title: ToxCast Chemical Landscape: Paving the Road to 21st Century Toxicology.
abstract: 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.
authors.affiliation: 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.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Richard
authors.affiliation: 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.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Judson
authors.affiliation: 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.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Houck
authors.affiliation: 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.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Grulke
authors.affiliation: Center for Food Safety and Nutrition, U.S. Food and Drug Administration , 5100 Paint Branch Parkway, College Park, Maryland 20740, United States.
authors.forename: Patra
authors.initials: P
authors.lastname: Volarath
authors.affiliation: Senior Environmental Employment Program, U.S. Environmental Protection Agency , Research Triangle Park, Durham, North Carolina 27711, United States.
authors.forename: Inthirany
authors.initials: I
authors.lastname: Thillainadarajah
authors.affiliation: Molecular Networks GmbH , Henkestraße 91, 91052 Erlangen, Germany.|Altamira, LLC , 1455 Candlewood Drive, Columbus, Ohio 43235, United States.
authors.forename: Chihae
authors.initials: C
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: James
authors.initials: J
authors.lastname: Rathman
authors.affiliation: 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.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Martin
authors.affiliation: 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.
authors.forename: John F
authors.initials: JF
authors.lastname: Wambaugh
authors.affiliation: 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.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Knudsen
authors.affiliation: ORISE Fellow, U.S. Environmental Protection Agency, Research Triangle Park, Durham, North Carolina 27711, United States.
authors.forename: Jayaram
authors.initials: J
authors.lastname: Kancherla
authors.affiliation: ORISE Fellow, U.S. Environmental Protection Agency, Research Triangle Park, Durham, North Carolina 27711, United States.
authors.forename: Kamel
authors.initials: K
authors.lastname: Mansouri
authors.affiliation: 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.
authors.forename: Grace
authors.initials: G
authors.lastname: Patlewicz
authors.affiliation: 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.
authors.forename: Antony J
authors.initials: AJ
authors.lastname: Williams
authors.affiliation: 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.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Little
authors.affiliation: 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.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Crofton
authors.affiliation: 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.
authors.forename: Russell S
authors.initials: RS
authors.lastname: Thomas
mesh_terms: D014116:Toxicology