College of Pharmacy, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju, 61186, Republic of Korea.
College of Pharmacy, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea.
Arch Toxicol. 2021 Jul;95(7):2385-2402. doi: 10.1007/s00204-021-03057-5. Epub 2021 Apr 27.
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.
邻苯二甲酸二异丁酯（DiBP）是一种常用于人类生活的物品生产中的物质。邻苯二甲酸单异丁酯（MiBP）是 DiBP 的主要体内代谢物，是 DiBP 暴露评估的生物标志物。因此，需要对尚未详细报道的 DiBP 和 MiBP 进行风险评估研究。本研究的目的是建立和评估大鼠体内 DiBP 和 MiBP 的基于生理学的药代动力学（PBPK）模型，并将其扩展到基于人体暴露的人体风险评估。在雄性大鼠中进行了 DiBP 给药后 5-100mg/kg 的药代动力学研究，并将这些结果用于 PBPK 模型的开发和验证。此外，还使用了雌性大鼠给药后 DiBP 的先前药代动力学结果以及雄性和雌性大鼠多次暴露于 DiBP 的药代动力学结果，用于开发和验证 PBPK 模型。DiBP 在体内转化为 MiBP 的代谢非常显著且迅速，MiBP 的生物分布广泛且主要。此外，体内 MiBP 的量与 DiBP 暴露量相关，由此开发了一个 PBPK 模型，以从 MiBP 的体内暴露来评估 DiBP 的外部暴露。使用开发的 PBPK 模型预测的大鼠血浆、尿液、粪便和组织浓度与观察值拟合良好。基于人体生理参数和比例缩放，将建立的大鼠 PBPK 模型外推到 DiBP 和 MiBP 的人体 PBPK 模型。根据韩国生物监测值，估算了 DiBP 的参考剂量 0.512mg/kg/天和 DiBP 的外部剂量 6.14-280.90μg/kg/天，用于人体风险评估。本研究为评估 DiBP 暴露相关的人体健康风险提供了有价值的见解和方法。
