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. 2020 Jul;94(7):2377-2400. doi: 10.1007/s00204-020-02748-9. Epub 2020 Apr 17.
Diethyl phthalate (DEP) belongs to phthalates with short alkyl chains. It is a substance frequently used to make various products. Thus, humans are widely exposed to DEP from the surrounding environment such as food, soil, air, and water. As previously reported in many studies, DEP is an endocrine disruptor with reproductive toxicity. Monoethyl phthalate (MEP), a major metabolite of DEP in vivo, is a biomarker for DEP exposure assessment. It is also an endocrine disruptor with reproductive toxicity, similar to DEP. However, toxicokinetic studies on both MEP and DEP have not been reported in detail yet. Therefore, the objective of this study was to evaluate and develop physiologically based pharmacokinetic (PBPK) model for both DEP and MEP in rats and extend this to human risk assessment based on human exposure. This study was conducted in vivo after intravenous or oral administration of DEP into female (2 mg/kg dose) and male (0.1-10 mg/kg dose) rats. Biological samples consisted of urine, plasma, and 11 different tissues. These samples were analyzed using UPLC-ESI-MS/MS method. For DEP, the tissue to plasma partition coefficient was the highest in the kidney, followed by that in the liver. For MEP, the tissue to plasma partition coefficient was the highest in the liver. It was less than unity in all other tissues. Plasma, urine, and fecal samples were also obtained after IV administration of MEP (10 mg/kg dose) to male rats. All results were reflected in a model developed in this study, including in vivo conversion from DEP to MEP. Predicted concentrations of DEP and MEP in rat urine, plasma, and tissue samples using the developed PBPK model fitted well with observed values. We then extrapolated the PBPK model in rats to a human PBPK model of DEP and MEP based on human physiological parameters. Reference dose of 0.63 mg/kg/day (or 0.18 mg/kg/day) for DEP and external doses of 0.246 μg/kg/day (pregnant), 0.193 μg/kg/day (fetus), 1.005-1.253 μg/kg/day (adults), 0.356-0.376 μg/kg/day (adolescents), and 0.595-0.603 μg/kg/day (children) for DEP for human risk assessment were estimated using Korean biomonitoring values. Our study provides valuable insight into human health risk assessment regarding DEP exposure.
邻苯二甲酸二乙酯（DEP）属于短链烷基邻苯二甲酸酯。它是一种常用于制造各种产品的物质。因此，人类广泛接触来自周围环境的 DEP，如食物、土壤、空气和水。正如许多研究之前报道的那样，DEP 是一种具有生殖毒性的内分泌干扰物。单乙基邻苯二甲酸酯（MEP）是 DEP 在体内的主要代谢物，是 DEP 暴露评估的生物标志物。它也是一种具有生殖毒性的内分泌干扰物，与 DEP 相似。然而，关于 MEP 和 DEP 的毒代动力学研究尚未详细报道。因此，本研究的目的是评估和建立大鼠体内 DEP 和 MEP 的基于生理学的药代动力学（PBPK）模型，并基于人体暴露将其扩展到人体风险评估。这项研究是在雌性（2mg/kg 剂量）和雄性（0.1-10mg/kg 剂量）大鼠静脉或口服给予 DEP 后进行的体内研究。生物样本包括尿液、血浆和 11 种不同的组织。这些样本使用 UPLC-ESI-MS/MS 方法进行分析。对于 DEP，组织与血浆的分配系数在肾脏中最高，其次是在肝脏中。对于 MEP，组织与血浆的分配系数在肝脏中最高，在所有其他组织中均小于 1。雄性大鼠静脉给予 MEP（10mg/kg 剂量）后还获得了血浆、尿液和粪便样本。所有结果都反映在本研究中建立的模型中，包括从 DEP 到 MEP 的体内转化。使用所开发的 PBPK 模型预测的大鼠尿液、血浆和组织样本中的 DEP 和 MEP 浓度与观察值拟合良好。然后，我们根据人体生理参数将大鼠的 PBPK 模型外推到 DEP 和 MEP 的人体 PBPK 模型。根据韩国生物监测值，为 DEP 估计了 0.63mg/kg/天（或 0.18mg/kg/天）的参考剂量，以及 0.246μg/kg/天（孕妇）、0.193μg/kg/天（胎儿）、1.005-1.253μg/kg/天（成人）、0.356-0.376μg/kg/天（青少年）和 0.595-0.603μg/kg/天（儿童）的 DEP 人体风险评估的外推剂量。我们的研究为 DEP 暴露的人体健康风险评估提供了有价值的见解。
