Application of a Framework for Grouping and Mixtures Toxicity Assessment of PFAS: A Closer Examination of Dose Additivity Approaches

Authors: P. Goodrum, J. Anderson, A. Luz, G. Ansell
Published: July 2020 in Toxicological Sciences.


Environmental occurrence and biomonitoring data for per- and polyfluoroalkyl substances (PFAS) demonstrate that humans are exposed to mixtures of PFAS. This paper presents a new and systematic analysis of available PFAS toxicity study data using a tiered mixtures risk assessment framework consistent with U.S. and international mixtures guidance. The lines of evidence presented herein include a critique of whole mixture toxicity studies and analysis of dose-response models based on data from subchronic oral toxicity studies in rats. Based on available data to-date, concentration addition and relative potency factor methods are found to be inappropriate due to differences among sensitive effects and target organ potencies and noncongruent dose-response curves for the same effect endpoints from studies using the same species and protocols. Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) lack a single mode of action or molecular initiating event and our evaluation herein shows they also have noncongruent dose-response curves. Dose-response curves for long chain perfluoroalkyl sulfonic acids (PFSAs) also significantly differ in shapes of the curves from short chain PFSAs and perfluoroalkyl carboxylic acids (PFCAs) evaluated, and additional differences are apparent when curves are evaluated based on internal or administered dose. Following well-established guidance, the hazard index (HI) method applied to PFCAs and PFSAs grouped separately is the most appropriate approach for conducting a screening level risk assessment for non-polymeric PFAS mixtures, given the current state-of-the science. A clear presentation of assumptions, uncertainties, and data gaps is needed before dose additivity methods, including HI, are used to support risk management decisions. Adverse outcome pathway(s) and mode(s) of action information for PFOA and PFOS and for other non-polymer PFAS are key data gaps precluding more robust mixtures methods. These findings can guide the prioritization of future studies on single chemical and whole mixture toxicity studies.

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