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Evaluation of dose additive effects of combined oral maternal exposure to PFOA and PFOS during pregnancy in the Sprague-Dawley rat
Citation:
Conley, J., C. Lambright, N. Evans, E. MedlockKakaley, D. Hill, J. Ford, J. McCord, M. Strynar, AND E. Gray. Evaluation of dose additive effects of combined oral maternal exposure to PFOA and PFOS during pregnancy in the Sprague-Dawley rat. 2022 Society of Toxicology Annual Meeting, San Diego, CA, March 27 - 31, 2022.
Impact/Purpose:
Per- and poly-fluoroalkyl substance (PFAS) health effects is a critical research area due to issues associated with environmental persistence, widespread occurrence, biological half-life, toxicity, and nearly ubiquitous human and environmental exposure. Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are two of the most widely detected and extensively studied PFAS; however the literature does not contain a single published study addressing a hypothesis of additivity for these two compounds in laboratory animals. Importantly, the USEPA Office of Water currently recommends a human health advisory level based on the combined concentration of PFOA and PFOS and is moving toward regulatory action similarly based on co-exposure assuming cumulative effects. As part of this effort OW requested and partially funded the series of experiments described in the present abstract, which address the combined developmental toxicity of PFOA and PFOS in the Sprague-Dawley rat. We hypothesized that exposure to PFOA and PFOS combined would produce cumulative adverse effects in maternal and F1 rats that are more accurately modeled by dose addition than response addition. We found thus far that PFOA, PFOS, and the mixture of PFOA plus PFOS all increased maternal and neonatal liver weights, reduced neonatal survival, reduced neonatal body weight, reduced newborn liver glycogen content, and reduced maternal and neonatal thyroid hormone concentrations. This is the first data generated from a rigorous experimental examination of the combined effects of PFOA and PFOS in a laboratory animal model. The data from this project will be highly useful to the USEPA Office of Water, who formally requested this study, in their effort to update the PFOA and PFOS Health Effect Support Documents, determine MCLGs, and formalize NPDWRs. Further, other state and international health-based regulatory agencies will benefit from clear evidence of combined toxicity of PFOA and PFOS. The apical effect data along with the additional data streams that will be investigated as part of these experiments will be highly instructive in furthering the characterization of adverse outcome pathways relevant to the developmental toxicity of PFAS. These key events will further the scientific knowledge of how PFOA and PFOS (among other PFAS) perturb maternal and fetal/neonatal physiology during pregnancy.
Description:
Co-exposure to more than one per- and polyfluoroalkyl substance (PFAS) is common, if not ubiquitous. Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are the two most frequently detected and extensively studied PFAS; however, an examination of their cumulative in vivo effects has not been rigorously conducted. We performed a series of oral exposures in pregnant Sprague-Dawley rats (dosed gestation day (GD) 8 – postnatal day (PND) 2) to first characterize individual dose responses to PFOA (10-250 mg/kg/d) and PFOS (0.1-5 mg/kg/d) across a range of endpoints, followed by a binary mixture study in which we repeated a dose response of PFOA (3-80 mg/kg/d) but with a fixed dose of PFOS (2 mg/kg/d) added to each PFOA dose. Numerous apical effects from each chemical and the mixture were significantly altered compared to controls including reduced maternal gestational weight gain, reduced pup body weight at multiple timepoints, reduced pup viability, and increased maternal and pup relative liver weights. As a clear demonstration of cumulative effects, individual exposures to 62.5 mg/kg PFOA and 2 mg/kg PFOS produced 12±7% and 8±6% post-implantation loss (PIL) by PND2, respectively; while a mixture of the two (62.5 mg/kg PFOA+2 mg/kg PFOS) produced 66±15% PIL, which was accurately predicted by dose addition (predicted PIL = 76%), but underestimated by response addition (predicted PIL = 21%). Further, the addition of PFOS significantly shifted the PFOA dose response curve towards effects at lower doses for post-implantation loss, pup body weight, and maternal and pup liver weights. Newborn pup liver glycogen concentration and PND2 maternal and pup serum total T3 and T4 were significantly reduced in all experiments. Clinical chemistry profiles in newborn pups and PND2 moms and pups had numerous dose-responsive alterations indicative of perturbed carbohydrate and lipid metabolism, as well as liver and kidney function. Studies are on-going with additional endpoints in-process including liver and kidney histopathology, liver gene expression, maternal serum metabolomics, and analytical determination of PFOA and PFOS levels in serum in liver. The data here demonstrate dose additive effects of combined exposure to PFOA and PFOS for multiple endpoints. Abstract does not necessarily reflect USEPA views or policy.