Development of an oral reference dose for the perfluorinated compound GenX

Abstract

Ammonium 2,3,3,3‐tetrafluoro‐2‐(heptafluoropropoxy)‐propanoate, also known as GenX, is a processing aid used in the manufacture of fluoropolymers. GenX is one of several chemistries developed as an alternative to long‐chain poly‐fluoroalkyl substances, which tend to have long clearance half‐lives and are environmentally persistent. Unlike poly‐fluoroalkyl substances, GenX has more rapid clearance, but has been detected in US and international water sources. There are currently no federal drinking water standards for GenX in the USA; therefore, we developed a non‐cancer oral reference dose (RfD) for GenX based on available repeated dose studies. The review of the available data indicate that GenX is unlikely to be genotoxic. A combination of traditional frequentist benchmark dose models and Bayesian benchmark dose models were used derive relevant points of departure from mammalian toxicity studies. In addition, deterministic and probabilistic RfD values were developed using available tools and regulatory guidance. The two approaches resulted in a narrow range of RfD values for liver lesions observed in a 2‐year bioassay in rats (0.01–0.02 mg/kg/day). The probabilistic approach resulted in the lower, i.e., more conservative RfD. The probabilistic RfD of 0.01 mg/kg/day results in a maximum contaminant level goal of 70 ppb. It is anticipated that these values, along with the hazard identification and dose‐response modeling described herein, should be informative for risk assessors and regulators interested in setting health‐protective drinking water guideline values for GenX.

Assessment of the Mode of Action Underlying the Effects of GenX in Mouse Liver and Implications for Assessing Human Health Risks

“…6 The increase in hepatic cell proliferation observed in that study is consistent with evidence for GenX activation of PPARa signaling, as evidenced by increased peroxisomal enzyme activity, liver hypertrophy, and transcriptomic signaling. 6,11 Relatedly, other PFAS have been shown to activate PPARa. 12 To further explore potential mechanisms of toxicity and relevance of such underlying the liver lesions observed in mice, herein we report transcriptomic and immunohistochemical analyses in male and female mice from a 90-day Organisation for Economic Co-operation and Development (OECD) 408 guideline oral toxicity study.…”

“…These findings align with a similar reevaluation of male mice exposed to GenX for approximately 90 days. 6,8 Therein, it was argued that apoptosis was part of a PPARa MOA and not indicative of liver toxicity per se. According to the Hall criteria 40 for assessing liver toxicity, sequelae related to PPARa have limited human relevance.…”

“…12 To further explore potential mechanisms of toxicity and relevance of such underlying the liver lesions observed in mice, herein we report transcriptomic and immunohistochemical analyses in male and female mice from a 90-day Organisation for Economic Co-operation and Development (OECD) 408 guideline oral toxicity study. 8 In addition, similar to the reevaluation of livers from male and female mice from a reproductive toxicity study 9 that was conducted in our earlier study, 6 we reevaluated livers from the 90-day OECD 408 guideline oral toxicity study 8 using current histopathological criteria to allow for phenotypic anchoring to findings from transcriptomic analyses of liver tissues from this same study. Transcriptomic data can provide additional and/or supporting information regarding mechanisms of disease associated with specific exposure scenarios.…”

Fisheries Volume 45 Number 3 March 2020

“…While many studies exist showing the dangers of PFOS and PFOA, currently there has been limited research on the health outcomes caused by other PFAS compounds. However, some mammalian studies on PFNA, GenX, and PFHxS have indicated similar negative health effects (Rockwell et al 2013 ;Ramhøj et al 2018 ;Thompson et al 2019 ). Thus, more research is needed on exposure levels in humans, the scale of exposure in the United States, and how exactly different PFAS affect human organs (CDC 2019 ).…”

Per‐ and Polyfluoroalkyl Substances (PFAS): Anglers May Be Exposed to Harmful Chemicals in Their Catch

“…; Thompson et al. ). Thus, more research is needed on exposure levels in humans, the scale of exposure in the United States, and how exactly different PFAS affect human organs (CDC ).…”