Development of Sex-Specific Physiologically Based Toxicokinetic (PBTK) Models for GenX in Mice and Their Application to Human Health Risk Assessment.

GenX (hexafluoropropylene oxide dimer acid, HFPO-DA), a widely used alternative to perfluorooctanoic acid (PFOA), has raised significant concerns due to its multi-system toxicity and potential human health risks. Accumulating evidence indicates that both the toxicokinetics and toxicity of GenX exhibit marked sex-specific differences. The current reference dose (RfD) derived by the U.S. Environmental Protection Agency (U.S. EPA) relies on allometric scaling for cross-species extrapolation, which may not adequately capture physiological determinants of toxicokinetics or account for sex-related variability. To address this gap, we developed the first sex-specific physiologically based toxicokinetic (PBTK) models for GenX in mice and extrapolated them to humans to derive sex-specific RfDs and assess population risks. A literature search identified nine mouse toxicokinetic publications contributing 14 sex-specific datasets for model calibration and evaluation, including nine male and five female datasets. The calibrated sex-specific models showed coefficients of determination (R2) exceeding 0.87 for both sexes, with 52.4% to 70.2% of predictions falling within twofold of the observations. The models were subsequently extrapolated to humans and evaluated using an independent human toxicokinetic dataset, with population biomonitoring data used for a separate consistency assessment. Using hepatocellular hypertrophy as the critical endpoint, the sex-specific RfDs were lower in males than in females (9.03 × 10-6 vs. 5.10 × 10-5 mg/kg/day). Risk assessment further indicated potential GenX-related health risks among populations living near fluorochemical industrial facilities. Overall, this study provides the first sex-specific PBTK models for GenX and supports more refined, sex-informed risk assessment and management.