Human Internal Exposures of Bisphenol A and Six Data-Poor Analogs Predicted by Physiologically Based Kinetic Models with Multimodal Parametrization

Bisphenols (BP) AF, B, E, F, M, and S are increasingly used as bisphenol A (BPA) substitutes. Despite widespread exposure and potential adverse health outcomes, they are poorly understood in terms of toxicokinetics, i.e., their absorption, distribution, metabolism, and excretion. We thus developed physiologically based kinetic models for different human physiological standards to predict internal concentrations of prevalent bisphenols following oral exposure. To address the imbalances in available human data among these chemicals, we used multimodal parametrization methods, including in vitro measurements of metabolism, computational prediction of gastrointestinal absorption, and rat-human extrapolation of enterohepatic circulation. Then, the models were evaluated against available human toxicokinetic data for BPA and BPS, revealing that 66% of predicted <i>C</i>_max, <i>t</i>_max, and AUC values fell within a 2-fold difference from in vivo measures. Using environmentally relevant exposure levels to compare internal levels of all tested bisphenols, we observed significant differences in the toxicokinetic profiles. Concerning tissues of toxicological concern, BPS had the highest concentration in blood and testes, while BPM accumulated in the thyroid and BPAF in the breasts. The present models are expected to facilitate a more precise evaluation of health risks induced by BPA analogs, guiding their safer use.