Exploring sex differences in human health risk assessment for PFNA and PFDA using a PBPK model

Abstract

Perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA), which are classified as perfluoroalkyl and polyfluoroalkyl substances (PFASs), have been widely used in industrial applications as a surface protectant. PFASs have been detected in wildlife and in humans around the globe. The purposes of this study are to develop and validate a physiologically based pharmacokinetic (PBPK) model for detecting PFNA and PFDA in male and female rats, and to apply the model to a human health risk assessment regarding the sex difference. A PBPK model of PFNA and PFDA was established based on an in vivo study in male and female rats. Analytes in biological samples (plasma, nine tissues, urine, and feces) were determined by ultra-liquid chromatography coupled tandem mass spectrometry (UPLC–MS/MS) method. PFNA and PFDA showed a gender differences in the elimination half-life and volume of distribution. The tissue–plasma partition coefficients were the highest in the liver in both male and female rats. The predicted rat plasma and urine concentrations simulated and fitted were in good agreement with the observed values. The PBPK models of PFNA and PFDA in male and female rats were then extrapolated to a human PBPK model based on human physiological parameters. The external doses were calculated at 3.35 ng/kg/day (male) and 17.0 ng/kg/day (female) for PFNA and 0.530 ng/kg/day (male) and 0.661 ng/kg/day (female) for PFDA. Human risk assessment was estimated using Korean biomonitoring values considering the gender differences. This study provides valuable insight into human health risk assessment regarding PFNA and PFDA exposure.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11

Abbreviations

AUC inf :

Area under the concentration–time curve from zero to infinity

CL :

Clearance

C max :

Maximum plasma concentration

C ss :

Steady-state concentration

F r :

Free fraction in plasma

IV:

Intravenous

Kp:

Tissue-to-plasma partition coefficient

K st :

Rate constant to storage compartment

K t :

Transporter affinity constant

K u :

Urinary elimination rate constant

MOE:

Margin of exposure

NOAEL:

No-observed-adverse-effect level

PBPK:

Physiologically based pharmacokinetic model

PFASs:

Perfluoroalkyl and polyfluoroalkyl substances

PFHxS:

Perfluorohexanesulfonic acid

PFDA:

Perfluorodecanoic acid

PFNA:

Perfluorononanoic acid

PFOA:

Perfluorooctanoic acid

PFOS:

Perfluorooctanesulfonic acid

PK:

Pharmacokinetic

POD:

Point of departure

t 1/2 :

The elimination half-life

TDI:

The tolerable daily intake

T m :

Transport maximum

UF:

Uncertainty factor

UFA :

Uncertainty factor for interspecies extrapolation from rats to humans

UFH :

Uncertainty factor for inter-individual variability in humans

UFS :

Uncertainty factor for subchronic to chronic extrapolation

V d :

Volume of distribution

References

  1. ATSDR (2018a) Agency for toxic substances and disease registry, Toxicological profile for Perfluoroalkyls. (Draft for Public Comment). Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service (draft). http://www.atsdr.cdc.gov/mrls/pdfs/atsdr_mrls.pdf. Accessed 14 Aug 2018

  2. ATSDR (2018b) Agency for toxic substances and disease registry, minimal risk levels (MRLs). https://www.atsdr.cdc.gov/mrls/index.asp. Accessed 2 Aug 2018

  3. Bartolome M, Gallego-Pico A, Cutanda F et al (2017) Perfluorinated alkyl substances in Spanish adults: geographical distribution and determinants of exposure. Sci Total Environ 603–604:352–360. https://doi.org/10.1016/j.scitotenv.2017.06.031

    CAS  Article  PubMed  Google Scholar 

  4. Benskin JP, De Silva AO, Martin LJ et al (2009) Disposition of perfluorinated acid isomers in Sprague–Dawley rats; part 1: single dose. Environ Toxicol Chem 28(3):542–554. https://doi.org/10.1897/08-239.1

    CAS  Article  PubMed  Google Scholar 

  5. Bischel HN, Macmanus-Spencer LA, Luthy RG (2010) Noncovalent interactions of long-chain perfluoroalkyl acids with serum albumin. Environ Sci Technol 44(13):5263–5269. https://doi.org/10.1021/es101334s

    CAS  Article  PubMed  Google Scholar 

  6. Borg D, Lund BO, Lindquist NG, Hakansson H (2013) Cumulative health risk assessment of 17 perfluoroalkylated and polyfluoroalkylated substances (PFASs) in the Swedish population. Environ Int 59:112–123. https://doi.org/10.1016/j.envint.2013.05.009

    CAS  Article  PubMed  Google Scholar 

  7. Chen Q, Huang R, Hua L et al (2018) Prenatal exposure to perfluoroalkyl and polyfluoroalkyl substances and childhood atopic dermatitis: a prospective birth cohort study. Environ Health 17(1):8. https://doi.org/10.1186/s12940-018-0352-7

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. Dong Z, Bahar MM, Jit J, Kennedy B, Priestly B, Ng J, Lamb D, Liu Y, Duan L, Naidu R (2017) Issues raised by the reference doses for perfluorooctane sulfonate and perfluorooctanoic acid. Environ Int 105:86–94. https://doi.org/10.1016/j.envint.2017.05.006

    CAS  Article  PubMed  Google Scholar 

  9. Dourson ML, Stara JF (1983) Regulatory history and experimental support of uncertainty (safety) factors. Regul Toxicol Pharmacol 3(3):224–238

    CAS  Article  Google Scholar 

  10. EPA (2006) Approaches for the Application of Physiologically Based Pharmacokinetic (PBPK) Models and Supporting Data in Risk Assessment. National Center for Environmental Assessment, Washington, DC; EPA/600/R-05/043F. Available from: National Technical Information Service, Springfield, VA, and online at http://epa.gov/ncea. https://doi.org/10.7748/ns.14.36.26.s40

    CAS  Article  Google Scholar 

  11. Fang X, Feng Y, Wang J, Dai J (2010) Perfluorononanoic acid-induced apoptosis in rat spleen involves oxidative stress and the activation of caspase-independent death pathway. Toxicology 267(1–3):54–59. https://doi.org/10.1016/j.tox.2009.10.020

    CAS  Article  PubMed  Google Scholar 

  12. Fang X, Gao G, Xue H, Zhang X, Wang H (2012a) Exposure of perfluorononanoic acid suppresses the hepatic insulin signal pathway and increases serum glucose in rats. Toxicology 294(2–3):109–115. https://doi.org/10.1016/j.tox.2012.02.008

    CAS  Article  PubMed  Google Scholar 

  13. Fang X, Gao G, Xue H, Zhang X, Wang H (2012b) In vitro and in vivo studies of the toxic effects of perfluorononanoic acid on rat hepatocytes and Kupffer cells. Environ Toxicol Pharmacol 34(2):484–494. https://doi.org/10.1016/j.etap.2012.06.011

    CAS  Article  PubMed  Google Scholar 

  14. FDA (2013) The guidance for industry: bioanalytical method validation. Department of Health and Human Services, US Food and Drug Administration. https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

  15. Guruge KS, Noguchi M, Yoshioka K et al (2016) Microminipigs as a new experimental animal model for toxicological studies: comparative pharmacokinetics of perfluoroalkyl acids. J Appl Toxicol 36(1):68–75. https://doi.org/10.1002/jat.3145

    CAS  Article  PubMed  Google Scholar 

  16. Han X, Snow TA, Kemper RA, Jepson GW (2003) Binding of perfluorooctanoic acid to rat and human plasma proteins. Chem Res Toxicol 16(6):775–781. https://doi.org/10.1021/tx034005w

    CAS  Article  PubMed  Google Scholar 

  17. Han X, Nabb DL, Russell MH, Kennedy GL, Rickard RW (2012) Renal elimination of perfluorocarboxylates (PFCAs). Chem Res Toxicol 25(1):35–46. https://doi.org/10.1021/tx200363w

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. Harris MW, Uraih LC, Birnbaum LS (1989) Acute toxicity of perfluorodecanoic acid in C57BL/6 mice differs from 2,3,7,8-tetrachlorodibenzo-p-dioxin. Fundam Appl Toxicol 13(4):723–736. https://doi.org/10.1016/0272-0590(89)90330-8

    CAS  Article  PubMed  Google Scholar 

  19. Iwabuchi K, Senzaki N, Mazawa D et al (2017) Tissue toxicokinetics of perfluoro compounds with single and chronic low doses in male rats. J Toxicol Sci 42(3):301–317. https://doi.org/10.2131/jts.42.301

    CAS  Article  PubMed  Google Scholar 

  20. Ji K, Kim S, Kho Y et al (2012) Serum concentrations of major perfluorinated compounds among the general population in Korea: dietary sources and potential impact on thyroid hormones. Environ Int 45:78–85. https://doi.org/10.1016/j.envint.2012.03.007

    CAS  Article  PubMed  Google Scholar 

  21. Kawashima Y, Kobayashi H, Miura H, Kozuka H (1995) Characterization of hepatic responses of rat to administration of perfluorooctanoic and perfluorodecanoic acids at low levels. Toxicology 99(3):169–178

    CAS  Article  Google Scholar 

  22. Khalil N, Ebert JR, Honda M et al (2018) Perfluoroalkyl substances, bone density, and cardio-metabolic risk factors in obese 8–12 year old children: a pilot study. Environ Res 160:314–321. https://doi.org/10.1016/j.envres.2017.10.014

    CAS  Article  PubMed  Google Scholar 

  23. Kim DH, Kim UJ, Kim HY, Choi SD, Oh JE (2016a) Perfluoroalkyl substances in serum from South Korean infants with congenital hypothyroidism and healthy infants—Its relationship with thyroid hormones. Environ Res 147:399–404. https://doi.org/10.1016/j.envres.2016.02.037

    CAS  Article  PubMed  Google Scholar 

  24. Kim SJ, Heo SH, Lee DS, Hwang IG, Lee YB, Cho HY (2016b) Gender differences in pharmacokinetics and tissue distribution of 3 perfluoroalkyl and polyfluoroalkyl substances in rats. Food Chem Toxicol 97:243–255. https://doi.org/10.1016/j.fct.2016.09.017

    CAS  Article  PubMed  Google Scholar 

  25. Kim SJ, Shin H, Lee YB, Cho HY (2018) Sex-specific risk assessment of PFHxS using a physiologically based pharmacokinetic model. Arch Toxicol 92(3):1113–1131. https://doi.org/10.1007/s00204-017-2116-5

    CAS  Article  PubMed  Google Scholar 

  26. Kudo N, Bandai N, Suzuki E, Katakura M, Kawashima Y (2000) Induction by perfluorinated fatty acids with different carbon chain length of peroxisomal beta-oxidation in the liver of rats. Chem Biol Interact 124(2):119–132

    CAS  Article  Google Scholar 

  27. Kudo N, Suzuki E, Katakura M, Ohmori K, Noshiro R, Kawashima Y (2001) Comparison of the elimination between perfluorinated fatty acids with different carbon chain length in rats. Chem Biol Interact 134(2):203–216

    CAS  Article  Google Scholar 

  28. Lee S, Kim S, Park J et al (2018) Perfluoroalkyl substances (PFASs) in breast milk from Korea: time-course trends, influencing factors, and infant exposure. Sci Total Environ 612:286–292. https://doi.org/10.1016/j.scitotenv.2017.08.094

    CAS  Article  PubMed  Google Scholar 

  29. Liu B, Zhang H, Yao D et al (2015) Perfluorinated compounds (PFCs) in the atmosphere of Shenzhen, China: spatial distribution, sources and health risk assessment. Chemosphere 138:511–518. https://doi.org/10.1016/j.chemosphere.2015.07.012

    CAS  Article  PubMed  Google Scholar 

  30. Loccisano AE, Campbell JL Jr, Andersen ME, Clewell HJ III (2011) Evaluation and prediction of pharmacokinetics of PFOA and PFOS in the monkey and human using a PBPK model. Regul Toxicol Pharmacol 59(1):157–175. https://doi.org/10.1016/j.yrtph.2010.12.004

    CAS  Article  PubMed  Google Scholar 

  31. Loccisano AE, Campbell JL Jr, Butenhoff JL, Andersen ME, Clewell HJ III (2012a) Comparison and evaluation of pharmacokinetics of PFOA and PFOS in the adult rat using a physiologically based pharmacokinetic model. Reprod Toxicol 33(4):452–467. https://doi.org/10.1016/j.reprotox.2011.04.006

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. Loccisano AE, Campbell JL Jr, Butenhoff JL, Andersen ME, Clewell HJ III (2012b) Evaluation of placental and lactational pharmacokinetics of PFOA and PFOS in the pregnant, lactating, fetal and neonatal rat using a physiologically based pharmacokinetic model. Reprod Toxicol 33(4):468–490. https://doi.org/10.1016/j.reprotox.2011.07.003

    CAS  Article  PubMed  Google Scholar 

  33. Loccisano AE, Longnecker MP, Campbell JL Jr, Andersen ME, Clewell HJ III (2013) Development of PBPK models for PFOA and PFOS for human pregnancy and lactation life stages. J Toxicol Environ Health A 76(1):25–57. https://doi.org/10.1080/15287394.2012.722523

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. Luebker DJ, Hansen KJ, Bass NM, Butenhoff JL, Seacat AM (2002) Interactions of fluorochemicals with rat liver fatty acid-binding protein. Toxicology 176(3):175–185

    CAS  Article  Google Scholar 

  35. Maher JM, Aleksunes LM, Dieter MZ et al (2008) Nrf2- and PPAR alpha-mediated regulation of hepatic Mrp transporters after exposure to perfluorooctanoic acid and perfluorodecanoic acid. Toxicol Sci 106(2):319–328. https://doi.org/10.1093/toxsci/kfn177

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. MFDS (2009) Exposure assessment of major perfluorinated compounds among Koreans. Ministry of Food and Drug Safety, 08182MFDS499. https://rnd.mfds.go.kr/

  37. OECD (2015) Risk reduction approaches for PFASs—a cross-country analysis. Health and safety publications series on risk management no. 29. Organisation for Economic Co-operation and Development Environment. http://www.oecd.org/chemicalsafety/portal-perfluorinated-chemicals/

  38. Ohmori K, Kudo N, Katayama K, Kawashima Y (2003) Comparison of the toxicokinetics between perfluorocarboxylic acids with different carbon chain length. Toxicology 184(2–3):135–140

    CAS  Article  Google Scholar 

  39. Ruark CD, Song G, Yoon M et al (2017) Quantitative bias analysis for epidemiological associations of perfluoroalkyl substance serum concentrations and early onset of menopause. Environ Int 99:245–254. https://doi.org/10.1016/j.envint.2016.11.030

    CAS  Article  PubMed  Google Scholar 

  40. Rush EL, Singer AB, Longnecker MP et al (2018) Oral contraceptive use as a determinant of plasma concentrations of perfluoroalkyl substances among women in the Norwegian Mother and Child Cohort (MoBa) study. Environ Int 112:156–164. https://doi.org/10.1016/j.envint.2017.12.015

    CAS  Article  PubMed  Google Scholar 

  41. Seo SH, Son MH, Choi SD, Lee DH, Chang YS (2018) Influence of exposure to perfluoroalkyl substances (PFASs) on the Korean general population: 10-year trend and health effects. Environ Int 113:149–161. https://doi.org/10.1016/j.envint.2018.01.025

    CAS  Article  PubMed  Google Scholar 

  42. Tatum-Gibbs K, Wambaugh JF, Das KP et al (2011) Comparative pharmacokinetics of perfluorononanoic acid in rat and mouse. Toxicology 281(1–3):48–55. https://doi.org/10.1016/j.tox.2011.01.003

    CAS  Article  PubMed  Google Scholar 

  43. Vanden Heuvel JP, Kuslikis BI, Van Rafelghem MJ, Peterson RE (1991) Disposition of perfluorodecanoic acid in male and female rats. Toxicol Appl Pharmacol 107(3):450–459

    CAS  Article  Google Scholar 

  44. Verner MA, Ngueta G, Jensen ET et al (2016) A Simple pharmacokinetic model of prenatal and postnatal exposure to perfluoroalkyl substances (PFASs). Environ Sci Technol 50(2):978–986. https://doi.org/10.1021/acs.est.5b04399

    CAS  Article  PubMed  Google Scholar 

  45. Wang B, Chen Q, Shen L, Zhao S, Pang W, Zhang J (2016) Perfluoroalkyl and polyfluoroalkyl substances in cord blood of newborns in Shanghai, China: implications for risk assessment. Environ Int 97:7–14. https://doi.org/10.1016/j.envint.2016.10.008

    CAS  Article  PubMed  Google Scholar 

  46. Weaver YM, Ehresman DJ, Butenhoff JL, Hagenbuch B (2010) Roles of rat renal organic anion transporters in transporting perfluorinated carboxylates with different chain lengths. Toxicol Sci 113(2):305–314. https://doi.org/10.1093/toxsci/kfp275

    CAS  Article  PubMed  Google Scholar 

  47. WHO (2010) Characterization and application of physiologically based pharmacokinetic models in risk assessment. World Health Organization (IPCS, 2010). http://www.who.int/ipcs/methods/harmonization/areas/pbpk/en. https://doi.org/10.7748/ns.14.36.26.s40. Accessed 15 Aug 2018

    CAS  Article  Google Scholar 

  48. Wong F, MacLeod M, Mueller JF, Cousins IT (2014) Enhanced elimination of perfluorooctane sulfonic acid by menstruating women: evidence from population-based pharmacokinetic modeling. Environ Sci Technol 48(15):8807–8814. https://doi.org/10.1021/es500796y

    CAS  Article  PubMed  Google Scholar 

  49. Worley RR, Moore SM, Tierney BC et al (2017) Per- and polyfluoroalkyl substances in human serum and urine samples from a residentially exposed community. Environ Int 106:135–143. https://doi.org/10.1016/j.envint.2017.06.007

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. Wu H, Yoon M, Verner MA et al (2015) Can the observed association between serum perfluoroalkyl substances and delayed menarche be explained on the basis of puberty-related changes in physiology and pharmacokinetics? Environ Int 82:61–68. https://doi.org/10.1016/j.envint.2015.05.006

    CAS  Article  PubMed  Google Scholar 

  51. Ylinen M, Auriola S (1990) Tissue distribution and elimination of perfluorodecanoic acid in the rat after single intraperitoneal administration. Pharmacol Toxicol 66(1):45–48

    CAS  Article  Google Scholar 

  52. Zhang H, Yolton K, Webster GM et al (2018) Prenatal and childhood perfluoroalkyl substances exposures and children’s reading skills at ages 5 and 8 years. Environ Int 111:224–231. https://doi.org/10.1016/j.envint.2017.11.031

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgements

This research was supported by a grant from Ministry of Food and Drug Safety in 2014–2017 (14162MFDS703 and 17162MFDS117).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Hea-Young Cho.

Ethics declarations

Conflict of interest

The authors have declared no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kim, S., Choi, E., Choi, G. et al. Exploring sex differences in human health risk assessment for PFNA and PFDA using a PBPK model. Arch Toxicol 93, 311–330 (2019). https://doi.org/10.1007/s00204-018-2365-y

Download citation

Keywords

  • PBPK
  • Perfluorononanoic acid (PFNA)
  • Perfluorodecanoic acid (PFDA)
  • Human health risk assessment
  • Rat