Archives of Toxicology

, Volume 92, Issue 3, pp 1113–1131 | Cite as

Sex-specific risk assessment of PFHxS using a physiologically based pharmacokinetic model

  • Sook-Jin Kim
  • Hwajin Shin
  • Yong-Bok Lee
  • Hea-Young Cho
Toxicokinetics and Metabolism
  • 168 Downloads

Abstract

Perfluorohexanesulfonate (PFHxS), which belongs to the group of perfluoroalkyl and polyfluoroalkyl substances (PFASs), has been extensively used in industry and subsequently detected in the environment. Its use may be problematic, as PFHxS is known to induce neuronal cell death, and has been associated with early onset menopause in women and with attention deficit/hyperactivity disorder. Due to these impending issues, the aim of this study is to develop and evaluate a physiologically based pharmacokinetic (PBPK) model for PFHxS in male and female rats, and apply this to a human health risk assessment. We conducted this study in vivo after the oral or intravenous administration of PFHxS in male (dose of 10 mg/kg) and female rats (dose of 0.5–10 mg/kg). The biological samples consisted of plasma, nine tissues, urine, and feces. We analyzed the sample using ultra-liquid chromatography coupled tandem mass spectrometry (UPLC–MS/MS). Our findings showed the tissue-plasma partition coefficients for PFHxS were highest in the liver. The predicted rat plasma and tissue concentrations using a simulation fitted well with the observed values. We extrapolated the PBPK model in male and female rats to a human PBPK model of PFHxS based on human physiological parameters. The reference doses of 0.711 µg/kg/day (male) and 0.159 µg/kg/day (female) and external doses of 0.007 µg/kg/day (male) and 0.006 µg/kg/day (female) for human risk assessment were estimated using Korean biomonitoring values. This study provides valuable insight into human health risk assessment regarding PFHxS exposure.

Keywords

PBPK Perfluorohexanesulfonate (PFHxS) Human health risk assessment Rat 

Abbreviations

AUC0−∞

Area under the concentration–time curve from zero to infinity

CL

Clearance

Cmax

Maximum plasma concentration

Css

Steady-state concentration

Fr

Free fraction in plasma

IV

Intravenous

Kp

Tissue-to-plasma partition coefficient

Kst

Rate constant to storage compartment

Kt

Transporter affinity constant

Ku

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

Perfluorohexanesulfonate

PFOA

Perfluorooctanoic acid

PFOS

Perfluorooctane sulfonate

PK

Pharmacokinetic

POD

Points of departure

RfD

Reference dose

t1/2

The elimination half-life

Tm

Transporter 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

UPLC-MS/MS

Ultra-liquid chromatography coupled tandem mass spectrometry

Vd

Volume of distribution

Notes

Acknowledgements

This research was supported by a Grant from the 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.

Supplementary material

204_2017_2116_MOESM1_ESM.docx (51 kb)
Supplementary material 1 (DOCX 48 KB)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2017

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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