Bayesian benchmark dose modeling analysis and derivation of points of departure for female reproductive toxicity following exposure to di(2-ethylhexyl) phthalate (DEHP) — effects on reproductive hormones, folliculogenesis and estrous cyclicity

Endocrine-disrupting chemicals such as di(2-ethylhexyl) phthalate (DEHP) pose significant risks to human reproductive health. However, regulatory frameworks often lack sufficient data on sensitive female-specific reproductive endpoints. This study investigates the sensitivity of hypothalamic-pituitary-ovarian (HPO) axis endpoints to DEHP exposure in adult female mice, applying Bayesian Benchmark dose (BBMD) modeling for dose-response assessment and derivation of points-of-departure (PODs) for risk assessment. Data from four studies where sexually mature female mice were exposed to DEHP (0.02 to 240 mg/kg bw/d) for 10 or 30 d via oral administration, or 30 d via diet, was modeled. Endpoints included ovarian follicle counts, serum hormones, estrous cyclicity, body, and organ weights. Results revealed dose-dependent changes and greater sensitivity of progesterone, ovarian follicle counts, and uterine weight, compared with estrous cyclicity, body weight, and other organ weights. For 10- and 30-d oral administration studies, the lowest nonzero BBMDLs were observed for serum progesterone levels (9.1 mg/kg bw/d) and primary follicle counts (19.5 mg/kg bw/d), respectively. These PODs were notably lower than most No-Adverse-Effect-Levels in the European Chemicals Agency's (ECHA's) "Registered substances factsheet" and "ECHA CHEM" databases. The majority of the studies derived PODs based on male (reproductive) endpoints. Finally, a derived no-effect level of 0.064 mg DEHP/kg bw/d was estimated, based on the overall lowest BBMDL, serum progesterone levels of the 10-d oral study. In conclusion, our study indicates that current guidelines may not fully capture reproductive risks for females, underscoring the need to refine regulatory endpoints to better protect female reproductive health in the context of DEHP exposure.