Exponent, Bellevue, WA, USA.
Exponent, Menlo Park, CA, USA.
Toxicology. 2021 Jun 15;457:152801. doi: 10.1016/j.tox.2021.152801. Epub 2021 Apr 24.
Scientifically robust selections of epidemiological studies and assessments of the dose-response of inorganic arsenic in the low-dose range must consider key issues specific to arsenic in order to reduce risk of bias. The abundance of toxicological, mechanistic, and epidemiological evidence on arsenic enables a nuanced assessment of risk of bias in epidemiological studies of low-level arsenic, as opposed to a generic evaluation based only on standard principles. Important concepts in this context include 1) arsenic metabolism and mode of action for toxicity and carcinogenicity; 2) effects of confounding factors such as diet, health status including nutritional deficiencies, use of tobacco and other substances, and body composition; 3) strengths and limitations of various metrics for assessing relevant exposures consistent with the mode of action; and 4) the potential for bias in the positive direction for the observed dose-response relationship as exposure increases in the low-dose range. As an example, evaluation of a recent dose-response modeling using eight epidemiological studies of inorganic arsenic and bladder cancer demonstrated that the pooled risk estimate was markedly affected by the single study that was ranked as having a high risk of bias, based on the above factors. The other seven studies were also affected by these factors to varying, albeit lesser, degrees that can influence the apparent dose-response in the low-dose range (i.e., drinking water concentration of 65 µg/L or dose of approximately ≤1 µg/kg-day). These issues are relevant considerations for assessing health risks of oral exposures to inorganic arsenic in the U.S. population, and setting evidence-based regulatory limits to protect human health.
为了降低偏倚风险，必须科学地选择流行病学研究，并评估无机砷在低剂量范围内的剂量反应，同时考虑砷的一些关键问题。大量的毒理学、机制和流行病学证据使我们能够对低水平砷的流行病学研究中的偏倚风险进行细致的评估，而不是仅基于标准原则进行一般性评估。在这种情况下，重要的概念包括：1）砷的代谢和毒性及致癌作用的作用模式；2）混杂因素的影响，如饮食、健康状况（包括营养缺乏）、烟草和其他物质的使用以及身体成分；3）与作用模式一致的各种相关暴露评估指标的优缺点；4）在低剂量范围内暴露增加时，观察到的剂量反应关系存在正向偏倚的可能性。例如，对最近一项使用 8 项无机砷和膀胱癌流行病学研究进行的剂量反应建模评估表明，基于上述因素，该汇总风险估计受到单个高偏倚风险研究的显著影响。其他七项研究也受到这些因素的不同程度的影响，这些影响可能会影响低剂量范围内的表观剂量反应（即饮用水中浓度为 65μg/L 或剂量约为≤1μg/kg-天）。这些问题是评估美国人口口服暴露于无机砷的健康风险并制定基于证据的监管限制以保护人类健康的相关考虑因素。
