Santillo_2021_SLAS.Discov__

Rapid, higher throughput, and predictive toxicological methods are needed to assess vast numbers of chemicals with unknown safety profiles. A current effort towards this goal is Toxicology in the 21st Century (Tox21), a United States government consortium using a battery of in vitro assays to screen a library of 10,000 compounds relevant to food, drug, and environmental safety. Recently, we implemented in vitro assays for measuring acetylcholinesterase (AChE) inhibition, a mechanism of toxicity, into Tox21's high-throughput screening campaign (Li S., et al. Environ Health Persp 2021;129:047008, doi:10.1289/EHP6993). In this Commentary, we provide detailed insights on two topics related to our article: (1) prioritizing recently discovered AChE inhibitors from our screening based upon physiological relevance and (2) incorporating human liver microsomes into the AChE inhibition assay to identify metabolically active AChE inhibitors.