Gradient, 20 University Road, Cambridge, MA 02138, USA.
Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, 4225 Roosevelt Way NE, Suite 301, Seattle, WA 98105, USA.
Environ Int. 2017 Sep;106:178-206. doi: 10.1016/j.envint.2017.04.008. Epub 2017 Jun 16.
Inorganic arsenic (iAs) in drinking water varies geographically and is prevalent worldwide. While exposures in the US are generally low, there are some areas with higher levels of naturally occurring iAs (potentially >100μg/L) where residents rely on unregulated drinking water wells. Much of the evidence on the association between iAs and cancer comes from epidemiological studies conducted in South American and Asian populations. These populations have generally been exposed to much higher levels of iAs and have differing underlying characteristics, both of which make comparing them to Western populations difficult. A key question is whether and how one should extrapolate from these high exposure studies to estimate cancer risk at lower exposures. We conducted an independent analysis to determine the most appropriate cancer endpoints, studies, and models to support an oral carcinogenicity assessment of iAs, taking into consideration factors that affect the apparent potency of iAs across geographically and culturally distinct populations. We identified bladder and lung cancer as high-priority endpoints and used meta-regression to pool data across studies from different regions of the world to derive oral cancer slope factors (CSFs) and unit risks (excess risk per μg/L) for iAs based on the background risks of bladder and lung cancer in the US. We also calculated concentrations of iAs in water that are not likely to result in cancer risk above what is considered acceptable by the United States Environmental Protection Agency (US EPA). While we derived these factors assuming a linear, no-threshold relationship between iAs and cancer risk, we also evaluated the shape of the dose-response curves and assessed the evidence for overall nonlinearity. Overall, we found that the incremental risks of bladder and lung cancer associated with iAs were relatively low. The sensitivity analyses we conducted suggested that populations with relatively high iAs exposures appeared to drive the pooled cancer risk estimates, but many of our other tested assumptions did not substantially alter these estimates. Finally, we found that the mode of action evidence supports there being a threshold, but making a robust quantitative demonstration of a threshold using epidemiological data is difficult. When considered in the context of typical exposure levels in the US, our potency estimates indicate that iAs-induced cancer risk is much lower than observed bladder and lung cancer incidences. This suggests that the low iAs levels to which much of the general US population is exposed likely do not result in substantial additional cancer risk.
饮用水中的无机砷（iAs）在地理上存在差异，并且在全球范围内普遍存在。虽然美国的暴露水平通常较低，但有些地区的天然 iAs 含量较高（可能 >100μg/L），居民依赖不受监管的饮用水井。关于 iAs 与癌症之间关联的大部分证据来自在南美洲和亚洲人群中进行的流行病学研究。这些人群通常受到更高水平的 iAs 暴露，并且具有不同的潜在特征，这使得将他们与西方人群进行比较变得困难。一个关键问题是是否以及如何从这些高暴露研究中推断出较低暴露水平下的癌症风险。我们进行了一项独立分析，以确定最合适的癌症终点、研究和模型，以支持对 iAs 的口服致癌性评估，同时考虑到影响不同地理位置和文化背景人群中 iAs 明显效力的因素。我们确定膀胱癌和肺癌为高优先级终点，并使用元回归来汇集来自世界各地不同地区的研究数据，以根据美国膀胱癌和肺癌的背景风险，为 iAs 推导口服癌症斜率因子（CSF）和单位风险（每μg/L 的超额风险）。我们还计算了水中 iAs 的浓度，这些浓度不太可能导致美国环境保护署（US EPA）认为可接受的癌症风险之上的风险。虽然我们假设 iAs 与癌症风险之间存在线性、无阈值关系来推导这些因素，但我们还评估了剂量-反应曲线的形状，并评估了整体非线性的证据。总体而言，我们发现与 iAs 相关的膀胱癌和肺癌的增量风险相对较低。我们进行的敏感性分析表明，iAs 暴露相对较高的人群似乎推动了汇总的癌症风险估计，但我们的许多其他测试假设并没有实质性改变这些估计。最后，我们发现作用模式证据支持存在阈值，但使用流行病学数据对阈值进行稳健的定量证明是困难的。当考虑到美国的典型暴露水平时，我们的效力估计表明，iAs 诱导的癌症风险远低于观察到的膀胱癌和肺癌发病率。这表明，美国大部分人群接触的低 iAs 水平不太可能导致实质性的额外癌症风险。
