Animal evidence considered in determination of cannabis smoke and Δ9 -tetrahydrocannabinol as causing reproductive toxicity (developmental endpoint): Part III. Proposed neurodevelopmental mechanisms of action.

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.

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.

Butylated hydroxyanisole: Carcinogenic food additive to be avoided or harmless antioxidant important to protect food supply?

Tumor data from rodent bioassays are used for cancer hazard classification with wide-ranging consequences. This paper presents a case study of the synthetic antioxidant butylated hydroxyanisole (BHA), which IARC classified as Group 2B ("possibly carcinogenic to humans") on the basis of forestomach tumors in rodents following chronic dietary exposure to high levels. IARC later determined that the mechanism by which BHA induces forestomach tumors is not relevant to humans; however, the classification has not been revoked. BHA was listed on California Proposition 65 as a direct consequence of the IARC classification, and there is widespread concern among consumers regarding the safety of BHA driven by the perception that it is a carcinogen. While many regulatory agencies have established safe exposure limits for BHA, the IARC classification and Proposition 65 listing resulted in the addition of BHA to lists of substances banned from children's products and products seeking credentials such as EPA's Safer Choice program, as well as mandatory product labeling. Classifications have consequences that many times pre-empt the ability to conduct an exposure-based risk-based assessment., It is imperative to consider human relevance of both the endpoint and exposure conditions as fundamental to hazard identification.

Derivation of an oral Maximum Allowable Dose Level for Bisphenol A.

Bisphenol A (BPA) is a high production volume chemical that is used in plastics and epoxy coatings. In 2015, California's Office of Environmental Health Hazard Assessment (OEHHA) added BPA to the Proposition 65 list of chemicals "known to cause reproductive toxicity" based on its Developmental and Reproductive Toxicant Identification Committee's (DART-IC) conclusion that BPA has been shown to cause female reproductive toxicity. A critical factor in determining compliance with Proposition 65 is a Maximum Allowable Dose Level (MADL), which is the exposure level at which a chemical would have no observable reproductive effect even if a person were exposed to 1000 times that level. We performed a comprehensive review of the literature, including the studies reviewed by DART-IC, and derived an oral MADL. Of all the studies we identified, Delclos et al. (2014) is of sufficient quality, has the lowest no observed effect level (NOEL), and results in the most conservative MADL of 157 µg/d. This is generally supported by other studies, including those that were considered by DART-IC. Also, the oral MADL provides a similar margin of safety as OEHHA's dermal MADL and other regulatory guidelines. Taken together, the scientific data support an oral MADL of 157 µg/d.

Derivation of a No-Significant-Risk-Level (NSRL) for diethanolamine (DEA).

Diethanolamine (DEA) has been listed on the State of California's Proposition 65 List. This listing is based in part on tumors reported in a National Toxicology Program (NTP) 2-year dermal carcinogenicity study in mice which found clear evidence of carcinogenic activity in B6C3F1 mice based on increased incidences of liver neoplasms in both sexes, and increased incidences of renal tubule neoplasms in males. Although considerable controversy exists on the relevance of the NTP study to humans, industries are obligated to comply with the Proposition 65 labeling requirement and drinking water discharge prohibition, unless they are able to demonstrate that DEA levels in their products are below a specific No Significant Risk Level (NSRL). The State of California has not published an NSRL for DEA. In this article, a NSRL of 5.6 µg/day and a life-stage-adjusted NSRL(adj) of 1.4 µg/day are derived from the NTP carcinogenicity study using a benchmark dose modeling method based on the incidence of hepatocellular carcinomas in female mice, in accordance with the guidelines of California EPA.