Probabilistic human health risk assessment of perfluorooctane sulfonate (PFOS) by integrating in vitro, in vivo toxicity, and human epidemiological studies using a Bayesian-based dose-response assessment coupled with physiologically based pharmacokinetic (PBPK) modeling approach

Background: Environmental exposure to perfluorooctane sulfonate (PFOS) is associated with various adverse outcomes in humans. However, risk assessment for PFOS with the traditional risk estimation method is faced with multiple challenges because there are high variabilities and uncertainties in its toxicokinetics and toxicity between species and among different types of studies. Objectives: This study aimed to develop a robust probabilistic risk assessment framework accounting for inter-species and inter-experiment variabilities and uncertainties to derive the human equivalent dose (HED) and reference dose for PFOS. Methods: A Bayesian dose-response model was developed to analyze selected 34 critical studies, including human epidemiological, animal in vivo, and ToxCast in vitro toxicity datasets. The dose-response results were incorporated into a multi-species physiologically based pharmacokinetic (PBPK) model to reduce the toxicokinetic/toxicodynamic variabilities. In addition, a population-based probabilistic risk assessment of PFOS was performed for Asian, Australian, European, and North American populations, respectively, based on reported environmental exposure levels. Results: The 5th percentile of HEDs derived from selected studies was estimated to be 21.5 (95% CI: 10.6-36.3) ng/kg/day. After exposure to environmental levels of PFOS, around 50% of the population in all studied populations would likely have > 20% of increase in serum cholesterol, but the effects on other endpoints were estimated to be minimal (< 10% changes). There was a small population (similar to 10% of the population) that was highly sensitive to endocrine disruption and cellular response by environmental PFOS exposure. Conclusion: Our results provide insights into a complete risk characterization of PFOS and may help regulatory agencies in the reevaluation of PFOS risk. Our new probabilistic approach can conduct dose-response analysis of different types of toxicity studies simultaneously and this method could be used to improve risk assessment for other perfluoroalkyl substances (PFAS).