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ICCVAM Biennial Report 2018-2019

Biennial Progress Report 2018-2019 Interagency Coordinating Committee on the Validation of Alternative Methods

Profiling Activity of Acetylcholinesterase Inhibitors

Acetylcholinesterase inhibitors cause a variety of adverse effects in the nervous system. Some acetylcholinesterase inhibitors serve as drugs, while others are used as pesticides or found in natural products. Scientists at FDA and NCATS developed acetylcholinesterase inhibition assays (Li et al. 2017) and screened the Tox21 10K chemical library to identify environmental and drug- or food-related chemicals that inhibit acetylcholinesterase activity. The screening study also provided an opportunity to evaluate performance characteristics of HTS assays intended to measure acetylcholinesterase inhibition. An accomplishment of the study included incorporating metabolism into the assays (Li et al. 2019), an important consideration as some acetylcholinesterase inhibitors become more potent when metabolized. Selected inhibitors were further characterized using stem cells and computational models to gain insights on their inhibitory mechanisms.