Department of Environmental and Occupational Health, School of Public Health - Bloomington, Indiana University, Bloomington, IN, 47405, USA.
Department of Epidemiology and Biostatistics, School of Public Health - Bloomington, Indiana University, Bloomington, IN, 47405, USA.
Toxicology. 2021 May 15;455:152752. doi: 10.1016/j.tox.2021.152752. Epub 2021 Mar 16.
Abundant epidemiological evidence has shown that there is a strong causal relationship between long-term exposure to inorganic arsenic (iAs) through drinking water and a few types of cancer (e.g., lung and bladder cancer). Traditionally, a linear low-dose extrapolation assumption was applied in risk assessment for iAs which resulted in a relatively conservative cancer risk estimate. Growing biological evidence suggests that the mode of action of iAs-induced cancer follows a threshold process (e.g., sufficient concentration of trivalent arsenic is required to disrupt normal cellular function). In this study, we applied the benchmark dose (BMD) methodology to model the relationship between the relative risk of bladder and lung cancer and the iAs concentration in drinking water using the high-quality epidemiological data reported in recently published papers, with a special focus on the low exposure range (i.e., <150 μg/L). Because of its biological plausibility and statistical flexibility, the Hill model has been chosen to model the data under a Bayesian framework. A Bayesian hierarchal model together with a bootstrap method for exposure estimation were applied to quantify uncertainty from various sources, including the within-study, between-study, and exposure uncertainties. Dose-response assessment results obtained from a number of alternative model structures and methods consistently demonstrate a threshold type dose-response curve with a threshold in the range between 40-60 μg/L of iAs concentration in drinking water. The BMD for iAs in drinking water associated with 0.1 % increase in relative risk of bladder cancer is 42.2 μg/L (BMDL 39.2 μg/L); for 0.05 % increase, the BMD is 41.6 μg/L (BMDL 38.6 μg/L). For lung cancer, the two counterpart BMD estimates are 57.0 μg/L (BMDL 43.6 μg/L) and 55.7 μg/L (BMDL 42.5 μg/L) for 0.1 % and 0.05 % increase, respectively. These analyses provide additional statistical support for a non-linear dose response for cancer risk from inorganic arsenic which may have important policy implications.
大量的流行病学证据表明，长期通过饮用水摄入无机砷（iAs）与几种癌症（如肺癌和膀胱癌）之间存在很强的因果关系。传统上，在 iAs 的风险评估中应用线性低剂量外推假设，导致相对保守的癌症风险估计。越来越多的生物学证据表明，iAs 诱导癌症的作用模式遵循阈值过程（例如，需要三价砷的足够浓度来破坏正常细胞功能）。在这项研究中，我们应用基准剂量（BMD）方法，使用最近发表的论文中报告的高质量流行病学数据，在饮水 iAs 浓度与膀胱癌和肺癌相对风险之间建立关系模型，特别关注低暴露范围（即，<150μg/L）。由于其生物学合理性和统计灵活性，Hill 模型被选择用于贝叶斯框架下的数据建模。贝叶斯层次模型和暴露估计的自举方法被应用于量化来自不同来源的不确定性，包括研究内、研究间和暴露不确定性。从多种替代模型结构和方法获得的剂量-反应评估结果一致表明，存在阈值型剂量-反应曲线，阈值范围在饮用水中 iAs 浓度 40-60μg/L 之间。与膀胱癌相对风险增加 0.1%相关的饮水 iAs 的 BMD 为 42.2μg/L（BMDL 为 39.2μg/L）；对于增加 0.05%，BMD 为 41.6μg/L（BMDL 为 38.6μg/L）。对于肺癌，对应的两个 BMD 估计值分别为 57.0μg/L（BMDL 为 43.6μg/L）和 55.7μg/L（BMDL 为 42.5μg/L），分别对应于相对风险增加 0.1%和 0.05%。这些分析为无机砷致癌风险的非线性剂量反应提供了额外的统计支持，这可能具有重要的政策意义。
