Can we integrate plasma protein binding data into IATA using new approach methodologies? A case study on bisphenol analogs.

The toxicological evaluation of bisphenol A (BPA) analogs is essential due to their increasing use as BPA substitutes and the limited availability of safety data. This study investigates the plasma protein binding (PPB) characteristics of 18 bisphenol analogs using biomimetic high-performance liquid chromatography with human serum albumin coated column (HSA-HPLC) and computational methods. Experimentally determined PPB values demonstrated very high binding exceeding 94 % across all compounds, with subtle yet meaningful differences particularly among structural isomers. A validated quantitative structure property relationship (QSPR) model was developed using three key molecular descriptors: van der Waals surface area, minimum projection area, and isoelectric point charge. The model successfully predicted PPB values and provided mechanistic insight into the molecular determinants of PPB. Molecular docking studies further characterized binding site preferences and stabilizing interactions with human serum albumin. These findings demonstrate that HSA-HPLC combined with QSPR modeling and docking simulations offers a reliable and human-relevant strategy for PPB assessment. Such integration is critical for enhancing the accuracy of in vitro to in vivo extrapolation (IVIVE) and supports using PPB data in chemical safety assessment under integrated approaches to testing and assessment (IATA).