Mechanistic PBPK/PD modeling of PFOS-associated cholesterol response and its application in human health risk assessment.

Authors

Go-Wun Choi, Dong Wook Kang, Ju Hee Kim, Hea-Young Cho

Published in

Environmental pollution (Barking, Essex : 1987). Pages 129008. Aug 21, 2026. Epub Aug 21, 2026.

Abstract

The present study aims to develop a PBPK/PD model of PFOS in rats and its extrapolation to humans for risk assessment. Age effect was explored in rats as a potential covariate impact on the pharmacokinetics of PFOS. Peri-adolescent rats showed lower exposure to PFOS compared to adult rats, suggesting immature reabsorption. Therefore, ontogenic development process was applied to the PBPK model for body weight, transport maximum (T_m), and distribution parameters in rats. Cholesterol level was selected as a pharmacodynamic (PD) biomarker with an indirect PD response model. The human PBPK model was developed through extrapolation from rats by applying allometric scaling. Furthermore, literature epidemiology data were used to build a PD response model in humans, with an association-based PD response model linking PFOS exposure to cholesterol production rate. The developed PBPK/PD model in humans was applied to risk assessment for forward and reverse dosimetry to set the threshold estimate of daily intake (EDI) and to investigate the current health risk of PFOS using Korean biomonitoring data, respectively. The threshold EDI was calculated for a target of 5% cholesterol increase using a Markov chain Monte Carlo simulation with a value of 3.48 ng/kg/day for the adult population. The estimated EDI was 1.02 ng/kg/day by reverse dosimetry in adults. The predicted increase in cholesterol was below 5% of the population median in every age group, although the 95^th percentile in the geriatric group reached 6.9%. In conclusion, the present study provides a mechanistic framework for integrating ontogenic development and PD response with the PBPK model for risk assessment.

PMID:
42628899
Bibliographic data and abstract were imported from PubMed on 22 Aug 2026.

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