Supplementary material of: Development of a generic lifetime PBPK model for female mice from the prenatal to lactation period applied to Methylmercury.

Methylmercury (MeHg) is frequently detected in human serum, umbilical cord blood, and breast milk, indicating prenatal and lactational exposure in the general population. Animal studies have raised concerns about MeHg’s developmental neurotoxicity. Physiologically Based Pharmacokinetic (PBPK) models provide a mechanistic approach to predict xenobiotic kinetics based on physiological and chemical properties. In this study, we developed a generic lifetime PBPK model for female mice, incorporating gestation and lactation. The model includes six compartments for the dam and six for the pup, including the brain, and accounts for growth dynamics and changes in organ volumes and blood flows. Parameterized for MeHg, the model simulates maternal oral exposure and predicts MeHg internal concentrations in offspring, including the developing brain. The model was used to determine the underlying key factors influencing internal MeHg body burden. Applications demonstrated how PBPK modeling can estimate key kinetic parameters (e.g., Cmax, AUC), identify the impact of timing and duration of the maternal exposure on the offspring’s exposure, and quantify the relative contributions of gestational and lactational exposure. These insights were incorporated in an in vitro–in vivo extrapolation (IVIVE) context to integrate New Approach Methodologies (NAMs) into neurotoxicity assessment. Ultimately, the model enhances risk assessment of prenatal and lactational exposure to MeHg by linking internal dose metrics in fetus and pup to observed effects and presenting new insights in developmental studies.