Framework for risk assessment of PFAS utilizing experimental studies and in-silico models

Perfluoroalkyl substances (PFAS), especially PFOS and PFOA, are two widely used synthetic chemicals that can impact human health based on evidence from animal and epidemiologic studies. In this paper, we have reviewed and summarized the influence of PFAS exposure on health, pointing the quality of evidence, and applied translational techniques to integrate evidence for PFAS policy making. This is the first review where highly referred articles on PFAS used for policymaking by several regulatory agencies were collected and evaluated based on the review guidelines developed by the US National Toxicology Program's Office of Health Assessment and Translation (OHAT) review guidelines. Several limitations were observed, including co-exposure to multiple chemicals and limited measurement of primary and secondary outcomes related to specific toxicity. However, data from all the studies provided a moderate to strong level of confidence for link between PFAS exposure and different adverse outcomes. Secondly, for translating the risk to humans, an in-silico model and scaling approach was utilized. Physiologically based pharmacokinetic model (PBPK) was used to calculate the human equivalent dose (HED) from two widely accepted studies and compared with tolerable daily intakes (TDIs) established by various regulatory agencies. Inter-species dose extrapolation was done to compare with human the relevance of dosing scenarios used in animals. Overall, a framework for translation of risk was proposed based on the conclusions of this review with the goal of improving policymaking. The current paper can improve the methodological protocols for PFAS experimental studies and encourage the utilization of in-silico models for translating risk.