Hormesis in biomedical and toxicological models: A generalizable phenomenon induced by per- and polyfluoroalkyl agents.

This paper provides the first critical review of the capacity of per- and polyfluoroalkyl substances (PFAS) agents to induce hormetic effects in mammalian toxicological and biomedical cellular and animal models. PFAS induced hormetic responses were reported in primary cells and cell lines from multiple organ systems (e.g., liver, lung, colon, breast, prostate, immune, brain) from animal models and humans. While more limited, PFAS induced hormetic dose responses in experimental animals for short-term and chronic studies. Hormetic effects were induced by long and shorter carbon length alternative PFAS agents, with hormesis dose-response features being similar. The PFAS-induced hormetic dose responses are consistent with quantitative features of hormetic responses of other chemical and physical agents, including PFAS effects on plants and ecological animal models. These findings suggest ways to optimize study designs to assess the nature of the dose response in the low-dose zone, including dose selection, number of doses and dose spacing strategies. The findings present challenges for interpretations concerning what is an adverse effect as some effects presented here may be desirable while others potentially harmful. The introduction of the hormesis concept into the hazard assessment process creates novel risk assessment considerations making the process more scientifically robust, creating a range of new regulatory options. These findings and those shown with plants and ecological animal models indicate that the hormetic concept should become a fundamental feature of ecological and human risk assessment principles and practices by regulatory agencies.