PFAS mixtures – Evaluation of dose additivity from combined exposure to multiple PFAS during pregnancy in a laboratory rat model - EPA PFAS Science Call

The six PFAS we have studied (PFOA, GenX, PFMOAA, PFOS, NBP2, PFHxS) produced multiple common effects across all compounds, however the compounds were not toxicologically identical.  Effects common across all compounds included reduced pup and maternal bodyweights, reduced pup survival, increased maternal and pup relative liver weights, reduced serum thyroid hormones, and increased liver expression of PPAR signaling pathway genes.  With limited exception across studies, these endpoints were modelled with equivalent or better predictions using dose addition compared to response addition equations.  Importantly, the relative potency factor (RPF) approach was accurate for predicting mixture effects, but the RPFs for the six PFAS we have studied vary by >20-fold across the range of endpoints modeled and it was not possible to predict all mixture effects with a single set of RPFs.  Combined exposure to mixtures of PFAS produced cumulative effects on multiple endpoints and these effects were generally well predicted by dose addition-based approaches.  The studies described here are some of the only mammalian in vivo mixture toxicity studies of PFAS that incorporate mixture modeling and analyses to characterize the type of mixture effects and the accuracy of predictions using well-established approaches.  The results directly support the proposed approaches by the Office of Water, as well as state and international health-based agencies that have adopted mixture-based risk assessment and regulatory approaches for exposure to multiple PFAS.  

Impact/Purpose

This is a slide deck for an invited presentation in the US EPA PFAS Science Call webinar series. This represents a synthesis of multiple individual PFAS and PFAS mixtures studies, each of which either have or will be published as individual manuscripts.  The studies described here are some of the only mammalian in vivo mixture toxicity studies of PFAS that incorporate mixture modeling and analyses to characterize the type of mixture effects and the accuracy of predictions using well-established approaches.  The results directly support the proposed approaches by the Office of Water, as well as state and international health-based agencies that have adopted mixture-based risk assessment and regulatory approaches for exposure to multiple PFAS. Nearly all effects that are shared across PFAS could be accurately predicted/estimated using mixture approaches based on dose addition.  However, the relative potencies vary across the six PFAS for the range of endpoints we have evaluated and thus a single set of RPFs could not accurately describe all effects.  Aside from the mixture evaluations, novel toxicological findings have been identified in these studies, including reduced pup liver glycogen at birth and dramatically increased neonatal serum bile acids.  

Citation

Conley, J. PFAS mixtures – Evaluation of dose additivity from combined exposure to multiple PFAS during pregnancy in a laboratory rat model - EPA PFAS Science Call. EPA April PFAS Science Call for States & Tribes, Virtual, NC, April 29, 2024.