Chen Chu-Chih, Liu Chia-Chu, Wang Yin-Han, Wu Chia-Fang, Tsai Yi-Chun, Li Sih-Syuan, Hsieh Tusty-Jiuan, Wu Ming-Tsang
Institute of Population Health Sciences, National Health Research Institutes, 35 Keyan Road, Miaoli 350401, Taiwan.
Research Center for Precision Environmental Medicine, Kaohsiung Medical University, Room 721, CS Research Building, 100 Shih-Chuan 1st Road, Kaohsiung 807378, Taiwan.
Toxics. 2024 Aug 11;12(8):584. doi: 10.3390/toxics12080584.
Establishing a safe exposure level from epidemiological studies while providing direct hazard characterization in humans often faces uncertainty in causality, especially cross-sectional data. With advances in molecular epidemiology, it is reasonable to integrate identified intermediate biomarkers into health risk assessment. In this study, by considering the mediation of the oxidative stress marker malondialdehyde (MDA), we explored the exposure threshold of melamine on the early renal injury marker N-acetyl-β-D glucosaminidase (NAG). The benchmark dose (BMD) was derived from model averaging of the composite direct effect of melamine exposure and the indirect effect through the mediation of MDA on NAG levels. As illustrative examples, we analyzed 309 adult patients with calcium urolithiasis and 80 occupational workers for the corresponding exposure thresholds. The derived threshold was subpopulation-dependent, with the one-sided lower bound BMDL for the patients with urolithiasis with (without) the mediator MDA for the patients with kidney stones and the occupational workers being 0.88 (0.96) μg/kg_bw/day and 22.82 (18.09) μg/kg_bw/day, respectively. The derived threshold levels, considering the oxidative stress marker MDA, were consistent with those without adjusting for the mediation effect. However, the study outcomes were further supported by the suggested mechanism pathway. The threshold for the patients with urolithiasis was up to two orders lower than the current tolerable daily intake level of 200 μg/kg_bw/day recommended by the WHO (EFSA).
从流行病学研究中确定安全暴露水平，同时在人体中进行直接危害特征描述，往往面临因果关系的不确定性，尤其是横断面数据。随着分子流行病学的发展，将已确定的中间生物标志物纳入健康风险评估是合理的。在本研究中，通过考虑氧化应激标志物丙二醛（MDA）的介导作用，我们探讨了三聚氰胺对早期肾损伤标志物N-乙酰-β-D-氨基葡萄糖苷酶（NAG）的暴露阈值。基准剂量（BMD）来自三聚氰胺暴露的复合直接效应以及通过MDA介导对NAG水平的间接效应的模型平均。作为示例，我们分析了309例成年钙尿路结石患者和80名职业工人的相应暴露阈值。得出的阈值依赖于亚组，对于有（无）介导物MDA的尿路结石患者和职业工人，肾结石患者的单侧下限BMDL分别为0.88（0.96）μg/kg_bw/天和22.82（18.09）μg/kg_bw/天。考虑氧化应激标志物MDA得出的阈值水平与未调整介导效应时的阈值一致。然而，研究结果得到了所提出的机制途径的进一步支持。尿路结石患者的阈值比世界卫生组织（欧洲食品安全局）建议的当前每日可耐受摄入量200μg/kg_bw/天低两个数量级。
