Development of human dermal PBPK models for the bisphenols BPA, BPS, BPF, and BPAF with parallel-layered skin compartment: Basing on dermal administration studies in humans

Risk assessment of human exposure to bisphenols (BPs) including bisphenol A, S, F and AF (BPA, BPS, BPF and BPAF) have suggested that except for ingestion, health risk resulting from dermal contact is not negligible. However, the absorption kinetics of BPA substitutes in humans following dermal exposure have been poorly studied. This study aimed to address the knowledge gap in physiologically based pharmacokinetic (PBPK) modeling of BPA and its high-concerned substitutes (BPS, BPF and BPAF) following dermal administration. Parallel-layered skin compartmental model for dermal absorption of BPs was for the first time proposed and human dermal administration studies were conducted to determine dermal bio-accessibility of BPS from thermal paper (TP) (n = 4), BPF (n = 4) and BPAF (n = 5) from personal care products (PCPs). Further, pharmacokinetics of BPS and its metabolites following human handling TP were investigated and the dermal PBPK models for BPA and BPS were validated using the available human biomonitoring data. Overall, 28.03 % ± 13.76 % of BPS in TP was transferred to fingers followed by absorption of 96.17 % ± 2.78 % of that. The dermal bio-accessibilities of BPs in PCPs were 31.65 % ± 2.90 % for BPF and 12.49 % ± 1.66 % for BPAF. Monte Carlo analysis indicated that 90 % of the predicted variability fell within one order of magnitude, which suggested that the developed PBPK models had medium uncertainty. Global sensitivity analysis revealed that the model uncertainty is mainly attributed to the variabilities of dermal absorption parameters. Compared with the previous models for BPs, the developed dermal PBPK models were capable of more accurate predictions of the internal dose metric in target organs following human dermal exposure to BPs via TP and PCPs routes. These results suggested that the developed human dermal PBPK models would provide an alternative tool for assessing the risk of human exposure to BPs through dermal absorption.