Citation:

Conley, J., C. Lambright, N. Evans, E. MedlockKakaley, D. Hill, A. Dixon, E. Hines, AND E. Gray. Dose additive developmental toxicity of a mixture of three PFAS (HFPO-DA, NBP2, PFOS) in the Sprague-Dawley rat. 2021 Society of Toxicology Annual Meeting-Virtual, NA, Virtual, March 12 - 26, 2021.

Impact/Purpose:

Per- and poly-fluoroalkyl substance (PFAS) research is an area of critical need due to issues associated with environmental persistence, widespread occurrence, biological half-life, and nearly ubiquitous human and environmental exposure to this chemical class. Numerous studies from EPA have demonstrated the developmental toxicity of legacy (PFOS, PFOA) and emerging (hexafluoropropylene oxide-dimer acid (HFPO-DA or GenX), Nafion byproduct 2 (NBP2)) PFAS in laboratory rodent experiments. However, despite widespread evidence of PFAS co-exposure, very little mixtures-based toxicity research has been conducted to test theories of chemical additivity. To our knowledge this is the first in vivo mixture-based study of the developmental toxicity of PFAS. We observed cumulative effects of PFAS co-exposure on maternal, fetal, and postnatal health in a Sprague-Dawley rat model. These types of studies are needed to inform and support cumulative risk assessment approaches at state and federal agencies. The data from this project will be useful to state, federal, and other regulatory agencies in the development of hazard assessments and regulatory action for the PFAS in the present mixture, among other PFAS. The EPA guidance for PFOA and PFOS is based on cumulative effects and multiple states and other nations are moving toward a mixture-based co-exposure risk assessment and regulatory model. The data from this study supports these efforts.

Description:

Human biomonitoring data from multiple countries have indicated that virtually all humans carry residues of multiple per- and polyfluorinated alkyl substances (PFAS). Despite the evidence of co-exposure there has been relatively little mixture-based PFAS toxicity research. Studies from EPA have reported that hexafluoropropylene oxide-dimer acid (HFPO-DA, or GenX), Nafion byproduct 2 (NBP2), and perfluorooctane sulfonate (PFOS) produce neonatal mortality, among other developmental effects, in rats when orally administered during pregnancy. Here we exposed timed-pregnant Sprague-Dawley rats from gestation day (GD)14-18 (n=4-6 per dose) to investigate maternal and fetal effects and from GD8-postnatal day (PND2) (n=5 per dose) to investigate maternal and postnatal effects. Dams were exposed to fixed-ratio dilutions of an equipotent mixture of HFPO-DA, NBP2, and PFOS where the top dose (100%) contained each chemical at their respective ED50 for neonatal mortality (PFOS, 3mg/kg; NBP2, 10mg/kg; HFPO-DA, 110mg/kg), followed by dilutions of 33, 10, 3, 1 and 0%. Dams exposed GD14-18 displayed increased relative liver weight at ≥33% dose and fetal livers displayed multiple upregulated PPAR target genes at ≥1% dose. GD8-PND2 exposed dams in the 100% dose had reduced weight gain during pregnancy and complete litter loss of all liveborn pups by PND2. Neonatal survival was also reduced on PND2 in the 3 and 33% dose groups and average pup birthweight was reduced at ≥33% dose. Newborn pup serum from the 100% dose had significantly elevated total protein and reduced cholesterol and triglycerides. On PND2, pup body weight was significantly lower and relative liver weight was significantly greater than control in all dose groups. Despite dosing ending at PND2, maternal rats in the 33% dose group had elevated relative liver weight at necropsy on PND21 (100% dose females had no remaining live pups and were necropsied on PND2). Mixture model analyses indicated that dose addition accurately predicted the mixture ED50 for neonatal mortality; whereas, response addition considerably underpredicted toxicity by 3.8-fold. To our knowledge this is the first in vivo mixture study on the developmental toxicity of co-exposure to multiple PFAS. Results of the study support the additive effects of PFAS co-exposure and a cumulative mixtures-based risk assessment approach. Abstract does not necessarily reflect the views or policy of USEPA.

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