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Activity profiles of 309 ToxCast™ chemicals evaluated across 292 biochemical targets
KNUDSEN, T. B., K. A. HOUCK, N. SIPES, A. V. SINGH, R. JUDSON, M. T. MARTIN, A. WEISSMAN, N. KLEINSTREUER, H. M. MORTENSEN, D. REIF, J. R. RABINOWITZ, R. W. SETZER, A. M. RICHARD, D. J. DIX, AND R. J. KAVLOCK. Activity profiles of 309 ToxCast™ chemicals evaluated across 292 biochemical targets. TOXICOLOGY. Elsevier Ireland Limited, Limerick, Ireland, 282(1-2):1-15, (2011).
The present study provides an initial survey of the biochemical HTS dataset comprising one technology platform in its entirety, to assess the performance of the dataset in the context of known and novel relationships, and then to bring these relationships together systematically. This survey revealed quality checks of assay performance and nuances in the source data. However imperfect or complex these data, they have the potential to shed light on chemical–biological interactions in a much larger data context than has previously been available. The larger battery of assays included in the ToxCast project includes cell-based assays, complex cultures, and small model organisms (zebrafish), which further expand opportunities to explore features of the data in an integrated way.
Understanding the potential health risks posed by environmental chemicals is a significant challenge elevated by the large number of diverse chemicals with generally uncharacterized exposures, mechanisms, and toxicities. The present study is a performance evaluation and critical analysis of assay results for an array of 292 high-throughput cell-free assays aimed at preliminary toxicity evaluation of 320 environmental chemicals in EPA's ToxCast™ project (Phase I). The chemicals (309 unique, 11 replicates) were mainly precursors or the active agent of commercial pesticides, for which a wealth of in vivo toxicity data is available. Biochemical HTS (high-throughput screening) profiled cell and tissue extracts using semi-automated biochemical and pharmacological methodologies to evaluate a subset of G-protein coupled receptors (GPCRs), CYP450 enzymes (CYPs), kinases, phosphatases, proteases, HDACs, nuclear receptors, ion channels, and transporters. The primary screen tested all chemicals at a relatively high concentration 25 μM concentration (or 10 μM for CYP assays), and a secondary screen re-tested 9132 chemical-assay pairs in 8-point concentration series from 0.023 to 50 μM (or 0.009–20 μM for CYPs). Mapping relationships across 93,440 chemical-assay pairs based on half-maximal activity concentration (AC50) revealed both known and novel targets in signaling and metabolic pathways.