Citation:

Villeneuve, D., B. Blackwell, J. Cavallin, J. Collins, J. Hoang, R. Hofer, K. Houck, K. Jensen, M. Kahl, R. Kutsi, A. Opseth, K. Santana Rodriguez, C. Schaupp, E. Stacy, AND G. Ankley. Verification of In Vivo Estrogenic Activity for Four Per- and Polyfluoroalkyl Substances (PFAS) Identified as Estrogen Receptor Agonists via New Approach Methodologies. ENVIRONMENTAL SCIENCE & TECHNOLOGY. American Chemical Society, Washington, DC, 57(9):3794-3803, (2023). https://doi.org/10.1021/acs.est.2c09315

Impact/Purpose:

Per- and polyfluoroalkyl substances (PFAS) are a large class of chemicals of concern to the Agency. Given that there are thousands of PFAS structures that need to be evaluated with regard to hazard, a tiered strategy employing high throughput screening has been proposed. As part of this research, we verified that PFAS identified as estrogen-like endocrine disrupting compounds through in vitro screening assays do indeed elicit estrogenic effects in vivo. Further, we demonstrate that once differences in bioconcentration are accounted for, relative potency in vitro predicts the rank order of potency in vivo. Finally, by identifying an in vivo effect level for the most potent known estrogenic PFAS, the data from this study can be applied in screening level (protective/conservative) risk assessment of PFAS mixtures with regard to potential for estrogenic endocrine disrupting effects. Results contribute to both the scientific validation of a tiered screening approach for evaluating PFAS and provide data that help to inform hazard assessments for specific PFAS. Such data are of high value to multiple program offices including OLEM, OW, OPPT, and multiple Regions.

Description:

Given concerns about potential toxicological hazards of the thousands of data-poor per- and polyfluorinated alkyl substances (PFAS) currently in commerce and detected in the environment, tiered testing strategies that employ high-throughput in vitro screening as an initial testing tier have been implemented. The present study evaluated the effectiveness of previous in vitro screening for identifying PFAS capable, or incapable, of inducing estrogenic responses in fish exposed in vivo. Fathead minnows (Pimephales promelas) were exposed for 96 h to five PFAS (perfluorooctanoic acid [PFOA]; 1H,1H,8H,8H-perfluorooctane-1,8-diol [FC8-diol]; 1H,1H,10H,10H-perfluorodecane-1,10-diol [FC10-diol]; 1H,1H,8H,8H-perfluoro-3,6-dioxaoctane-1,8-diol [FC8-DOD]; and perfluoro-2-methyl-3-oxahexanoic acid [HFPO-DA]) that showed varying levels of in vitro estrogenic potency. In agreement with in vitro screening results, exposure to FC8-diol, FC10-diol, and FC8-DOD caused concentration-dependent increases in the expression of transcript coding for vitellogenin and estrogen receptor alpha and reduced expression of insulin-like growth factor and apolipoprotein eb. Once differences in bioconcentration were accounted for, the rank order of potency in vivo matched that determined in vitro. These results provide a screening level benchmark for worst-case estimates of potential estrogenic hazards of PFAS and a basis for identifying structurally similar PFAS to scrutinize for putative estrogenic activity.

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