Oral reference dose (RfD) derivation for five bisphenol A alternatives integrating BMD and NOAEL/LOAEL approaches

Bisphenols (BPs) are widely used in plastic manufacturing, food packaging, and other industrial applications, with bisphenol A (BPA) being one of the most extensively produced chemicals globally. However, due to its endocrine-disrupting properties, BPA has been linked to reproductive abnormalities, metabolic disorders, neurodevelopmental impairments, and other adverse health effects, leading to regulatory restrictions. These restrictions have resulted in increased usage of BPA alternatives and thus exposure to the alternatives, whose toxicity thresholds remain insufficiently characterized. To address this gap, this study derived reference doses (RfDs) for five BPA alternatives, i.e., bisphenol B (BPB), bisphenol P (BPP), bisphenol Z (BPZ), bisphenol AF (BPAF), and bisphenol AP (BPAP), by integrating epidemiological data and animal experiments. The RfDs were calculated using Benchmark Dose (BMD) modeling and no observed adverse effect level/lowest observed adverse effect level (NOAEL/LOAEL) approaches, combined with uncertainty analysis to quantify risk metrics. The results demonstrated that the BMD-derived RfDs for BPB, BPP, and BPZ were 1.05, 0.23, and 5.13 μg/kg-bw/day, respectively, while the NOAEL/LOAEL-based RfDs for BPAF and BPAP were 0.04 and 2.31 ng/kg-bw/day. By refining toxicity thresholds and risk assessment methodologies, this study not only highlights the potential health risks posed by BPs but also supports evidence-based policymaking to safeguard public health.