Development and Human Extrapolation of Physiologically Based Toxicokinetic Models for Chlorinated Polyfluoroalkyl Ether Sulfonates from Rats

Chlorinated polyfluoroalkyl ether sulfonates (F-53B, including 6:2 Cl-PFESA and 8:2 Cl-PFESA) are typical alternatives to perfluorooctanesulfonate in China. However, they are persistent and frequently detected in the environment and humans and pose bioaccumulation and health risks. The limited understanding of F-53B's toxicokinetic data hinders its risk assessment. This study aimed to develop physiologically based toxicokinetic (PBTK) models for 6:2 Cl-PFESA and 8:2 Cl-PFESA in rats and to extrapolate the models to humans. Male rats were administered a single 100 μg/kg dose of F-53B (with a 6:2 Cl-PFESA to 8:2 Cl-PFESA ratio of about 9:1) via gavage and intravenous injection, and biosample concentrations were quantified using ultrahigh-performance liquid chromatography-mass spectrometry. Results showed that 6:2 Cl-PFESA was mainly distributed to the liver and plasma, while 8:2 Cl-PFESA was primarily distributed to the liver and lung. The developed PBTK models successfully predicted 100% of 6:2 Cl-PFESA and 92% of 8:2 Cl-PFESA concentrations within a 2-fold range of the observed values. These models were subsequently extrapolated to humans and validated with human biomonitoring data. This study establishes PBTK models for F-53B in the general adult population, enhancing quantitative risk assessments under real-world scenarios.