By Wolfgang Dekant, et al. Dekant et al., developed a quantitative weight of evidence methodology to assess confidence in postulated mode(s) of action for adverse effects in animal toxicology studies and to assess the appropriateness of the adverse effects as relevant endpoints in human health risk assessments and for classification and labeling. To demonstrate the applicability of the QWoE approach, the authors applied the methodology assessing two separate effects induced by inhalation of D4 (impaired female fertility and induction of benign uterine tumors observed in rats); The authors concluded that when evaluating human relevance of the molecular initiating/key events, the chain of key steps is broken at key step #3, decreased LH surge, due to the absence of an association between a decrease in prolactin and the LH surge in humans. Therefore, the mode of action for reproductive effects and the proliferative endometrial lesions is not relevant to humans, based on lack of a role for prolactin in human ovulatory function.
These recent assessments are consistent with a large body of peer reviewed publications supporting the safety of D4 and independent government assessments in Australia and Canada concluding that the use of D4 does not pose a danger to human health. These publications provide further support that the use of D4 in consumer products does not warrant any marketplace restrictions, which would unnecessarily hinder trade and limit consumer choice without any corresponding human health benefit.
By Jean Domoradzki et al. They examined how rats absorbed, distributed, metabolized, and eliminated a single oral low dose of D4 and D5, offering a realistic oral exposure scenario. The previously developed multi-species and multi-dose route (MC-MD) PBPK model for examining the effects of D4 and D5 primarily describes effects from inhalation and dermal exposure.
The study’s findings suggest differences in the metabolism of low and high oral doses of D4 and D5 and suggest the pharmacokinetics of D4 and D5 following oral dosing is different than inhalation or dermal exposure and require a refined model. This work by Domoradzki et al. allows for the refining the PBPK to better account for the effects of low dose oral exposure, which may be used in risk assessment to better define the internal dose of D4 and D5 following different routes of exposure.
By Allison Franzen et al. She summarizes the results of toxicity and mechanistic studies of D4. The review notes that studies have not found significant toxicological effects following acute dermal, oral, or inhalation exposures to D4, nor is D4 reported to be an eye irritant, skin irritant, or skin sensitizer. Liver effects reported in rats following inhalation exposure to D4 were not adverse, reversible and of no relevance to in determining human risk. Studies of D4’s potential endocrine activity suggest that D4 has very weak estrogenic activity, and effects of D4 on fertility as observed in rats are unlikely to be relevant to humans.
By Paul Jean et al. They compare the effects on reproductive cyclicity of aging female rats of chronic inhalation exposure to D4 and D5. The authors find that while exposure to D4 and D5 can affect cyclicity, the results suggest that D4 and D5 are not classical dopamine agonists. These findings are important to understanding the results of chronic exposure to D4 and D5 in rats. The authors’ findings support that the D4 and D5-induced uterine tumors are specific to this strain of rat and are not biologically relevant to humans based on the distinct differences in reproductive systems, the high exposure levels and duration required for the tumors to occur.
By Robinan Gentry, et al. The authors conducted a global “harmonized” risk assessment to meet the various governments’ substance-specific risk assessment requirements. Gentry et al. incorporate global exposure information combined with a Monte Carlo analysis to determine the most significant routes of exposure. The multi-species, multi-route physiologically based pharmacokinetic (PBPK) model is included to estimate internal dose metrics, benchmark modeling is used to determine a point of departure POD, and a margin of safety (MOS) evaluation is used to compare the estimates of intake with the POD. Gentry et al. find that MOS were greater than 1,000 for workers, consumers, and the general public who may be exposed to D4 either in the workplace, through the use of consumer products containing D4, or to D4 released in the environment, indicating a lack of any anticipated significant risk of adverse effects.