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

Kim, Sook-Jin; Shin, Hwajin; Lee, Yong-Bok; Cho, Hea-Young

doi:10.1007/s00204-017-2116-5

Toxicokinetics and Metabolism
Published: 16 November 2017

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

Archives of Toxicology volume 92, pages 1113–1131 (2018)Cite this article

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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.

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Abbreviations

AUC_0−∞ :: 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
K _p :: 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:: Perfluorohexanesulfonate
PFOA:: Perfluorooctanoic acid
PFOS:: Perfluorooctane sulfonate
PK:: Pharmacokinetic
POD:: Points of departure
RfD:: Reference dose
t _1/2 :: The elimination half-life
T _m :: Transporter maximum
UF:: Uncertainty factor
UF_A :: Uncertainty factor for interspecies extrapolation from rats to humans
UF_H :: Uncertainty factor for inter-individual variability in humans
UF_S :: Uncertainty factor for subchronic to chronic extrapolation
UPLC-MS/MS:: Ultra-liquid chromatography coupled tandem mass spectrometry
V _d :: Volume of distribution

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Acknowledgements

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

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College of Pharmacy, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea
Sook-Jin Kim, Hwajin Shin & Hea-Young Cho
College of Pharmacy, Chonnam National University, 77 Yongbong-ro, Buk-Gu, Gwangju, 61186, Republic of Korea
Yong-Bok Lee

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Sook-Jin Kim
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Hwajin Shin
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Yong-Bok Lee
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Hea-Young Cho
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Correspondence to Hea-Young Cho.

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

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Received: 05 October 2017
Accepted: 08 November 2017
Published: 16 November 2017
Issue Date: March 2018
DOI: https://doi.org/10.1007/s00204-017-2116-5

Keywords

PBPK
Perfluorohexanesulfonate (PFHxS)
Human health risk assessment
Rat