PBPK modeling of C7 HFPO-TA: Linking mouse pharmacokinetics to human exposure and risk through biomonitoring data

C7 hexafluoropropylene oxide trimer acid (C7 HFPO-TA), a next-generation replacement for perfluorooctanoic acid (PFOA), has been increasingly detected across diverse environmental matrices and in human serum, yet its toxicokinetic behavior remains largely uncharacterized, complicating human risk assessment. To address this, a physiologically based pharmacokinetic (PBPK) model was constructed for male CD-1 mice and extrapolated to human physiology. Following a single oral gavage of 1 mg/kg C7 HFPO-TA, concentrations were quantified in serum, liver, kidney, adipose tissue, gastrointestinal tract, urine, and feces. These data informed the development of a comprehensive PBPK model that reproduced observed kinetics across multiple tissues with good agreement (R² ≥ 0.88, except urine) and predicted a serum elimination half-life of approximately 76 h. Sensitivity analysis identified the serum free fraction and renal transport as key determinants of C7 HFPO-TA exposure. Monte Carlo simulations under realistic dietary exposure scenarios estimated a median steady-state serum concentration of 0.0181 ng/mL, closely aligning with empirical biomonitoring data. Using the U.S. EPA reference dose for HFPO-DA as a surrogate benchmark, the model-derived provisional human health guidance value (P-HGV) had a median of 0.3036 ng/mL and an uncertainty-bounded range of 0.1069-0.7067 ng/mL. Comparison with the P-HGV suggested relatively low population-level non-carcinogenic concern among adults in Zhejiang Province under the current surrogate RfD and exposure assumptions. By integrating animal-derived kinetics, human biomonitoring evidence, and risk assessment indicators, this study provides a quantitative foundation for evaluating C7 HFPO-TA health risks and informing regulatory decisions.