Developmental toxicity of emerging perfluoroalkyl ether carboxylic acids of varying chain length: PFMOAA, PFO4DA and PFO5DoA
Citation:
Conley, J., C. Lambright, N. Evans, E. MedlockKakaley, D. Hill, M. Strynar, AND E. Gray. Developmental toxicity of emerging perfluoroalkyl ether carboxylic acids of varying chain length: PFMOAA, PFO4DA and PFO5DoA. Society for Birth Defects Research and Prevention, Raleigh, NC, June 25 - 29, 2022.
Impact/Purpose:
Per- and polyfluoroalkyl ether acids (e.g., GenX) are currently used as replacement compounds for legacy, straight chain PFAS (e.g., PFOA) and byproducts have recently been detected in drinking water and human serum. Perfluoro-2-methoxyacetic acid (PFMOAA) is a short chain ether carboxylate (3 carbons+1 oxygen) and was reported in microgram per liter concentrations in eastern North Carolina drinking water. Conversely, perfluoro-3,5,7,9-tetraoxadecanoic acid (PFO4DA) and perfluoro-3,5,7,9,11-pentaoxadodecanoic acid (PFO5DoA) are long chain ether carboxylates (C6+O4 and C7+O5, respectively) and were recently detected in 99% and 88% of human serum samples in an eastern NC cohort. There are little or no toxicity data available to assess human risk from exposure to these compounds. Further, these three compounds do not currently meet the EPA OPPT definition of PFAS, even though they contain fluorinated carbons and have been detected in proximity to known PFAS manufacturing facilities. The data reported here are the only developmental toxicity data for all three test compounds (PFMOAA, PFO5DoA, PFO4DA) and the maternal and offspring effects are consistent with those reported for legacy PFAS such as PFOA and PFNA. The data from this project will be useful to the USEPA Office of Water and other state (particularly NC) and international health-based regulatory agencies in their continued evaluations of PFAS toxicity and human health risk from exposure. The range of key event and adverse outcome data will be highly instructive for characterizing adverse outcome pathways (AOPs) relevant to PFAS compounds.
Description:
Multiple per- and polyfluoroalkyl ether acids have recently been detected in drinking water and/or human serum, but there is a paucity of data on potential toxicity despite known exposure. Perfluoro-2-methoxyacetic acid (PFMOAA) is a short chain ether carboxylate (3 carbons+1 oxygen) and was reported in µg/L concentrations in eastern North Carolina drinking water. Conversely, perfluoro-3,5,7,9-tetraoxadecanoic acid (PFO4DA) and perfluoro-3,5,7,9,11-pentaoxadodecanoic acid (PFO5DoA) are long chain ether carboxylates (C6+O4 and C7+O5, respectively) and were recently detected in 99% and 88% of human serum samples in an eastern NC cohort. We conducted a postnatal developmental toxicity experiment with pregnant Sprague-Dawley rats dosed with PFMOAA from gestation day (GD) 8-postnatal day (PND) 2, and preliminary experiments with PFO4DA and PFO5DoA dosed from GD18-22. PFMOAA had no effect on maternal gestational weight gain up to 450 mg/kg, but produced multiple significant effects including decreased pup birthweight (≥30 mg/kg), increased pup liver weight (≥10 mg/kg), decreased pup liver glycogen (≥10 mg/kg), increased maternal liver weight (≥30 mg/kg), and increased pup mortality (≥100 mg/kg). Further, PFMOAA significantly altered many clinical chemistry parameters in newborn and PND2 pups including reduced glucose and elevated cholesterol, AST, GLDH, and BUN, and in PND2 maternal serum including elevated ALT, AST, triglycerides, BUN, and GLDH and reduced total protein and globulin. In contrast, PFO5DoA was considerably more orally potent with short term exposure producing increased maternal liver (≥3 mg/kg) and kidney (≥30 mg/kg) weights, reduced maternal weight gain and fetal body weight (≥30 mg/kg) and was overtly maternally toxic at 62.5 mg/kg. PFO4DA appears less potent than PFO5DoA thus far at doses up to 30 mg/kg. Similar to our prior studies with hexafluoropropylene oxide dimer acid (HFPO-DA or GenX), PFAS replacement chemistries utilizing ether bonds to disrupt the alkyl carbon chain length have maternal and offspring toxic effects similar to legacy PFAS (e.g., PFOA, PFNA) with oral potencies related to total carbon+oxygen chain length (i.e., longer chain more orally potent than shorter chain). The views expressed in this abstract are those of the author(s) and do not necessarily represent the views or policies of the U.S. Environmental Protection Agency.