Cumulative maternal and neonatal effects of combined exposure to a mixture of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) during pregnancy in the Sprague-Dawley rat

This sub-product will describe data generated from postnatal studies in Sprague-Dawley rats on the key events and adverse outcomes of oral gestational exposure to a mixture of PFOA and PFOS. Each of these compounds has been shown to individually produce numerous maternal and offspring effects following in utero exposure. This study investigates a theory of dose additivity in which the chemicals were predicted to produce cumulative effects.

Impact/Purpose

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 mammals.  Importantly, the USEPA Office of Water is currently updating the toxicity assessments and preparing to issue National Primary Drinking Water Regulations for these compounds and potentially other PFAS.  State, federal, and international regulatory actions on PFAS are moving toward cumulative assessment approaches based on co-exposure to multiple PFAS.  As part of this effort OW requested and partially funded the series of experiments described in the present manuscript, which addresses 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.  We report that numerous maternal and pup effects were observed for PFOA, PFOS, and the mixture of PFOA plus PFOS.  Importantly, cumulative toxicity was clearly demonstrated by statistically significant shifts in the dose response curves for PFOA (towards effects at lower doses of PFOA) compared to PFOA alone for multiple endpoints.  Further, statistical evaluation of mixture models traditionally used in risk assessment indicated that dose addition was equivalent or better than response addition for predicting mixture based effects for all endpoints amenable to mixture modeling. This is the first data generated from a rigorous experimental examination of the combined effects of any mixture of PFAS in an in vivo mammalian 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 Maximum Contaminant Level Goals (MCLGs), and formalize National Primary Drinking Water Regulations (NPDWRs).  Further, other state and international health-based regulatory agencies will benefit from clear evidence of combined toxicity of two model PFAS, PFOA and PFOS. 

Citation

Conley, J., C. Lambright, N. Evans, E. Medlock Kakaley, A. Dixon, D. Jenkins-Hill, J. McCord, M. Strynar, J. Ford, AND L. Gray. Cumulative maternal and neonatal effects of combined exposure to a mixture of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) during pregnancy in the Sprague-Dawley rat. Elsevier B.V., Amsterdam, NETHERLANDS, 170:107631, (2022). [DOI: 10.1016/j.envint.2022.107631]

DOI: Cumulative maternal and neonatal effects of combined exposure to a mixture of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) during pregnancy in the Sprague-Dawley rat