Borghoff SJ, Fitch S, Huggett, Wikoff D. A hypothesis-driven weight-of-evidence analysis to evaluate potential endocrine disrupting properties of perfluorohexanoic acid (PFHxA). 2019. Poster at Society of Toxicology Annual Meeting, Baltimore, MD, March 2019.
Perfluorohexanoic acid (PFHxA) is a potential impurity and environmental degradation product of C6-based fluorotelomer products. Based on the concern that perfluoroalkyl acids have endocrine activity, a hypothesis driven weight-of-evidence (WoE) analysis of PFHxA was conducted to evaluate endocrine disrupting properties as defined by World Health Organization (WHO). Following a comprehensive literature search within PubMed and Embase databases, followed by hand-searching and evaluation of secondary sources, a total of 21 in vitro and in vivo studies across species were identified for review. High Throughput Screening (HTS) assay data within the ToxCast/Tox21 database were also included in this assessment. Studies identified consisted of Level 1 to 4 methods within the OECD Conceptual Framework for assessing endocrine disruptors (ED) were reviewed for reliability and endocrine endpoints extracted that represented lines of evidence for positive or negative activity across the estrogen (E), androgen (A), thyroid (T) and steroidogenesis (S) pathways. The endpoints extracted were ranked based on their specificity and sensitivity for identifying PFHxA activity across 8 endocrine hypotheses (e.g., E, A, or T agonist or antagonist or S inducer or inhibitor). Overall, PFHxA showed no endocrine effects in Japanese medaka, juvenile rainbow trout, chickens or reproductive parameters in northern bobwhite quail. In rodent studies, there was no significant activity associated with PFHxA exposure in endocrine endpoints identified in repeat-dose toxicity studies, a lifetime cancer study, or guideline and non-guideline reproductive and developmental studies. In vitro, there was weak or negative activity for T transport protein or activation of E, A or T receptors. PFHxA was also negative for disrupting steroidogenesis in vivo and in vitro. Based on this WoE analysis across these endocrine pathways (e.g., E, A, T, and S), PFHxA exposure was found not to cause adverse effects associated with alterations in endocrine activity in any of the experimental models evaluated, as such would not be characterized as an ED according to the WHO definition.