Characterizing biopersistence potential of the metabolite 5:3 fluorotelomer carboxylic acid after repeated oral exposure to the 6:2 fluorotelomer alcohol

https://doi.org/10.1016/j.taap.2020.114878Get rights and content

Highlights

  • 6:2 FTOH-based PFAS used as greaseproofing agents for paper and paperboard.

  • First characterization of biopersistence of 5:3 acid after 6:2 FTOH exposure.

  • Times to steady state of 5:3 acid in plasma, fat, and liver of rats about 1 year.

  • Impact on future toxicology studies; extend 6:2 FTOH testing to at least 1 year.

Abstract

Our previous report on pharmacokinetic (PK) evaluation of 6:2 fluorotelomer alcohol (6:2 FTOH) examined the biopersistence potential of its metabolites based on data published from single inhalation and occupational 6:2 FTOH exposure studies. We calculated internal exposure estimates of three key metabolites of 6:2 FTOH, of which 5:3 fluorotelomer carboxylic acid (5:3 acid) had the highest internal exposure and the slowest clearance. No oral repeated 6:2 FTOH exposure data were available at the time to fully characterize the biopersistence potential of the metabolite 5:3 acid. We recently received additional data on 6:2 FTOH and 5:3 acid, which included a 90-day toxicokinetic study report on repeated oral 6:2 FTOH exposure to rats. We reviewed the study and analyzed the reported 5:3 acid concentrations in plasma, liver, and fat using one-compartment PK modeling and calculated elimination rate constants (kel), elimination half-lives (t1/2) and times to steady state (tss) of 5:3 acid at three 6:2 FTOH doses. Our results showed that tss of 5:3 acid in plasma and evaluated tissues were approximately close to 1 year, such that the majority of highest values were observed at the lowest 6:2 FTOH dose, indicating its association with the biopersistence of 6:2 FTOH. The results of our PK analysis are the first to characterize biopersistence potential of the 5:3 acid after repeated oral exposure to the parent compound 6:2 FTOH based on steady state PK parameters, and therefore, may have an impact on future study designs when conducting toxicity assays for such compounds.

Introduction

Per- and polyfluorinated alkyl substance (PFAS)-based polymeric compounds are used as greaseproofing agents for food contact paper and paperboard (Rice, 2015) and as stain- and waterproof coatings for textiles and surfaces (EPA, 2009). Due to concerns of C8-PFAS (PFAS ≥8‑carbons in length) for environmental persistence, bioaccumulation in humans, and long-term toxicity (Ladics et al., 2008; Martin et al., 2009; Nabb et al., 2007; Nilsson et al., 2010a; Nilsson et al., 2010b), the United States Food and Drug Administration (US FDA) (FDA, 2011; Rice, 2015) and Environmental Protection Agency (EPA) (EPA, 2009; EPA, 2013) reached a voluntary agreement with industry to remove C8-PFAS from commercial applications in the United States. Industry replaced C8-PFAS with shorter-chain C6-PFAS (typically PFAS ≤6‑carbons in length) with similar greaseproofing properties.

The 6:2 fluorotelomer alcohol (6:2 FTOH, CASRN: 647-42-7; Fig. 1), a C6-PFAS, is a major impurity in, and degradation product of polymers used as stain-, water-, and greaseproof coatings, and a degradation product of components of aqueous film-forming foam (AFFF) (Li et al., 2017; Trier et al., 2017; Washington et al., 2009; Yuan et al., 2016). Migration of the 6:2 FTOH into food is expected as a result of its use in food contact substances as coatings for paper and paperboard (Trier et al., 2017; Yuan et al., 2016). Furthermore, FTOHs have been also reported in indoor air and dust at a median concentration of 3570 pg/m3 (Winkens et al., 2017) and wastewater treatment plant effluent at concentrations of 3.05–12.4 ng/l (Chen et al., 2017).

Although the pharmacokinetics (PK) of the 6:2 FTOH have not been fully evaluated, its metabolites perfluorohexanoic acid (PFHxA) and perfluorobutanoic acid (PFBA) have been reported to have shorter elimination half-lives (t1/2) than the C8-PFAS, perfluorooctanoic acid (PFOA) (Wang et al., 2013). We recently examined the metabolism of 6:2 FTOH and reviewed PK data published in the scientific literature (Russell et al., 2015) on some perfluorinated carboxylic acid (PFCA) metabolites of 6:2 FTOH: PFHxA, perfluoroheptanoic acid (PFHpA), and 5:3 fluorotelomer carboxylic acid (5:3 acid, CASRN: 914637-49-3; Fig. 1) (Kabadi et al., 2018). These data included plasma concentration versus time profiles of the three metabolites after single inhalation exposure of 6:2 FTOH to rats and repeated occupational exposure of 6:2 FTOH to humans (Russell et al., 2015). Using noncompartment PK modeling, we identified 5:3 acid as the metabolite with the highest potential for biopersistence of the evaluated 6:2 FTOH metabolites (Kabadi et al., 2018). We also determined that the elimination of 5:3 acid was nonlinear, as the clearance changed with an increase in external 6:2 FTOH inhalation exposure. In general, the PK profiles of PFAS after single exposure are not representative of that after repeated exposure (Fasano et al., 2006; Fasano et al., 2009; Rand and Mabury, 2017). Although we were able to predict the general PK profile of 6:2 FTOH after single exposure and identify 5:3 acid as a biomarker of internal 6:2 FTOH exposure, there were no repeated dosing studies available at that time to fully characterize the PK profile of 5:3 acid under conditions of repeated 6:2 FTOH exposure.

More recently, we received additional PK data on 6:2 FTOH and 5:3 acid, which included a toxicokinetic study report of a 90-day oral toxicity study of 6:2 FTOH in rats at different dose levels (DuPont, 2012). We reviewed the reported plasma and tissue concentration data of the 5:3 acid and calculated the elimination rate constants (kel), t1/2, and times to steady state (tss) of 5:3 acid in plasma and assessed tissues of rats using one-compartment classical PK modeling (Dhillon and Gill, 2006; Shen, 2013). Furthermore, we compared the PK parameters of 5:3 acid with the 6:2 FTOH dose levels and examined any dose-dependent changes and sex-based differences. Our assessment is the first to characterize the biopersistence potential of the metabolite 5:3 acid after repeated oral exposure to the parent compound 6:2 FTOH based on calculated steady state PK parameters of the 5:3 acid, and therefore, demonstrates the important role of the 5:3 acid in the biopersistence resulting from long-term exposure to the 6:2 FTOH.

Section snippets

Review of the 90-day repeated-dosing oral 6:2 FTOH PK study (DuPont, 2012)

As stated in the toxicokinetic report of the 90-day oral toxicity study of 6:2 FTOH (DuPont, 2012), male and female Sprague Dawley rats (n at the beginning of the study = 10 rats/sex/group) were administered 6:2 FTOH via oral gavage at dose levels of 5, 25, 125, and 250 mg/kg/d for 90 days. Plasma, liver, and fat samples were collected at 91 days (1-day recovery), 120 days (1-month recovery), and 180 days (3-month recovery) from the 250 mg/kg/d groups, and at 91 and 180 days from the 5 and

Results and analysis

Our analysis of the results from the 90-day repeated oral 6:2 FTOH exposure study in rats (DuPont, 2012) indicated that 5:3 acid was the only metabolite consistently detected at most dose levels throughout the study. The study (DuPont, 2012) described 5:3 acid as a marker of internal exposure to 6:2 FTOH. Furthermore, the study reported that although there were quantifiable levels of 5:3 acid present in the plasma even at the 2-month recovery time point, considering the dose rate, the

Discussion

Metabolism has been reported to play an important role in the disposition of 6:2 FTOH (DeLorme et al., 2011; Gannon et al., 2011; Gannon et al., 2012; Gannon et al., 2010; Himmelstein et al., 2012; Kelly et al., 2011; Ruan et al., 2014; Russell et al., 2015). 6:2 FTOH is metabolized to first form transient intermediates, 6:2 fluorotelomer aldehyde (6:2 FTAL), 6:2 A and 6:2 UA in rats as well as humans (Kabadi et al., 2018). The parent 6:2 FTOH and the intermediates then undergo competitive

Conclusion

Our analysis based on data reviewed in a 90-day repeated oral 6:2 FTOH exposure study in rats represents the first report of steady state PK parameters of the 5:3 acid under conditions of repeated oral 6:2 FTOH exposure. A characterization of biopersistence of the 5:3 acid in plasma and evaluated tissues is supported by the calculated time taken for 5:3 acid to reach steady state of approximately close to a year, with the highest tss observed at the lowest 6:2 FTOH dose for most of the analyzed

Declaration of competing interest

The authors disclose that they have no competing financial and other interests.

Acknowledgements

The authors would like to thank the following peer reviewers from the FDA for their intellectual contribution to this work: Dr. Omari Bandele (CFSAN), Dr. Jessica Cooper (CFSAN), Dr. Barry Delclos (NCTR), Dr. David Goldman (CFSAN), Dr. Dennis Keefe (CFSAN), Dr. Sharon Koh-Fallet (CFSAN), Dr. Paul Honigfort (CFSAN), Dr. Susan Mayne (CFSAN), Dr. Steven Musser (CFSAN), Dr. Paul South (CFSAN), and Dr. Volodymyr Tryndyak (NCTR).

Author contributions

Dr. Shruti Kabadi is the first and corresponding author of this manuscript. She conceptualized, analyzed and wrote the pharmacokinetic assessment described in this manuscript. The pharmacokinetic assessment was completed with expert guidance from Dr. Jeffrey Fisher and important intellectual contribution by Dr. Daniel Doerge, Dr. Jason Aungst and Dr. Penelope Rice. Dr. Darshan Mehta performed the statistical analysis described in this manuscript. Dr. Rice is the lead toxicologist and Dr. Kabadi

Disclaimer

The information in this paper is not a formal dissemination of information by FDA and does not represent the Agency's position or policy.

References (51)

  • Z. Wang et al.

    Fluorinated alternatives to long-chain perfluoroalkyl carboxylic acids (PFCAs), perfluoroalkane sulfonic acids (PFSAs) and their potential precursors

    Environ. Int.

    (2013)
  • K. Winkens et al.

    Perfluoroalkyl acids and their precursors in indoor air sampled in children’s bedrooms

    Environ. Pollut.

    (2017)
  • R.R. Worley et al.

    Application of physiologically-based pharmacokinetic modeling to explore the role of kidney transporters in renal reabsorption of perfluorooctanoic acid in the rat

    Toxicol. Appl. Pharmacol.

    (2015)
  • C.H. Yang et al.

    Organic anion transporting polypeptide (Oatp) 1a1-mediated perfluorooctanoate transport and evidence for a renal reabsorption mechanism of Oatp1a1 in renal elimination of perfluorocarboxylates in rats

    Toxicol. Lett.

    (2009)
  • H. Chen et al.

    Detection, occurrence, and fate of fluorotelomer alcohols in municipal wastewater treatment plants

    Environ. Sci. Technol.

    (2017)
  • M. Convertino et al.

    Stochastic pharmacokinetic-pharmacodynamic modeling for assessing the systemic health risk of perfluorooctanoate (PFOA)

    Toxicol. Sci.

    (2018)
  • M.P.S. DeLorme et al.

    6:2 fluorotelomer alcohol: one-week inhalation toxicity study

    The Toxicologist

    (2011)
  • S. Dhillon et al.
  • N.R. Draper et al.

    Applied Regression Analysis

    (1998)
  • DuPont

    Oral gavage repeated dose 90-day toxicity study of [6:2 fluorotelomer alcohol] in rats

  • EPA

    U.S. EPA: Long-Chain Perfluorinated Chemicals Action Plan

    (2009)
  • Fact sheet: 2010/2015 PFOA Stewardship Program

  • W.J. Fasano et al.

    Absorption, distribution, metabolism, and elimination of 8-2 fluorotelomer alcohol in the rat

    Toxicol. Sci.

    (2006)
  • FDA

    Update on Perfluorinated Grease-Proofing Agents

  • A.J. Fischman et al.

    Pharmacokinetics of [18F]fleroxacin in healthy human subjects studied by using positron emission tomography

    Antimicrob. Agents Chemother.

    (1993)
  • Cited by (19)

    • Comparative analysis of the toxicological databases for 6:2 fluorotelomer alcohol (6:2 FTOH) and perfluorohexanoic acid (PFHxA)

      2020, Food and Chemical Toxicology
      Citation Excerpt :

      The TK segment of the 90-day repeated-dose oral toxicity study in rats conducted with 6:2 FTOH (DuPont, 2012a) was determined to be adequately conducted and reported 5:3 acid concentrations in the plasma, fat, and liver at certain time points; all data that were utilized to calculate kel, t1/2, and tss of 5:3 acid in plasma and assessed tissues. Consistent with the conclusions of the prior analysis of the published data (Kabadi et al., 2018), the updated analysis concluded that 5:3 acid had the longest t1/2 of the evaluated metabolites in male and female rats, as may be seen in Table 1 (Kabadi et al., 2020). The calculated values for tss of 5:3 acid at toxicologically relevant doses of 5 and 25 mg/kg/d ranged from close to one year to more than one year in the plasma, liver, and fat of both sexes of rats, with tss increasing with a decrease in dose in all samples, except fat of female rats (Kabadi et al., 2020).

    • Physiologically based pharmacokinetic modeling: A promising tool for translational research and regulatory toxicology

      2020, Current Opinion in Toxicology
      Citation Excerpt :

      This work demonstrated that assuming a single mode of action is not sufficient to capture thiocyanate's dose––response relationship [39]. More recently, noncompartmental [40] and compartmental [41] PK modeling was used to demonstrate that 5:3 fluorotelomer carboxylic acid (5:3 acid), a metabolite of the PFAS chemical, 6:2 fluorotelomer alcohol (6:2 FTOH), had the potential to biopersist in plasma and tissues of rats on repeated exposure to 6:2 FTOH. These analyses also identified certain factors, such as changes in dose levels and sex and physiological processes, such as renal transporter-mediated reabsorption or secretion and enterohepatic circulation, that could be evaluated using PBPK modeling for further understanding the mechanisms that contribute to the biopersistence potential of the 5:3 acid after long-term exposure to 6:2 FTOH.

    View all citing articles on Scopus
    View full text