Mixing PFAS – Mechanistic observations and dose additive effects in developmental toxicity studies of PFAS

This is a slide deck for an invited research seminar at the University of Rochester Medical Center. 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 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.     

Impact/Purpose

Due to the pervasive detection of multiple PFAS in human and environmental matrices, many health-based agencies are employing or pursuing cumulative assessment and regulatory approaches.  However, the literature is lacking mammalian in vivo studies that test additivity by comparing observed mixture responses to mixture model predictions.  We have conducted three different PFAS mixture studies investigating maternal and neonatal effects from maternal exposure during pregnancy in a rat model.  Experimental data were compared to predictions using established mixtures toxicology approaches and effects were well predicted using dose addition methods.  One of the mixture studies discussed here (PFOA+PFOS mixture) was the result of a request from the Office of Water for technical support of cumulative effects of exposure to multiple PFAS. 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.    

Citation

Conley, J. Mixing PFAS – Mechanistic observations and dose additive effects in developmental toxicity studies of PFAS. University of Rochester Medical Center Environmental Health Sciences Center Seminar Series, Rochester, NY, May 11, 2023.