Archives of Toxicology

, Volume 93, Issue 2, pp 311–330 | Cite as

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

  • Sook-Jin Kim
  • Eun-Jeong Choi
  • Go-Wun Choi
  • Yong-Bok Lee
  • Hea-Young ChoEmail author
Toxicokinetics and Metabolism


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.


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



Area under the concentration–time curve from zero to infinity




Maximum plasma concentration


Steady-state concentration


Free fraction in plasma




Tissue-to-plasma partition coefficient


Rate constant to storage compartment


Transporter affinity constant


Urinary elimination rate constant


Margin of exposure


No-observed-adverse-effect level


Physiologically based pharmacokinetic model


Perfluoroalkyl and polyfluoroalkyl substances


Perfluorohexanesulfonic acid


Perfluorodecanoic acid


Perfluorononanoic acid


Perfluorooctanoic acid


Perfluorooctanesulfonic acid




Point of departure


The elimination half-life


The tolerable daily intake


Transport maximum


Uncertainty factor


Uncertainty factor for interspecies extrapolation from rats to humans


Uncertainty factor for inter-individual variability in humans


Uncertainty factor for subchronic to chronic extrapolation


Volume of distribution



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

Compliance with ethical standards

Conflict of interest

The authors have declared no conflict of interest.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.College of PharmacyCHA UniversitySeongnam-siRepublic of Korea
  2. 2.College of PharmacyChonnam National UniversityGwangjuRepublic of Korea

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