Dose Addition Models Accurately Predict the Subacute Effects of a Mixture of Perfluorooctane Sulfonate (PFOS) and Perfluorooctanoic Acid (PFOA) 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 if these chemicals act in a cumulative, dose-additive manner or if 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 as well as define appropriate regulatory actions. The primary objective of this communication was to evaluate the previously published Japanese quail chick mortality concentration-response data for PFOS and PFOA and the mixture of PFOS+PFOA and use statistical modeling to determine if the effects of the mixtures were accurately predicted by either dose- (DA) or response addition (RA) modeling. In addition, we wanted to compare different DA models to determine if one model produced more accurate predictions than the others. Results support the hypothesis of cumulative effects on shared endpoints from PFOA and PFOS co-exposure and dose additive 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 reanalysis 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.