Advancing probabilistic risk assessment of perfluorooctanoic acid through integration of in vitro data and physiologically based toxicokinetic modeling coupled with population-specific analysis

Here, we applied benchmark dose-response modeling to derive benchmark concentrations (BMCs) for apical and transcriptomic changes in human endothelial cells EA.hy926 following both high-concentration short-term (48 h) and human-relevant long-term (6 and 12 weeks) PFOA exposures. BMCs were translated into human equivalent doses (HEDs) using a physiologically based toxicokinetic model.

Long-term exposure produced sensitive biological responses: 10th percentile HEDs for apical and transcriptomic data were 0.59 and 3.84 ng/kg bw/week, respectively, both below the estimated U.S. general population exposure level (9.91 ng/kg bw/week). Predicted 10th percentile HED thresholds in individuals with certain conditions were: end-stage renal disease 0.50 ng/kg bw/week, moderate to severe reductions in glomerular filtration rate 0.18–1.00 ng/kg bw/week, cirrhosis class A 0.18 ng/kg bw/week, NAFLD 0.79 ng/kg bw/week, and class 1 obesity 0.43 ng/kg bw/week, compared to healthy individuals (1.18 ng/kg bw/week), suggesting that PFOA can elicit adverse effects in endothelial cells at exposure levels below those currently experienced by the general population.