Department of Pathology and Microbiology, University of Nebraska Medical Center , Omaha, NE , USA .
Crit Rev Toxicol. 2013 Oct;43(9):711-52. doi: 10.3109/10408444.2013.827152.
Inorganic arsenic (iAs) at high exposures is a human carcinogen, affecting mainly the urinary bladder, lung and skin. We present an assessment of the mode of action (MOA) of iAs's carcinogenicity based on the United States Environmental Protection Agency/International Programme on Chemical Safety (USEPA/IPCS) framework, focusing primarily on bladder cancer. Evidence is presented for a MOA involving formation of reactive trivalent metabolites interacting with critical cellular sulfhydryl groups, leading to cytotoxicity and regenerative cell proliferation. Metabolism, kinetics, cell transport, and reaction with specific proteins play a critical role in producing the effects at the cellular level, regardless of cell type, whether urothelium, lung epithelium or epidermis. The cytotoxicity induced by iAs results in non-cancer toxicities, and the regenerative cell proliferation enhances development of epithelial cancers. In other tissues, such as vascular endothelium, different toxicities develop, not cancer. Evidence supporting this MOA comes from in vitro investigations on animal and human cells, from animal models, and from epidemiological studies. This MOA implies a non-linear, threshold dose-response relationship for both non-cancer and cancer end points. The no effect levels in animal models (approximately 1 ppm of water or diet) and in vitro (>0.1 µM trivalent arsenicals) are strikingly consistent. Cancer effects of iAs in humans generally are not observed below exposures of 100-150 ppb in drinking water: below these exposures, human urine concentrations of trivalent metabolites are generally below 0.1 µM, a concentration not associated with bladder cell cytotoxicity in in vitro or animal models. Environmental exposures to iAs in most of the United States do not approach this threshold.
无机砷（iAs）在高暴露水平下是一种人类致癌物质，主要影响膀胱、肺和皮肤。我们根据美国环境保护署/国际化学品安全方案（USEPA/IPCS）框架，对 iAs 致癌性的作用模式（MOA）进行评估，主要关注膀胱癌。有证据表明，其作用模式涉及形成与关键细胞巯基相互作用的反应性三价代谢物，导致细胞毒性和再生细胞增殖。代谢、动力学、细胞转运以及与特定蛋白质的反应在产生细胞水平的影响方面起着关键作用，而与细胞类型无关，无论是尿路上皮、肺上皮还是表皮。iAs 诱导的细胞毒性导致非癌症毒性，而再生细胞增殖增强了上皮癌的发展。在其他组织中，如血管内皮，会产生不同的毒性，而不是癌症。支持这种作用模式的证据来自于动物和人类细胞的体外研究、动物模型和流行病学研究。这种作用模式意味着非癌症和癌症终点都存在非线性、阈值剂量反应关系。动物模型（约 1ppm 的水或饮食）和体外（>0.1µM 三价砷化物）的无效应水平惊人地一致。在饮用水中暴露水平低于 100-150ppb 时，一般不会观察到 iAs 对人类的致癌作用：在这些暴露水平以下，人类尿液中三价代谢物的浓度通常低于 0.1µM，这一浓度与体外或动物模型中的膀胱细胞毒性无关。美国大部分地区的环境 iAs 暴露都不会接近这一阈值。
