Dermal Permeability of Perfluorohexane Sulfonic Acid (PFHxS) and Perfluorohexanoic Acid (PFHxA) in Varying Vehicles and the Effects on Skin Integrity in a Reconstructed Human Epidermis Model

Per- and polyfluoroalkyl substances (PFAS) are widespread environmental contaminants associated with adverse health effects, yet dermal exposure remains poorly characterized. This study evaluated the influence of vehicle and chemical structure on dermal absorption and skin barrier integrity using a reconstructed human epidermis model (EpiDermFT). Two C6 PFAS, perfluorohexane sulfonate (PFHxS) and perfluorohexanoic acid (PFHxA), were applied in three vehicles (acetone, water, and diethylene glycol monobutyl ether [DEGME]) at concentrations of 0–0.015% for 4 or 24 h. PFAS concentrations were quantified in tissue and receptor media, and skin barrier integrity was assessed using histological and immunological endpoints. Increasing exposure resulted in higher concentrations of PFHxS and PFHxA in both tissue and media across all vehicles, indicating dermal penetration and absorption. PFHxS exhibited greater tissue retention but only a few small, isolated changes in cytokine and gene expression and no significant effect on barrier integrity. In contrast, PFHxA induced increased expression of inflammatory mediators and alterations in skin barrier function. These findings indicate a divergence between dermal retention and biological activity. Overall, while the vehicle influenced PFAS transport, biological responses were more strongly associated with functional group. These results suggest that functional group-dependent toxicity is an important determinant of dermal PFAS effects and should be considered when characterizing PFAS dermal hazard and grouping structurally related compounds for assessment.