Risk Assessment of Per‐ and Polyfluoroalkyl Substance Mixtures: A Relative Potency Factor Approach

Abstract

Per‐ and polyfluoroalkyl substances (PFAS) often occur together as contamination in exposure media such as drinking water or food. The relative potency factor (RPF) methodology facilitates the risk assessment of mixture exposure. A database of liver endpoints was established for 16 PFAS, using data with the same species (rat), sex (male), and exposure route (oral) and comparable exposure duration (42–90 d). Dose–response analysis was applied to derive the relative potencies of 3 perfluoroalkyl sulfonic acids (perfluorobutane sulfonic acid, perfluorohexane sulfonic acid, perfluorooctane sulfonic acid), 8 perfluoroalkyl carboxylic acids (perfluorobutanoic acid, perfluorohexanoic acid, perfluorononanoic acid, perfluoroundecanoic acid, perfluorododecanoic acid, perfluorotetradecanoic acid, perfluorohexadecanoic acid, perfluorooctadecanoic acid), 2 perfluoroalkyl ether carboxylic acids (tetrafluoro‐2‐[heptafluoropropoxy]propanoic acid, 3H‐perfluoro‐3‐[(3‐methoxy‐propoxy)propanoic acid]), and 2 fluorotelomer alcohols (6:2 FTOH, 8:2 FTOH) compared to perfluorooctanoic acid (PFOA), based on liver effects. In addition, the RPFs of 7 other perfluoroalkyl acids were estimated based on read‐across. This resulted in the relative potencies of 22 PFAS compared to the potency of index compound PFOA. The obtained RPFs can be applied to measured PFAS quantities, resulting in the sum of PFOA equivalents in a mixture. This sum can be compared with an established PFOA concentration limit (e.g., in drinking water or food) or an external health‐based guidance value (e.g., tolerable daily intake, acceptable daily intake, or reference dose) to estimate the risk resulting from direct oral exposure to mixtures. Assessing mixture exposure is particularly relevant for PFAS, with omnipresent exposure in our daily lives. Environ Toxicol Chem 2021;40:859–870. © 2020 SETAC

Bioaccumulation, Biodistribution, Toxicology and Biomonitoring of Organofluorine Compounds in Aquatic Organisms

“…The effects of perfluoroalkylic emerging pollutants are worrying since they involve the functionality of several organs and are generally more severe with increasing time of exposure and concentration of the contaminant [8, 26,38,121]. Compared to the effects of PFCs studied in humans, the biomolecular effects shown in aquatic organisms are more subject to controlled laboratory conditions, derive from a variety of experiments, and thus represent a wider panorama of possible consequences to PFCs exposure [16,17,87,[122][123][124][125][126][127][128][129][130][131][132].…”

Letter to the Editor on Bil et al. 2021 “Risk Assessment of Per‐ and Polyfluoroalkyl Substance Mixtures: A Relative Potency Factor Approach”

“…We welcome the use of RPFs for combined risk assessment of PFAS. However, we argue that the recommendation to use the RPFs proposed by Bil et al (2021) in risk assessment and risk management strategies is difficult to defend. Although we support the development of a toxic equivalency approach for risk assessment of PFAS, the RPF values proposed by Bil et al (2021) are in themselves not robust enough for direct application in risk assessment.…”

“…With respect to the robustness of the proposed RPF values, Bil et al (2021) indicate that the proposed values are based on liver toxicity in rats and that it may be relevant to validate whether they are relevant to other endpoints. This is important given that the EFSA TWI is based on an immune effect in humans as the critical effect.…”

Predicting the Effects of Per- and Polyfluoroalkyl Substance Mixtures on Peroxisome Proliferator-Activated Receptor Alpha Activity in Vitro

“…This approach assumes individual concentration response curves have the same shape and maximal effect and differ only in potency. RPF compares the potency of each chemical in the mixture to a reference compound; this approach is employed in the toxic equivalency factors used to assess additive effects of dioxin-like compounds (Van den Berg et al 2006) and has been proposed as a method to model additive effects of PFAS on liver endpoints (Bil et al 2021). The response predicted by RPF for a binary mixture is given by:…”

“…An RFP-based approach for modeling effects of PFAS mixtures in vivo also has been proposed. Bil et al, 2021 derived relative potency factors for 14 PFAS and two PFAS precursors based on liver endpoints including changes in relative and absolute liver weight and liver hypertrophy in male rats following chronic or subchronic oral PFAS exposure. PPARα activation is a critical mechanism contributing to liver hypertrophy in rodents (Hall et al 2012;Lee et al 1995).…”