Mechanistic Evidence for Evaluation of Perfluorodecanoic Acid (PFDA)-induced Hepatotoxicity: A Case Study
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Background and Purpose: Traditionally, human health assessment has relied on epidemiological studies and toxicity studies in experimental animals to identify phenotypic health outcomes associated with chemical exposures. Increasingly, mechanistic evidence, including data derived from New Approach Methods (NAMs), has been used to address key scientific questions and uncertainties in support of chemical hazard characterization. Frameworks for evaluating mode-of-action and constructs such as adverse outcome pathways (AOP) are available to organize and integrate different types of mechanistic evidence. Methods: An AOP approach was employed to evaluate potential mechanisms of hepatotoxicity associated with perfluorodecanoic acid (PFDA), a long-chain per¿ and polyfluoroalkyl substance (PFAS). Peer-reviewed studies and in vitro high-throughput screening assay data, accessed through the U.S. EPA’s CompTox Chemicals Dashboard, were compiled and synthesized to examine plausible mechanisms of PFDA-induced non-cancer hepatic effects, including the potential role of peroxisome proliferator-activated receptor alpha (PPARα) and its implications to human health. Results: Mechanistic data from in vivo and in vitro rodent models indicate that PFDA can activate several xenobiotic-sensing nuclear receptors and other cell signaling pathways (including PPARα). PFDA exposure was also associated with alterations in the hepatic expression and activity of xenobiotic metabolism enzymes, reactive oxygen species production, disruption of mitochondrial function, induction of inflammatory responses, cellular damage/stress, and abnormal liver metabolic function in animals. These molecular and cellular mechanisms are commonly associated with chemical-induced liver disorders in mammals such as steatohepatitis and fibrosis. Although limited, the evidence in human models suggests some concordance with the evidence from experimental animal models. Conclusion: The available data indicate a role for both PPARα-dependent and -independent mechanisms in the hepatotoxicity of PFDA in animals. And importantly, some target gene and cell-based responses were conserved across species. This case study highlights the utility of mechanistic evidence, including data from NAMs, to inform biological plausibility and human relevance in support of human health assessment. The views expressed are those of the authors and do not necessarily reflect the views and policies of the US EPA.