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

Abstract

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.

Chronic Reproductive Toxicity Thresholds for Northern Bobwhite Quail (Colinus virginianus) Exposed to Perfluorohexanoic Acid (PFHxA) and a Mixture of Perfluorooctane Sulfonic Acid (PFOS) and PFHxA

“…To provide data useful to risk assessors that also satisfy varying opinions regarding hypothesis testing and regression analysis (Allard et al 2010; Green et al 2013; McCarthy et al 2017; Hill et al 2018; Divine et al 2019; Conder et al 2020; Goodrum et al 2020), we fitted all endpoints producing a statistical effect relative to the controls to a nonlinear dose–response model (Ritz et al 2019; drc package; R Development Core Team 2020) and reported the predicted EC10 and EC20 values for each variable that was effectively modeled (see Thursby et al 1997; Suter et al 2000, 2005; Field et al 2002). In the absence of monotonicity, it remains difficult to accurately model dose–response data and subsequently predict EC x estimates from the modeled exposure.…”

Considerations for toxicity experiments and risk assessments with PFAS mixtures

“…However, simplified binary‐mixture studies have both pros and cons (Altenberger et al, 2013; Cedergreen et al, 2007). Based on their literature review, Goodrum et al (2020) note that most of the PFAS mixture studies conducted to date are binary exposures. For binary‐mixture studies, concentration‐gradient exposures generally consist of one chemical (Chemical A) exposed at a specific, constant concentration, while the concentration of a second chemical (Chemical B) co‐varies across a gradient.…”

“…The study was designed to evaluate the sensitivity of PFOS when combined with PFHxS, based on analysis by East et al (2020) indicating that these are the two most commonly detected PFAS at AFFF sites at military installations. According to Goodrum et al (2020), there has been some indication of a similar MOA for PFOS and PFHxS, proliferator‐activated receptor alpha (PPARα), which Food Standards Australia New Zealand (FSANZ, 2017) used to conclude that the PFOS guidance levels could be used for the sum of PFOS and PFHxS. The Australian National Environmental Management Plan also applies biota guidelines to the sum of PFOS and PFHxS.…”

“…Perhaps the greatest challenge of trying to understand PFAS mixtures is that there are thousands of PFAS for which there is little or no information about individual toxicity or mode of action (MOA). In a thorough review and analysis related primarily to mammalian toxicity, Goodrum et al (2020) examined PFAS mixtures and concluded that short‐ and long‐chain perfluorinated sulfonates, perfluorinated carboxylates, and fluorotelomer alcohols can interact with nearly two dozen nuclear receptors, indicating multiple MOAs. PFAS are often found as complex mixtures that usually vary in concentration, proportionality, and overall chemical signature, and some of these chemicals have precursors that change the distribution and signature over time.…”

On Per‐ and Polyfluoroalkyl Substances: Suggested Resources and Considerations for Groundwater Professionals

“…In the end, some argue for regulation as a class (Kwiatkowski et al 2020), while others argue for consideration of some PFAS individually, with emphasis on resolution of key data gaps to support a more consistent, defensible, and comprehensive evaluation approach (Goodrum et al 2020). These considerations also reflect differences in opinion on priorities, such as additional regulation now versus waiting on further studies.…”