Animal evidence considered in determination of cannabis smoke and Δ9 -tetrahydrocannabinol (Δ9 -THC) as causing reproductive toxicity (developmental endpoint); Part II. Neurodevelopmental effects.

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.

Animal evidence considered in determination of cannabis smoke and Δ9 -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 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.

Application of the Navigation Guide systematic review methodology to the evidence for developmental and reproductive toxicity of triclosan.

BACKGROUND: There are reports of developmental and reproductive health effects associated with the widely used biocide triclosan. OBJECTIVE: Apply the Navigation Guide systematic review methodology to answer the question: Does exposure to triclosan have adverse effects on human development or reproduction? METHODS: We applied the first 3 steps of the Navigation Guide methodology: 1) Specify a study question, 2) Select the evidence, and 3) Rate quality and strength of the evidence. We developed a protocol, conducted a comprehensive search of the literature, and identified relevant studies using pre-specified criteria. We assessed the number and type of all relevant studies. We evaluated each included study for risk of bias and rated the quality and strength of the evidence for the selected outcomes. We conducted a meta-analysis on a subset of suitable data. RESULTS: We found 4282 potentially relevant records, and 81 records met our inclusion criteria. Of the more than 100 endpoints identified by our search, we focused our evaluation on hormone concentration outcomes, which had the largest human and non-human mammalian data set. Three human studies and 8 studies conducted in rats reported thyroxine levels as outcomes. The rat data were amenable to meta-analysis. Because only one of the human thyroxine studies quantified exposure, we did not conduct a meta-analysis of the human data. Through meta-analysis of the data for rats, we estimated for prenatal exposure a 0.09% (95% CI: -0.20, 0.02) reduction in thyroxine concentration per mg triclosan/kg-bw in fetal and young rats compared to control. For postnatal exposure we estimated a 0.31% (95% CI: -0.38, -0.23) reduction in thyroxine per mg triclosan/kg-bw, also compared to control. Overall, we found low to moderate risk of bias across the human studies and moderate to high risk of bias across the non-human studies, and assigned a "moderate/low" quality rating to the body of evidence for human thyroid hormone alterations and a "moderate" quality rating to the body of evidence for non-human thyroid hormone alterations. CONCLUSION: Based on this application of the Navigation Guide systematic review methodology, we concluded that there was "sufficient" non-human evidence and "inadequate" human evidence of an association between triclosan exposure and thyroxine concentrations, and consequently, triclosan is "possibly toxic" to reproductive and developmental health. Thyroid hormone disruption is an upstream indicator of developmental toxicity. Additional endpoints may be identified as being of equal or greater concern as other data are developed or evaluated.