Derivation of the oral reference dose (RfD) for bisphenol S and bisphenol F based on epidemiological and experimental studies

With bisphenol A (BPA) restricted, its analogs are appearing frequently in the environment, raising health concerns. However, no reasonable threshold of toxicity has been established at the current international level for BPA analogs. The aim of this study was to derive oral reference doses (RfD) for two BPA substitutes, bisphenol S (BPS) and bisphenol F (BPF). A systematic search was conducted to screen epidemiologic and experimental rodent studies. Based on a thorough evaluation of those data, this study performed accurate model fitting using the Benchmark Dose Software (BMDS) to determine the recommended lower limit of the benchmark dose (BMDL) for BPS and BPF. Based on the dose-effect curves of the recommended models from BMDS, and incorporating the decline in male semen quality in epidemiologic studies as a critical effect, the present study further determined the departure point (POD) of BPS and BPF. After integrating uncertainty analysis, the RfD values of BPS and BPF were 0.37 and 8.09 ng/kg-bw/day, respectively, which were lower than the RfD value of BPA, but greater than the established minimum international toxicity thresholds of the tolerable daily intake of BPA. This study provides critical scientific evidence and important references for international environmental health regulatory agencies to improve their toxicity threshold settings, while emphasizing their increased attention to BPA alternatives.