Despite international regulatory efforts and voluntary phase-out of long-chain perfluorinated alkyl acids—so-called “legacy PFAS”—the true scale of the environmental PFAS problem is only beginning to emerge. The most recent estimate indicates that per- and polyfluorinated alkyl substances (PFAS), as a class, may include nearly 5000 different structures. Many of these “emerging” PFAS, about which we have very little property and effects data, are now being found as complex mixtures in various environmental matrices, foods, and drinking water. Because of the extreme persistence of perfluorinated PFAS (the terminal transformation products of partially fluorinated PFAS), understanding the impacts of chronic exposure of wildlife and humans to these complex mixtures is a priority for scientists, regulators, and the public. Because of the substantial expenses in time, resources, and animals associated with a chemical-by-chemical testing approach, reliable structure-activity relationships or other predictive modeling approaches would be of great benefit to address the wide variety of PFAS structures currently in the environment. Model-based approaches can facilitate high-throughput screening and prioritization, and provide valuable insight into the behavior of PFAS mixtures. Here, we discuss integrative strategies our group has developed to combine molecular- and organism-scale mechanistic models of PFAS fate and behavior within biological systems. Used together, our models can provide valuable insight into relative PFAS bioaccumulation potential, interactions with key tissue-specific receptors, and whole-body tissue distribution. Moreover, they can be used to answer key questions regarding the suitability of different animal models for understanding implications of human exposure to PFAS. From an ecotoxicological perspective, they may provide insight into the relative susceptibility of different species and populations to different PFAS. Our approach uses molecular dynamics as a screening tool, supported by targeted validation experiments, followed by toxicokinetic modeling to assess the implications of differences across species and substances. Finally, we discuss opportunities for using mechanistic models to aid in PFAS hazard and risk assessment, facilitating in silico- in vitro- in vivo extrapolation, and integrating structure-specific information into sound policy.

Beyond legacy PFAS: Models to inform assessment across structural classes and species

2019 Spring National Meeting

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