Using Dose-Additive Models To Predict Exposure and Effects of a Military Site Risk-Relevant PFAS Mixture in Mice

Per- and polyfluoroalkyl substances (PFAS) are widespread environmental contaminants that are largely observed as mixtures. PFAS-focused ecological risk assessments largely assess individual PFAS, but understanding PFAS mixture exposure and potential ecological and biological effects is critical to characterizing real-world risk. To address this, we exposed CD-1 mice to individual PFAS and mixtures of PFAS that are relevant to surveyed environmental media and aqueous film-forming foams (AFFF) used on Department of Defense (DoD) sites. Our study was performed in two parts: (1) assess the whole-body concentration of PFAS and (2) assess tissue compartment concentrations of PFAS (i.e., serum, liver, kidney, and brain). Organ weights and clinical chemistry were collected in the tissue compartment study to measure potential toxicological effects of individual and mixtures of PFAS. Mixed-effect models were used to evaluate how well relationships between dose and body compartments predicted exposure with and without the influence of mixtures. A PFOS-relative weighting factor was evaluated for the potential to predict select effects from dose and tissue concentrations. We apply the laboratory-based finding to a desktop ecological risk assessment scenario and find that while changes in PFAS dietary concentrations may alter exposure and effect estimates, differentiating reference vs impacted sites is difficult. Our results indicate that dose addition methods are successful predictors of PFAS exposure and liver effects and, importantly, provide efficient predictive screening tools for ecological risk assessors evaluating sites' PFAS risks.