17163
title and abstract
Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays.
Understanding potential health risks is a significant challenge due to large numbers of diverse chemicals with poorly characterized exposures and mechanisms of toxicities. The present study analyzes 976 chemicals (including failed pharmaceuticals, alternative plasticizers, food additives, and pesticides) in Phase I and II of the U.S. EPA's ToxCast™ project across 331 cell-free enzymatic and ligand-binding high-throughput screening (HTS) assays. Half-maximal activity concentrations (AC50) were identified for 729 chemicals in 256 assays (7,135 chemical-assay pairs). Some of the most commonly affected assays were CYPs (CYP2C9, CYP2C19), transporters (mitochondrial TSPO, norepinephrine, dopaminergic), and GPCRs (aminergic). Heavy metals, surfactants, and dithiocarbamate fungicides showed promiscuous, but distinctly different patterns of activity whereas many of the pharma compounds showed promiscuous activity across GPCRs. Literature analysis confirmed >50% of the activities for the most potent chemical-assay pairs (56), but also revealed 10 missed interactions. Twenty-two chemicals with known estrogenic activity were correctly identified for the majority (77%), missing only the weaker interactions. In many cases, novel findings for previously unreported chemical-target combinations clustered with known chemical-target interactions. Results from this large inventory of chemical-biological interactions can inform read-across methods as well as to link potential targets to molecular initiating events in adverse outcome pathways for diverse toxicities. This abstract does not necessarily reflect U.S. EPA policy.