College of Pharmacy, Sunchon National University, 255 Jungang-ro, Suncheon-si, Jeollanam-do, 57922, Republic of Korea; College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, Suncheon-Si 57922, Republic of Korea.
College of Pharmacy, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju, 61186, Republic of Korea.
Environ Pollut. 2023 Nov 1;336:122388. doi: 10.1016/j.envpol.2023.122388. Epub 2023 Aug 18.
Age-related changes and interindividual variability in the degree of exposure to hazardous substances in the environment are pertinent factors to be considered in human risk assessment. Existing risk assessments remain in a one-size-fits-all approach, often without due consideration of inter-individual toxicokinetic variability factors, such as age. The purpose of this study was to advance from the existing risk assessment of hazardous substances based on toxicokinetics to a precise human risk assessment by additionally considering the effects of physiologic and metabolic fluctuations and interindividual variability in age. Qualitative age-associated physiologic and metabolic changes in humans, obtained through a meta-analysis, were quantitatively modeled to produce the final biological age algorithm (BAA). The developed BAAs (for males) were extended and applied to the reported testicular reproductive toxicity-focused di-isobutyl-phthalate (DiBP)-mono-isobutyl-phthalate (MiBP) physiologically based toxicokinetic (PBTK) model in males. The advanced PBTK model combined with the BAA was applied to the human risk assessment based on MiBP biomonitoring data. As a result, the specialized DiBP external exposure values for each age could be estimated. Additionally, by applying the Monte Carlo simulation, the distribution of internal exposure diversity among individuals according to the same external exposure dose could be estimated. The contributions of physiologic and metabolic factors to the age-dependent toxicokinetic changes were approximately 93.41-99.99 and 0.01-6.59%, respectively. In addition, the relative contribution of metabolic factors was major in infants and continued to decrease as age increased (up to about age 30 years). This study provides a step-by-step platform that can be widely applied to overcome the limitations of existing toxicokinetic models that still require interindividual pharmacokinetic variability explanations. This will be important for the rationalization and explanation of inter-individual variability in the pharmacokinetics of many substances.
与环境中有害物质接触程度的年龄相关变化和个体间差异是人类风险评估中需要考虑的相关因素。现有的风险评估仍然采用一刀切的方法，通常没有充分考虑个体间毒代动力学变异性因素，如年龄。本研究旨在从现有的基于毒代动力学的危险物质风险评估方法，通过进一步考虑生理和代谢波动以及年龄个体间变异性的影响，推进到精确的人类风险评估。通过荟萃分析获得的人类与年龄相关的定性生理和代谢变化被定量建模，以产生最终的生物年龄算法 (BAA)。开发的 BAA（男性）被扩展并应用于报告的睾丸生殖毒性为重点的邻苯二甲酸二异丁酯（DiBP）-单异丁基邻苯二甲酸酯（MiBP）雄性生理毒物动力学（PBTK）模型。先进的 PBTK 模型结合 BAA 应用于基于 MiBP 生物监测数据的人类风险评估。结果，可以估计每个年龄的专门 DiBP 外部暴露值。此外，通过应用蒙特卡罗模拟，可以估计根据相同的外部暴露剂量个体内部暴露多样性的分布。生理和代谢因素对年龄依赖性毒代动力学变化的贡献分别约为 93.41-99.99%和 0.01-6.59%。此外，代谢因素的相对贡献在婴儿中较大，并随着年龄的增长而持续下降（约 30 岁左右）。本研究提供了一个逐步的平台，可以广泛应用于克服现有毒代动力学模型仍然需要个体间药代动力学变异性解释的局限性。这对于许多物质药代动力学个体间变异性的合理化和解释将是重要的。
