Dose Addition Models Accurately Predict the Subacute Effects of a Mixture of Perfluorooctane Sulfonate and Perfluorooctanoic Acid on Japanese Quail (Coturnix japonica) Chick Mortality

Biomonitoring data have consistently demonstrated that fish, wildlife, and humans are exposed to multiple per- and polyfluoroalkyl substances (PFAS) in drinking water and foods. Despite ubiquitous exposure to mixtures of PFAS, there is a lack of in vivo PFAS mixture research that addresses whether these chemicals act in a cumulative, dose-additive (DA) manner or whether they behave independently. For this reason, there is a critical need for mixtures studies designed to evaluate the cumulative toxicity and potential chemical interactions to support the assessment of human and ecological risks and also to define appropriate regulatory actions. Our primary objective was to evaluate the previously published Japanese quail chick mortality concentration-response data for perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), and the mixture of PFOS + PFOA and to use statistical modeling to determine whether the effects of the mixtures were accurately predicted by either DA or response addition modeling. In addition, we wanted to compare different DA models to determine whether one model produced more accurate predictions than the others. Our results support the hypothesis of cumulative effects on shared endpoints from PFOA and PFOS co-exposure and DA approaches for predictive estimates of cumulative effects. Given the limited number of in vivo studies that have been executed with enough individual PFAS and PFAS mixture concentration-response data to test the hypothesis of DA for PFAS mixtures, this re-analysis of the data is an important contribution to our understanding of how PFAS mixtures act. The analysis will provide support for regulatory agencies as they begin to implement PFAS cumulative hazard assessments in higher vertebrates. Environ Toxicol Chem 2023;00:1-8. (c) 2023 SETAC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.