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.
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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
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This research was supported by a grant from Ministry of Food and Drug Safety in 2014–2017 (14162MFDS703 and 17162MFDS117).
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Kim, SJ., Choi, EJ., Choi, GW. 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
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DOI: https://doi.org/10.1007/s00204-018-2365-y