Citation:

Conley, J., C. Lambright, N. Evans, E. Medlock Kakaley, V. Wilson, AND L. Gray. In utero exposure to hexafluoropropylene oxide-dimer acid (GenX) produces low birth weight and neonatal mortality. Society of Environmental Toxicology and Chemistry Environmental Risk Assessment of PFAS, Durham, NC, August 12 - 15, 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 exposure to this chemical class. Few PFAS have undergone thorough toxicological testing, including GenX, which is a current, high profile contaminant of concern due to recent reports of elevated concentrations being detected in surface water and drinking water in the US and abroad. There is a critical need to better understand the toxicology of this chemical class and specifically to generate relevant, in vivo toxicity data for GenX in order to assist risk assessors. The data from this project will be useful to state, federal, and other regulatory agencies in the development of hazard assessments on GenX.

Description:

Hexafluoropropylene oxide dimer acid (HFPO-DA, aka GenX) is a member of the per- and polyfluoroalkyl substances (PFAS) chemical class. More specifically, HFPO-DA is a perfluoroalkyl ether carboxylic acid (PFECA) which, along with perfluoroalkyl ether sulfonic acids (PFESA), have recently been used as industrial replacements for straight-chain PFAS, presumably due to favorable toxicity profiles. Previously, we dosed Sprague-Dawley rat dams daily via oral gavage with 1-500 mg HFPO-DA/kg/d from gestation day (GD) 14-18 and reported significant dose-responsive increases in maternal liver weight (≥62.5 mg/kg), reduced maternal serum thyroid hormone and lipid profiles (≥30 mg/kg), and highly upregulated expression of genes related to PPAR signaling pathways in maternal and fetal livers (≥1 mg/kg). Here, we dosed dams with 1-125 mg/kg/d (n=4 litters per dose) from GD16-20 and with 10-250 mg/kg/d (n=5 litters per dose) from GD8 – postnatal day (PND) 3. Results analyzed thus far from GD16-20 dosing have not been distinct from GD14-18 dosing. Dosing from GD8-PND3 resulted in a significant dose-responsive increase in neonatal mortality (≥62.5 mg/kg), which occurred shortly after birth (<24 hrs). There was a significant decrease in pup body weight at birth, PND1, and PND2 (≥30 mg/kg) and increased relative liver weight at necropsy (PND2) in all dose groups (≥10 mg/kg). The only histopathological finding from PND0 pup livers was a dose-responsive decrease in glycogen stores. Dam weight gain during gestation was significantly reduced at ≥125 mg/kg and liver weight (measured on PND2) was increased at all doses (≥10 mg/kg). Dam serum HFPO-DA concentrations were ~3-fold greater than fetal serum concentrations at a given maternal dose; however, liver concentrations were identical between mother and fetus. Further, fetal livers contained ~10-fold greater HFPO-DA concentrations than PND2 pup livers, indicating a lack of appreciable lactational transfer and rapid clearance. Overall, HFPO-DA exposure produced multiple adverse effects similar to PFOS and PFOA; however, at higher oral doses. The specific mechanism by which these effects occur is still unknown. Studies have begun with other PFAS with known human exposure, including perfluoromethoxy acetic acide (PFMOAA) and nafion byproduct 2. To date PFMOAA appears less toxic than HFPO-DA. The views presented here do not necessarily reflect the views or policy of the USEPA.

Record Details: