Citation:

Renyer, A., K. Ravindra, B. Wetmore, J. Ford, M. Devito, M. Hughes, L. Wehmas, AND D. Macmillan. Dose Response, Dosimetric, and Metabolic Evaluations of Replacement PFAS Perfluoro-(2,5,8-trimethyl-3,6,9-trioxadodecanoic) Acid (HFPO-TeA). Toxics. MDPI, Basel, Switzerland, 11(12):951, (2023). https://doi.org/10.3390/toxics11120951

Impact/Purpose:

The evidence of thyroid hormone dysregulation, sex-based differences in clinical results and dosimetry, and IVIVE predictions provided in the manuscript suggest the replacement PFECA HFPO-TeA induces a complex and toxic exposure response in rodents. The dissemination of these in vivo toxicity observations and dose responses alongside the in vitro assay data will address key data gaps as scientists seek to estimate the risk of currently understudied PFAS. The emerging PFAS studied here, HFPO-TeA, is a homologue of HFPO-DA, a known environmental and human health risk. This data helps clarify and inform decisions on whether further investigation of HFPO-TeA exposure as a potential hazard should be undertaken.

Description:

Few studies are available on the environmental and toxicological effects of perfluoroalkyl ether carboxylic acids (PFECAs), such as GenX, which are replacing legacy PFAS in manufacturing processes. To collect initial data on the toxicity and toxicokinetics of a longer-chain PFECA, male and female Sprague Dawley rats were exposed to perfluoro-(2,5,8-trimethyl-3,6,9-trioxadodecanoic) acid (HFPO-TeA) by oral gavage for five days over multiple dose levels (0.3-335.2 mg/kg/day). Clinically, we observed mortality at doses >17 mg/kg/day and body weight changes at doses ≤17 mg/kg/day. For the 17 mg/kg/day dose level, T3 and T4 thyroid hormone concentrations were significantly decreased (p < 0.05) from controls and HFPO-TeA plasma concentrations were significantly different between sexes. Non-targeted analysis of plasma and in vitro hepatocyte assay extractions revealed the presence of another GenX oligomer, perfluoro-(2,5-dimethyl-3,6-dioxanonanoic) acid (HFPO-TA). In vitro to in vivo extrapolation (IVIVE) parameterized with in vitro toxicokinetic data predicted steady-state blood concentrations that were within seven-fold of those observed in the in vivo study, demonstrating reasonable predictivity. The evidence of thyroid hormone dysregulation, sex-based differences in clinical results and dosimetry, and IVIVE predictions presented here suggest that the replacement PFECA HFPO-TeA induces a complex and toxic exposure response in rodents.

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