Lifetime PBPK model for female mice from the prenatal to lactation period: New insights for neurodevelopmental risk assessment of methylmercury

Methylmercury (MeHg) is a ubiquitous environmental contaminant and developmental neurotoxicant. A generic lifetime PBPK model was developed for female mice and their offspring that integrates gestation and lactation within a continuous exposure framework and accounts for growth-related physiological changes. Parameterized for MeHg, the model reproduced reported tissue concentrations in dams and offspring across gestation and lactation following maternal oral dosing. Model outputs indicate that offspring brain level is driven primarily by gestational transfer (≈80% of total), with a smaller contribution from lactational exposure. The model was further used to estimate key kinetic parameters (e.g., Cmax and AUC) and applied in four case studies, to assess the impact of exposure timing and duration in offspring brain exposure. These results provide quantitative insight into early-life MeHg toxicokinetics and support comparisons between predicted internal doses in vivo and effect levels from neuronal in vitro assays.