ToxCast library coverage of important toxicity, regulatory, and exposure inventories. Structure-based representations of ToxCast chemicals are then used to compute physicochemical properties, substructural features, and structural alerts for toxicity and biotransformation. Cheminformatics approaches using these varied representations are applied to defining the boundaries of HTS testability, evaluating chemical diversity, and comparing the ToxCast library to potential target application inventories, such as used in EPA's Endocrine Disruption Screening Program (EDSP). Through several examples, the ToxCast chemical library is demonstrated to provide comprehensive coverage of the knowledge domains and target inventories of potential interest to EPA. Furthermore, the varied representations and approaches presented here define local chemistry domains potentially worthy of further investigation (e.g., not currently covered in the testing library or defined by toxicity "alerts") to strategically support data mining and predictive toxicology modeling moving forward.

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