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Objectives: On December 11, 2019, California's Developmental and Reproductive Toxicant Identification Committee (DARTIC) met to consider the addition of cannabis smoke and Δ9‐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. Δ9‐THC can interfere with these functions. Mechanistic studies employed techniques including: blocking Δ9‐THC binding to endocannabinoid (EC) receptors, inhibiting Δ9‐THC metabolism, and/or using animals expressing knockout mutations of EC receptors. Apical somatic effects of cannabis smoke or Δ9‐THC reported in whole animal studies included decreases in offspring viability and growth. Mechanistic studies discussed in Part I focused on Δ9‐THC effects on early embryos and implantation, immune development, and bone growth. Conclusions: In reaching its decision to list cannabis and Δ9‐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. [ABSTRACT FROM AUTHOR]

This review summarizes the most common potential pathways of neurodevelopmental toxicity due to perinatal exposure to Δ9‐tetrahydrocannabinol (Δ9‐THC) that lead to behavioral and other adverse outcomes (AOs). This is Part III in a set of reviews highlighting the animal‐derived data considered by California's Developmental and Reproductive Toxicant Identification Committee (DARTIC) in 2019. The Hazard Identification Document (HID) provided to the DARTIC included a summary of human, whole animal, and mechanistic data on the neurodevelopmental toxicity of cannabis smoke and Δ9‐THC. The literature search for mechanistic data has been updated through 2020. We focus on mechanistic pathways relating to behavioral and other neurodevelopmental outcomes of perinatal exposure to Δ9‐THC. The endocannabinoid system (EC system) plays a crucial role in many processes involved in neurodevelopment and exposure to Δ9‐THC can alter these processes. Whole animal studies report changes in cognitive ability, behavior, and motor function after prenatal exposure to Δ9‐THC. Findings from mechanistic studies add to this evidence and further provide information regarding the pathways leading to these outcomes. Neuromechanistic studies can bridge the gaps between molecular initiating events and apical neurodevelopmental endpoints caused by a chemical. They offer insight into potential alterations in the same pathways by other chemicals that can also result in AOs. Studies of cannabinoid receptor agonist‐induced molecular alterations and provide deep biological plausibility at the mechanistic level for the cognitive, behavioral, and motor impairments observed in animal studies after perinatal exposure to Δ9‐THC. [ABSTRACT FROM AUTHOR]

This review focuses on neurodevelopmental effects observed in animal studies of cannabis smoke and Δ9‐THC. Effects in offspring after preconceptional, prenatal, or perinatal exposure to cannabis smoke or Δ9‐THC were considered. Locomotor and exploratory behavior effects were noted in rats. Cognitive effects observed included impairment of memory and learning, attention deficits, time taken to complete tasks (rats) and alterations in response to visual stimuli (rats/monkeys). Emotionality was observed in rodents as an increase in separation‐induced ultrasonic vocalizations, reduced social interaction and play behavior, and increased generalized anxiety. Increased rate of acquisition of morphine self‐administration and/or enhanced sensitivity towards the rewarding effects of morphine or heroin were observed in adult rats prenatally exposed to Δ9‐THC. Expression of cannabinoid receptors was examined in rodent studies along with behavioral parameters. Altered mRNA levels of genes relevant to synaptic plasticity in the nucleus accumbens (the brain region associated with compulsivity, addiction vulnerability, and reward sensitivity) were noted. Findings in zebrafish supported effects in mammalian models. Neurochemical effects on specific brain regions and neurotransmitter systems seen in these animal studies appear to impact cognitive function, motor activity, and drug sensitivity. Mechanistic studies provided evidence for the biological plausibility of effects observed. Observations from animal studies of changes in motor behavior, cognitive performance, emotionality and susceptibility to drug sensitivity later in life were among the findings from animal and human studies considered by California's Developmental and Reproductive Toxicant Identification Committee, in concluding that cannabis smoke and Δ9‐THC are developmental toxicants. [ABSTRACT FROM AUTHOR]