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The ToxCast Chemical Landscape - Paving the Road to 21st Century Toxicology
Citation:
Richard, A., R. Judson, K. Houck, C. Grulke, P. Volarath, I. Thillainadarajah, C. Yang, J. Rathman, M. Martin, J. Wambaugh, T. Knudsen, K. Mansouri, J. Kancherla, G. Tier, A. Williams, S. Little, K. Crofton, AND R. Thomas. The ToxCast Chemical Landscape - Paving the Road to 21st Century Toxicology. CHEMICAL RESEARCH IN TOXICOLOGY. American Chemical Society, Washington, DC, 29(8):1225-1251, (2016).
Impact/Purpose:
A history of the phased construction of EPA’s ToxCast library is presented, considering factors influencing chemical selection as well as the various quality measures implemented. ToxCast chemicals are described in terms of generalized physico-chemical properties, substructural features, and structural alerts for toxicity and metabolism. Employing cheminformatics approaches, these structure-based representations are used to assess coverage and diversity of EPA’s ToxCast library in relation to potential target application inventories.
Description:
The ToxCast high-throughput screening (HTS) program within the U.S. Environmental Protection Agency (EPA) was 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. Concurrently, a larger EPA library of 3726 chemicals (including the Phase II chemicals) was undergoing screening in the cross-federal agency Tox21 HTS project. Four years later, Phase III of EPA’s ToxCast program is actively screening a diverse library consisting of more than 3800 chemicals, 96% of which are also undergoing Tox21 screening. The majority of ToxCast studies, to date, have focused on using HTS results to build biologically based models for predicting in vivo toxicity endpoints. The focus of the present article, in contrast, is on the EPA chemical library underpinning these efforts. A history of the phased construction of EPA’s ToxCast library is presented, considering factors influencing chemical selection as well as the various quality measures implemented. Next, Chemical Abstracts Service Registry Numbers (CASRN), which were used to compile initial chemical nominations for ToxCast testing, are used to assess overlaps of the current ToxCast library with important toxicity, regulatory, and exposure inventories. Lastly, ToxCast chemicals are described in terms of generalized physico-chemical properties, substructural features, and structural alerts for toxicity and metabolism. Employing cheminformatics approaches, these structure-based representations are used to assess coverage and diversity of EPA’s ToxCast library in relation to potential target application inventories, such as included in EPA’s Endocrine Disruption Screening Program (EDSP) Universe of chemicals. By these varied means, it is demonstrated that the ToxCast chemical library provides excellent coverage of the knowledge domains and target inventories of potential interest to EPA. Additionally, the approaches employed here offer promising opportunities for aiding predictive toxicology modeling moving forward.
