New Approach Methodologies and Open Access Tools Help Characterize Risks for DART, DNT, or Endocrine Effects From Exposure to Hallucinogens With Potential Pesticide Contaminants.

Abstract

Psilocybe mushrooms (psilocybin/psilocin [PSI/PSC]) and ayahuasca (N,N-dimethyltryptamine [DMT]) are hallucinogenic serotonergic agonists. Pregnant and lactating women are frequently omitted from clinical studies; hence minimal developmental/reproductive/neurotoxicity (DART/DNT) and endocrine disruption (ED) data in humans are available. Hallucinogens contaminated with pesticides may have overlapping metabolic pathways affecting toxicity. An examination of potential adverse effects on pregnancy and development from exposure to hallucinogenic plants, hypothetically contaminated with organophosphates (OP) or organochlorines (OC), was performed using new approach methodologies (NAMs) and open access tools. Cheminformatics Modules, Predicting Developmental Toxicity Potential Project, Toxicity Estimation Software Tool (TEST) using quantitative structure-activity relationships, Endocrine Disruptor Screening Program, California's Proposition 65 list, and ToxCast assays were investigated for DART/DNT and ED reported effects and/or predictions related to PSI/PSC, DMT, and sentinel pesticides (chlorpyrifos/chlorpyrifos-oxon and endosulfan). ToxCast data were inputs for Integrated Chemical Environment (ICE) PBTK adult and fetal models to generate adjusted human Administered Equivalent Doses (AdjAEDs) that were compared to regulatory dose ranges for hallucinogens and pesticides to assess model predictions. Cheminformatics Modules, PregPred, and TEST-QSAR predicted that hallucinogens and pesticides have DART, DNT, and ED effects. No ToxCast data were reported for DMT and PSI was ToxCast inactive. PSC/pesticide overlapping metabolic pathways were CYP2C9 modulated by serotonin, thyroid hormones and sonic hedgehog, each associated with development. Clinical PSC and regulatory pesticide points of departure were generally within range of predicted fetal AdjAEDs. Open access NAMs tools identified risks to fetal development from exposure to hallucinogens and pesticides.