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.

Thresholds of Toxicological Concern for cosmetics-related substances: New database, thresholds, and enrichment of chemical space

“…The structural feature space was described by ToxPrint chemotypes (Toxprint, 2017). The use of this method to profile the chemical space of inventories and databases has been reported previously (Richard et al, 2016;Yang et al, 2015). The Structure-Data (SD) files of the Munro and COSMOS TTC datasets were prepared based on structures in the COSMOS DB v2.…”

In SilicoPrediction of Organ Level Toxicity: Linking Chemistry to Adverse Effects

“…As noted previously, so-called “chemistry” alerts for use in grouping and read-across are very general; for organ level toxicity these will need to be more carefully defined. Indeed, such alerts could go further into what are being termed “chemotypes” (64). Chemotypes have the capability to incorporate structural features with physicochemical properties.…”

The need for strategic development of safety sciences

“…The website of the Balanced Scoreboard Institute 2 and Strategy Management Group 3 , two consultancies for organizations in strategic planning, define: "Strategic planning is an organizational management activity that is used to set priorities, focus energy and resources, strengthen though harmonized via the International Conference on Harmonization 9 , as the US, which has 6% of the world population, consumes about 60% of drugs under patent, which gives them a lighthouse function for the pharmaceutical industry (Rovida et al, 2015a Wambaugh et al, 2015), ToxCast (Richard et al, 2016), the Tox 21 collaboration with the NIH and the FDA, the Virtual Tissues 5 and computation toxicology in general (Patlewicz and Fitzpatrick, 2016) It promotes mechanism-based toxicity testing and risk assessment according to the principles laid down for toxicology for Tox21. The project will integrate advances in in vitro and in silico toxicology, read-across methods, and adverse outcome pathways.…”