The development of a pregnancy PBPK Model for Bisphenol A and its evaluation with the available biomonitoring data

Recent studies suggest universal fetal exposure to Bisphenol A (BPA) and its association with the adverse birth outcomes. Estimation of the fetal plasma BPA concentration from the maternal plasma BPA would be highly useful to predict its associated risk to this specific population. The objective of current work is to develop a pregnancy-physiologically based pharmacokinetic (P-PBPK) model to predict the toxicokinetic profile of BPA in the fetus during gestational growth, and to evaluate the developed model using biomonitoring data obtained from different pregnancy cohort studies. To achieve this objective, first, the adult PBPK model was developed and validated with the human BPA toxicokinetic data. This validated human PBPK model was extended to develop a P-PBPK model, which included the physiological changes during pregnancy and the fetus sub-model. The developed model would be able to predict the BPA pharmacokinetics (PKs) in both mother and fetus. Transplacental BPA kinetics parameters for this study were taken from the previous pregnant mice study. Both oral and dermal exposure routes were included into the model to simulate total BPA internal exposure. The impact of conjugation and deconjugation of the BPA and its metabolites on fetal PKs was investigated. The developed P-PBPK model was evaluated against the observed BPA concentrations in cord blood, fetus liver and amniotic fluid considering maternal blood concentration as an exposure source. A range of maternal exposure dose for the oral and dermal routes was estimated, so that simulation concentration matched the observed highest and lowest mother plasma concentration in different cohorts' studies. The developed model could be used to address the concerns regarding possible adverse health effects in the fetus being exposed to BPA and might be useful in identifying critical windows of exposure during pregnancy