Citation:

Conley, J., C. Lambright, N. Evans, E. Medlock Kakaley, V. Wilson, AND L. Gray. Developmental toxicity of perfluoroalkyl ether acids following oral gestational exposure: Comparison of GenX, Nafion byproduct 2, and Perfluoro-2-methoxyacetic acid. Society of Environmental Toxicology and Chemistry, Toronto, Ontario, CANADA, November 03 - 07, 2019.

Impact/Purpose:

Per- and poly-fluoroalkyl substance (PFAS) research is an area of critical need due to the extreme environmental persistence, widespread occurrence, long biological half-lives, and nearly ubiquitous human and environmental exposure to this chemical class. Perfluoroalkyl ether acids (PFEAs) are a sub-class of PFAS and include the compounds hexafluoropropylene oxide dimer acid (GenX), nafion byproduct 2 (NBP2), and perfluoro-2-methoxyacetic acid (PFMOAA). PFEAs are currently used in the production of fluoropolymers following the phase-out of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS), presumably due to more favorable fate and toxicity profiles. However, monitoring studies have detected GenX, NBP2, PFMOAA, and others in a wide range of matrices including surface water, drinking water, and/or human serum. Little to no published research is available regarding the potential toxicity of these compounds compared to the legacy PFAS. The data from this project will be useful to state, federal, and other regulatory agencies in the development of hazard assessments for PFMOAA and NBP2, among other PFAS. This study characterizes the toxic effects of oral NBP2 and PFMOAA exposure during pregnancy to both the mother and the offspring (fetal and newborn) using a laboratory rat model. We found multiple, severe effects for NBP2 that were consistent with other PFAS, such as PFOS. Importantly, it appears that NBP2 is only slightly less potent than PFOS based on the orally administered dose. Continuation of this work will focus on characterizing the internal serum and liver doses for NBP2 and PFMOAA because toxicokinetics appears to be a major factor in the oral toxicity. The data presented here will be highly valuable for regulators to make scientifically based decisions on the potential adverse effects of NBP2 on human health and informing future toxicity studies of additional PFAS.

Description:

Perfluoroalkyl ether acids (PFEAs) are a sub-class of per- and polyfluoroalkyl substances (PFAS) and include the compounds hexafluoropropylene oxide dimer acid (GenX), Nafion byproduct 2 (NBP2), and perfluoro-2-methoxyacetic acid (PFMOAA). PFEAs are currently used in the production of fluoropolymers following the phase-out of the legacy PFAS, perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS), presumably due to more favorable fate and toxicity profiles. However, recent monitoring studies have detected GenX, NBP2, PFMOAA, and other PFEAs in a wide range of matrices including surface water, drinking water, and/or human serum. Little to no published research is available regarding the potential toxicity of these compounds compared to the legacy PFAS. We previously investigated the fetal, neonatal, and maternal toxicity of GenX in the Sprague-Dawley rat following shorter term (gestation day (GD) 14-18 and GD 16-20) and longer term (GD8 – postnatal day (PND) 2) oral dosing and found that it produced similar effects, but was less potent than PFOA. Here, we assessed the in utero toxicity of PFMOAA (0.01-200 mg/kg/d, GD14-18 and GD9-13) and NBP2 (0.1-30 mg/kg/d from GD14-18 and 0.3-30 mg/kg/d from GD8-PND2) for comparison to GenX and the legacy PFAS. PFMOAA produced no adverse effects on maternal weight gain, maternal liver weight, fetal viability, or fetal liver weight at any dose in either dosing interval. In contrast, NBP2 reduced maternal weight gain following GD14-18 dosing. Importantly, following longer term dosing (GD8-PND2) NBP2 exposure reduced maternal weight gain, produced neonatal mortality (≥10 mg/kg) shortly after birth (<24 hours), and reduced pup weight. Neonatal mortality and low pup weight has also been reported in the rat for PFOS and GenX following gestational exposure. Comparison of oral ED50s indicates that NBP2 is only a factor of ~4 less potent than PFOS (ED50s of 3 mg/kg versus 12 mg/kg for PFOS and NBP2, respectively); whereas, GenX is a factor of ~40 less potent than PFOS. Data collected to date indicate that the spectrum of adverse developmental effects is similar between some of the PFEAs and the legacy PFAS and that the oral potency is also relatively similar for some compounds. Ongoing research in our group is investigating the putative mechanism(s) of action and key events that lead to adverse maternal and neonatal outcomes, comparison of internal dosimetry for extrapolation to human exposures, and mixture-based effects of exposure to multiple PFAS. Abstract does not necessarily reflect USEPA policy.

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