Citation:

Conley, J., C. Lambright, N. Evans, J. Bangma, J. Ford, D. Jenkins-Hill, AND L. Gray. Maternal, fetal, and neonatal toxicity of the long-chain, multi-ether PFAS PFO5DoA in the Sprague-Dawley rat. Society of Toxicology 2024 Annual Meeting, Salt Lake City, UT, March 10 - 14, 2024.

Impact/Purpose:

Recent human and ecological biomonitoring studies in the US and China have identified novel perfluoroalkyl carboxylic acids with ether linkages between each fluorinated carbon in a homologous series of increasing chain length.  These include the long-chain compound perfluoro-3,5,7,9,11-pentaoxadodecanoic acid (PFO5DoA).  OECD PFAS terminology counts the oxygen ether linkage as part of PFAS chain length, making PFO5DoA a C12 PFAS.  However, because this compound does not contain adjacent fluorinated carbons, it did not meet the USEPA/OPPT definition of a PFAS in the USEPA National PFAS Testing Strategy, despite structural similarity to the legacy straight-chain perfluoroalkyl carboxylic acids.  PFO5DoA was detected in human serum at high frequency (>85%) in a human biomonitoring study in North Carolina, USA; however, only limited toxicity data are available to inform risk assessment and there are no published studies of effects on mammalian development.  The studies described here are some of the only developmental PFAS exposures to emerging PFAS with multiple ether bonds, and these are the only studies to our knowledge of PFO5DoA developmental toxicity. These results are critical for understanding the potential developmental toxicity of this emerging contaminant.  The data will be highly useful for state and federal risk assessment and regulatory scientists evaluating PFAS with known human exposure.

Description:

Abstract reduced to fit RAPID character limits - full abstract attached Background and Purpose Recent human and ecological biomonitoring studies in the US and China have identified novel perfluoroalkyl carboxylic acids with ether linkages between each fluorinated carbon in a homologous series of increasing chain length.  These include the long-chain compound perfluoro-3,5,7,9,11-pentaoxadodecanoic acid (PFO5DoA).  OECD PFAS terminology counts the oxygen ether linkage as part of PFAS chain length, making PFO5DoA a C12 PFAS.  However, because this compound does not contain adjacent fluorinated carbons, it did not meet the USEPA/OPPT definition of a PFAS in the USEPA National PFAS Testing Strategy, despite structural similarity to the legacy straight-chain perfluoroalkyl carboxylic acids.  PFO5DoA was detected in human serum at high frequency (>85%) in a human biomonitoring study in North Carolina, USA; however, only limited toxicity data are available to inform risk assessment and there are no published studies of effects on mammalian development.  Results PFO5DoA exposure was overtly toxic to rat dams in the top dose (62.5 mg/kg) and dosing was terminated after 3 days (GD18-20) due to significant body weight loss.  At 30 mg/kg dam bodyweight and weight gain were significantly reduced, along with reduced mean fetal bodyweight.  At ≤10 mg/kg there were no effects on maternal or fetal bodyweight.  PFO5DoA significantly reduced GD22 maternal serum total T3 at ≥3 mg/kg and total T4 at ≥10 mg/kg, while fetal serum total T3 and T4 were both significantly reduced at ≥1 mg/kg.  GD22 fetal liver glycogen concentration was significantly reduced at ≥0.3 mg/kg.  PFO5DoA significantly increased maternal liver weight at ≥3 mg/kg.  GD22 fetal livers displayed significantly altered glucose metabolism genes at ≥0.3 mg/kg, including >170-fold upregulation of Pck1 and >20-fold downregulation of Ugp2. GD22 dam clinical chemistry displayed multiple significant dose-related changes at ≥3 mg/kg including elevated ALT and BUN:creatinine and reduced cholesterol, triglycerides, albumin, globulin, and total protein.  Fetal serum displayed significantly elevated BUN at ≥0.3 mg/kg and elevated total bile acids and glucose at ≥3 mg/kg. In the GD8-PND2 exposure study PFO5DoA from 0.1-10 mg/kg produced no overt maternal toxicity with bodyweights and weight gains similar to control at all doses.  Pup birthweight and bodyweight on PND2 were significantly reduced at ≥3 mg/kg.  Maternal and pup liver weights were significantly increased at ≥1 mg/kg.  Pup survival was significantly reduced at ≥3 mg/kg.   Conclusions PFO5DoA produced toxic key events and adverse outcomes in maternal, fetal, and neonatal rats consistent with other straight chain and ether-linked PFAS carboxylates we have investigated in similar study designs, including PFOA, HFPO-DA (GenX), and PFMOAA.  The most sensitive of these effects include reduced serum thyroid hormone concentration, increased liver weights, and multiple alterations to glucose, lipid, and protein homeostasis.  The most notable difference was the greater oral potency of PFO5DoA compared to the other carboxylate PFAS we have studied.  The rank order of oral dose potency for effects on reduced pup survival were PFO5DoA>HFPO-DA>PFOA>PFMOAA.  Despite the presence of multiple ether linkages disrupting the carbon chain, PFO5DoA behaved nearly identical to PFOA and other carboxylate PFAS.  This is particularly important for estimating human health risk from exposure to multiple PFAS, which have been shown to produce dose additive joint toxicity. 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.    

Record Details: