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ICCVAM Biennial Report 2020-2021

Biennial Progress Report 2020-2021 Interagency Coordinating Committee on the Validation of Alternative Methods

Human Neuronal Cell Line as a Model for Organophosphorus Pesticide-induced Neurotoxicity

Non-animal screening methods that can rapidly and accurately characterize organophosphorus compound-induced neurotoxicity are needed. Scientists at the U.S. Army Engineer Research and Development Center examined molecular and cellular responses characteristic of this neurotoxicity pathway via an in vitro model using the SYSY5Y human neuroblastoma cell line and the model organophosphorus compound ethyl parathion. In these studies, ethyl parathion was found to increase reactive oxygen species and cell membrane lipid peroxidation and reduce mitochondrial membrane potential, contributing ultimately to cell death. Overall, the mechanistic responses observed in the SYSY5Y cells corresponded closely with in vivo mammalian results, demonstrating potential for this non-animal model to provide accurate neurotoxicology screening for organophosphorus compounds. These investigations also provide data to support development of the AOP for this endpoint. In 2022, the research team will use these methods to investigate time-dynamic neurotoxicity responses to ethyl parathion. They will also begin developing in vitro methods that provide mechanistic toxicology indicators characteristic of mammalian acute ammonia inhalation exposures.