Human health risk assessment of 6:2 Cl-PFESA through quantitative in vitro to in vivo extrapolation by integrating cell-based assays, an epigenetic key event, and physiologically based pharmacokinetic modeling.

Human health risk assessment of chemicals is essential but often relies on time-consuming and animal and labor-extensive procedures. Here, we develop a population-based, quantitative in vitro to in vivo extrapolation (QIVIVE) approach which depended on cellular effects monitored by in vitro assays, considered chemical internal concentration determined by LC-MS/MS, extrapolated into in vivo target tissue concentration through physiologically based pharmacokinetic (PBPK) modelling, and assessed populational health risk using in silico modelling. By applying this QIVIVE approach to 6:2 chlorinated polyfluorinated ether sulfonate (6:2 Cl-PFESA), as a representative of the emerging pollutants, we find that 6:2 Cl-PFESA disturbed lipid homeostasis in HepG2 cells through enhancement of lipid accumulation and fatty acid β-oxidation, during which miR-93-5p served as a key event towards toxicity and thus, could serve as an efficient toxicity marker for risk assessment; further, the disruption potency of lipid homeostasis of 6:2 Cl-PFESA for the most of studied populations in China might be of moderate concern. Together, our approach improved the reliability of QIVIVE during human health risk assessment, which can readily be used for other chemicals.