Abstract

Chlorpyrifos (CPF: organophosphate) use on cannabis crops is not regulated in the United States. CPF residue, including the metabolite CPF-oxon (CPFO), in combination with Δ9Tetrahydrocannabinol (Δ9THC) on/in cannabis plants disrupts the endocannabinoid system (ECS) resulting in neurodevelopmental/behavioral defects. This case study used computational toxicology (CompTox) tools with CPF/CPFO and Δ9THC to compare known toxicity to predicted toxicity. This was accomplished by: (1) Active hit-calls from the ToxCast/Tox21 assay database were downloaded and sorted; (2) Activities in intended target families were ranked by chemical using the Toxicology Priority Index (ToxPi); (3) Integrated Chemical Environment physiologically based toxicokinetic (PBTK) models calculated assay-specific human equivalent administered dose (EADHuman) to compare to literature-based ECS-related in vivo animal endpoints. ToxCast/Tox21 assays identified critical targets in the CPF/CPFO and Δ9THC metabolic pathways, including neurological receptors related to the ECS. ToxPi ranking (CPF > CPFO >Δ9THC) and PBTK (i.v.) EADHuman values were concordant with in vivo measured endpoints associated with the ECS.

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