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Internal Dose and In-Life Results of Perfluoro-2,5,8-trimethyl-3,6,9-trioxadodecanoic acid Exposure from Short Term Dosing Studies in Rats
Citation:
Renyer, A., D. MacMillan, M. Devito, M. Hughes, AND L. Wehmas. Internal Dose and In-Life Results of Perfluoro-2,5,8-trimethyl-3,6,9-trioxadodecanoic acid Exposure from Short Term Dosing Studies in Rats. ASMS Conference on Mass Spectrometry and Allied Topics, Minneapolis, MN, June 05 - 09, 2022. https://doi.org/10.23645/epacomptox.19890808
Impact/Purpose:
Per- and polyfluorinated chemicals (PFAS), are persistent environmental contaminants that are slow to degrade. They number near 5000 yet most lack available toxicological data. Our series of 5-day oral exposures to multiple dose levels of PFAS plus vehicle controls will provide a more rapid assessment of potential toxicity of these data-lacking compounds. The prioritization will be based upon benchmark dose response (BMD) modeling based upon primary points of departure generated from quantitation of internal dose and toxicogenomics. We are presenting the plasma concentrations and in-life observations of perfluoro-2,5,8-trimethyl-3,6,9-trioxadodecanoic acid (PF-TODoA). The general public would be interested in these findings, as they could hlep guide a portion of the EPA's approach to PFAS going forward.
Description:
Consistent documented environmental presence of per- and polyfluoroalkyl substances (PFAS) has generated global concern about their potential toxicity yet only a few of the nearly 5000 compounds have available toxicological data. The primary goal of our research is to provide a rapid assessment of potential PFAS toxicity through 5-day oral exposures to multiple dose levels of PFAS plus vehicles. For this study, Sprague-Dawley rats were exposed to perfluoro-2,5,8-trimethyl-3,6,9-trioxadodecanoic acid (PF-TODoA), a 12-carbon perfluoroether carboxylic acid. Plasma concentrations will be paired with multiple omics results to facilitate the calculation of the benchmark dose (BMD). This information could be used to inform risk assessment of data-poor, emerging PFAS. Sprague-Dawley rats were dosed daily for five sequential days via oral gavage with PF-TODoA ranging from 0.3 - 335 mg/kg/day plus a control. Weights and in-life observations were documented daily. Plasma samples were collected 24 hours after the last dose. Plasma was prepared using protein precipitation and isotope dilution. Matrix-matched calibrations at the same dilution as samples were used for quantitation. PF-TODoA concentrations were determined using a Sciex x500R QTOF operated in multiple reaction monitoring mode with electrospray ionization and negative ion polarity. The PF-TODoA molecular ion of (m/z 660, nominal) exhibited poor sensitivity thus largest in-source fragment (m/z 351, nominal) was used for quantitation. Gradient elution paired with a Phenomenex Kinetex XB-C18 (100 × 2.1 mm) column achieved chromatographic separation. Samples from the three highest dose levels were not considered for analysis due to the observance of severe negative health effects. Weight loss and clinical effects including lethargy, abnormal breathing, and decreased movement were observed at the remaining levels. Plasma was prepared at two dilutions with matrix-matched curves (r ≥ 0.995) generated for each dilution to accommodate the anticipated PF-TODoA concentrations. Limits of quantitation for PF-TODoA were in the low ng/mL range. Control samples composed of commercial rat plasma and a known amount of PF-TODoA consistently showed recoveries between 80-120%. Female rats had the higher average PF-TODoA plasma concentrations which ranged from 565 ± 57 ng/mL for the 0.3 mg/kg/day dose to 174 ± 20 µg/mL for the 17 mg/kg/day dose. PF-TODoA plasma concentrations from male rats were found to be up to approximately 2 times lower than those observed in females for dose levels 0.9 - 17 mg/kg/day, suggesting differences in processing by the sexes. The observed PF-TODoA increase in both male and female rats over the dose range suggest the potential for bioaccumulation. Internal dose measurements inform potential toxicokinetics and help confirm dose administration for PF-TODoA. Data obtained from acute chemical exposures may help regulators more quickly understand the health and safety risks of data-poor PFAS chemicals. Disclaimer: This abstract does not necessarily reflect EPA policy.
URLs/Downloads:
DOI: Internal Dose and In-Life Results of Perfluoro-2,5,8-trimethyl-3,6,9-trioxadodecanoic acid Exposure from Short Term Dosing Studies in Rats
ASMS MINNEAPOLIS POSTER V4.PDF (PDF, NA pp, 286.028 KB, about PDF)