Citation

Richard AM, Judson RS, Houck KA, Grulke CM, Volarath P, Thillainadarajah I, Yang C, Rathman JF, Martin MT, Wambaugh JF, Knudsen TB, Kancherla J, Mansouri K, Patlewicz GY, Williams AJ, Little SB, Crofton KM, Thomas RS. Chem. Res. Toxicol. 2016; 29(8): 1225-1251.

Copyright

(Copyright © 2016, American Chemical Society)

DOI

10.1021/acs.chemrestox.6b00135

PMID

27367298

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 in order to support development of improved toxicity prediction models. Launched in 2007, Phase I of the program screened 310 chemicals, mostly pesticides, across hundreds of ToxCast assay endpoints. In Phase II, the ToxCast library was expanded to 1878 chemicals, culminating in 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 here, followed by a survey of the library contents from several different vantage points. First, 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 excellent 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 testing library, or defined by toxicity "alerts") to strategically support data mining and predictive toxicology modeling moving forward.

Language: en