Activity profiles of 309 ToxCast™ chemicals evaluated across 292 biochemical targets.
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. The primary dataset, summary data and details on quality control checks are available for download at http://www.epa.gov/ncct/toxcast/.
National Center for Computational Toxicology (B205-01), Office of Research & Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA. knudsen.thomas@epa.gov
Thomas B
TB
Knudsen
Keith A
KA
Houck
Nisha S
NS
Sipes
Amar V
AV
Singh
Richard S
RS
Judson
Matthew T
MT
Martin
Arthur
A
Weissman
Nicole C
NC
Kleinstreuer
Holly M
HM
Mortensen
David M
DM
Reif
James R
JR
Rabinowitz
R Woodrow
RW
Setzer
Ann M
AM
Richard
David J
DJ
Dix
Robert J
RJ
Kavlock
D023401:Animal Use Alternatives; D000818:Animals; D057205:Automation, Laboratory; D002474:Cell-Free System; D003627:Data Interpretation, Statistical; D016208:Databases, Factual; D004785:Environmental Pollutants / Q000145:classification / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000633:toxicity; D057166:High-Throughput Screening Assays; D006801:Humans; D008024:Ligands; D008954:Models, Biological; D009994:Osmolar Concentration; D010573:Pesticide Residues / Q000633:toxicity; D051381:Rats; D015203:Reproducibility of Results; D018675:Toxicity Tests; D014481:United States; D014484:United States Environmental Protection Agency
D004785:Environmental Pollutants; D004791:Enzyme Inhibitors; D008024:Ligands; D010573:Pesticide Residues