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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.
Highlights
IntroductionThe ToxCast program within the U.S Environmental Protection Agency (EPA) employs high-throughput in vitro assays to efficiently screen large numbers of chemicals to support the development of improved toxicity prediction models, to be applied to environmental chemicals for which limited or no in vivo animal toxicity data are available
The main objectives are to provide a historical account of Environmental Protection Agency (EPA)’s efforts to construct the ToxCast chemical library, to characterize and provide representations of the library that can aid in future investigations, and to offer metrics to assess the degree to which the current library is fit for the purpose and vision of the ToxCast project
Subportions of the ToxCast chemical structure file (TOXCST) chemical inventory whose predicted toxicity is more likely to be impacted by metabolic transformation can be highlighted. This segregation of chemicals, in turn, should inform the utilization and interpretation of ToxCast in vitro results as they relate to in vivo animal outcomes. Our objectives for this perspective were to describe EPA’s efforts to construct the current ToxCast high-throughput screening (HTS) chemical library, to characterize and provide representations of the library that can aid in future investigations, and to provide metrics to assess whether the resulting inventory is fit for the purpose and goals of the ToxCast project
Summary
The ToxCast program within the U.S Environmental Protection Agency (EPA) employs high-throughput in vitro assays to efficiently screen large numbers of chemicals to support the development of improved toxicity prediction models, to be applied to environmental chemicals for which limited or no in vivo animal toxicity data are available. EPA’s ToxCast program has significantly expanded coverage of both chemicals and assays in a series of testing phases extending to the present. In ToxCast Phase I, a set of 310 mostly pesticidal chemicals were tested across a panel of several hundred commercially available, medium and highthroughput screening (HTS) assays spanning nine diverse technologies.. Phase II of EPA’s ToxCast program expanded the size and diversity of the chemical library undergoing ToxCast screening to 1878 chemicals and officially concluded with the December 2013 ToxCast data release.
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