Abstract
Di-isobutyl phthalate (DiBP) is a substance used in the production of objects frequently used in human life. Mono-isobutyl phthalate (MiBP), a major in vivo metabolite of DiBP, is a biomarker for DiBP exposure assessment. Therefore, risk assessment studies on DiBP and MiBP, which have not yet been reported in detail, are needed. The aim of this study was to develop and evaluate a physiologically based pharmacokinetic (PBPK) model for DiBP and MiBP in rats and extend this to human risk assessment based on human exposure. Pharmacokinetic studies were performed in male rats following the administration of 5–100 mg/kg DiBP, and these results were used for the development and validation of the PBPK model. In addition, the previous pharmacokinetic results in female rats following DiBP administration and the pharmacokinetic results in both males and females according to multiple exposures to DiBP were used to develop and validate the PBPK model. The metabolism of DiBP to MiBP in the body was very significant and rapid, and the biodistribution of MiBP was broad and major. Furthermore, the amount of MiBP in the body showed a correlation with DiBP exposure, and from this, a PBPK model was developed to evaluate the external exposure of DiBP from the internal exposure of MiBP. The predicted rat plasma, urine, fecal, and tissue concentrations using the developed PBPK model fitted well with the observed values. The established PBPK model for rats was extrapolated to a human PBPK model of DiBP and MiBP based on human physiological parameters and allometric scaling. The reference dose of 0.512 mg/kg/day of DiBP and external doses of 6.14–280.90 μg/kg/day DiBP for human risk assessment were estimated using Korean biomonitoring values. Valuable insight and approaches to assessing human health risks associated with DiBP exposure were provided by this study.
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Abbreviations
- DiBP:
-
Di-isobutyl phthalate
- MiBP:
-
Mono-isobutyl phthalate
- PBPK:
-
Physiologically based pharmacokinetic
- UHPLC–ESI-MS/MS:
-
Ultrahigh-performance liquid chromatography–electrospray ionization-mass spectrometry
- HPLC:
-
High-performance liquid chromatography
- IS:
-
Internal standard
- LLOQ:
-
Lower limit of quantification
- PEG:
-
Polyethylene glycol
- PBS:
-
Phosphate-buffered saline
- GI:
-
Gastrointestinal
- ESI:
-
Electrospray ionization
- SD:
-
Standard deviation
- NOAEL:
-
No-observed-adverse-effect level
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Acknowledgements
This research was also supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (No. 2020R1A6A3A13074075).
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S-HJ: conceptualization, investigation, methodology, writing—original draft, writing—review and editing, software, data analysis, and visualization; J-HJ: conceptualization, investigation, writing—review and editing, software, and data analysis; H-YC: writing—review, project administration, and conceptualization; Y-BL: conceptualization, methodology, writing—review and editing, funding acquisition, and supervision.
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Jeong, SH., Jang, JH., Cho, HY. et al. Human risk assessment of di-isobutyl phthalate through the application of a developed physiologically based pharmacokinetic model of di-isobutyl phthalate and its major metabolite mono-isobutyl phthalate. Arch Toxicol 95, 2385–2402 (2021). https://doi.org/10.1007/s00204-021-03057-5
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DOI: https://doi.org/10.1007/s00204-021-03057-5