Development of a physiologically based pharmacokinetic model to improve risk assessment of 6:2 Chlorinated polyfluoroalkyl ether sulfonate on human health

The pervasive detection of 6:2 chlorinated polyfluoroalkyl ether sulfonic acid (6:2 Cl-PFESA, commercial name: F-53B), a commonly utilized alternative for perfluorooctane sulfonate (PFOS), has raised concern. However, the lack of comprehensive toxicokinetic information poses a significant challenge in estimating associated human risk. This study aimed to develop a physiologically based pharmacokinetic (PBPK) model for 6:2 Cl-PFESA in male mice, derive a human-equivalent reference dose (RfD) using toxicokinetic data, and assess associated health risks based on measured serum concentrations. Results revealed that 6:2 Cl-PFESA exhibited tissue-specific accumulation in male mice following oral and intravenous administration, with the distribution ranked as liver > blood > fat > kidney > other tissues. The bioavailability of 6:2 Cl-PFESA was approximately 65 %. Based on these toxicokinetic data, the newly developed PBPK model estimated a half-life of up to 46.5 days at low exposure levels and a volume of distribution between 0.592 and 0.604 L/kg. The resulting RfD was 0.02 ng/kg/day, indicating higher toxicity and greater human health risks than PFOS. The population-weighted hazard quotient (HQ) for 6:2 Cl-PFESA was 1.95, suggesting a significant health risk in China. These findings highlight the urgent need for stringent regulatory measures targeting PFOS alternatives, including 6:2 Cl-PFESA.