Animal evidence considered in determination of cannabis smoke and Δ -tetrahydrocannabinol as causing reproductive toxicity (developmental endpoint); Part I. Somatic development.

Objectives: On December 11, 2019, California's Developmental and Reproductive Toxicant Identification Committee (DARTIC) met to consider the addition of cannabis smoke and Δ -THC to the Proposition 65 list as causing reproductive toxicity (developmental endpoint). As the lead state agency for implementing Proposition 65, the Office of Environmental Health Hazard Assessment (OEHHA) reviewed and summarized the relevant scientific literature in the form of a hazard identification document (HID). Here we provide reviews based on the HID: shortened, revised, and reformatted for a larger audience.

Methods: While the HID included both human and animal data, this set of three reviews will highlight the animal-derived data pertaining to somatic development (Part I), neurodevelopmental effects (Part II), and proposed neurodevelopmental mechanisms of action (Part III).

Results: Endogenous cannabinoids (eCBs) and their receptors serve many critical functions in normal development. Δ -THC can interfere with these functions. Mechanistic studies employed techniques including: blocking Δ -THC binding to endocannabinoid (EC) receptors, inhibiting Δ -THC metabolism, and/or using animals expressing knockout mutations of EC receptors. Apical somatic effects of cannabis smoke or Δ -THC reported in whole animal studies included decreases in offspring viability and growth. Mechanistic studies discussed in Part I focused on Δ -THC effects on early embryos and implantation, immune development, and bone growth.

Conclusions: In reaching its decision to list cannabis and Δ -THC as a developmental toxicant under California's Proposition 65, the DARTIC considered biological plausibility and the consistency of mechanistic information with effects reported in human and whole animal studies.