De Flora Silvio, D'Agostini Francesco, Balansky Roumen, Micale Rosanna, Baluce Barbara, Izzotti Alberto
Department of Health Sciences, University of Genoa, Via A. Pastore 1, I-16132 Genoa, Italy.
Mutat Res. 2008 Jul-Aug;659(1-2):60-7. doi: 10.1016/j.mrrev.2007.11.005. Epub 2007 Nov 19.
Chromium(VI) is genotoxic when tested in vitro or injected parenterally in such a way to escape detoxification mechanisms. However, its genotoxicity and potential carcinogenicity are lost, depending on dose and administration route, due to efficient reduction in body fluids and nontarget cells. Chromium(VI) is a Group 1 IARC carcinogen, but only in the respiratory tract and in well-defined occupational settings that involved heavy exposures. Recently, concern has been expressed that oral chromium(VI) may be a gastric carcinogen. We demonstrated that administration of very high doses of chromium(VI) with the drinking water does not induce any clastogenic effect in hematopoietic cells of adult mice and their fetuses. Thereafter, we investigated whether administration of chromium(VI) with the drinking water may induce local genotoxic effects in the gastrointestinal tract. Sodium dichromate dihydrate was administered to mice for 9 consecutive months, at doses corresponding to 5 and 20 mg chromium(VI)/l, which exceed drinking water standards by 100 and 400 times, respectively. Under these conditions, chromium(VI) failed to enhance the frequency of DNA-protein crosslinks and did not cause oxidative DNA damage, measured in terms of 8-oxo-2'-deoxyguanosine, in the forestomach, glandular stomach and duodenum. When cells from the same organs were isolated and challenged in vitro with chromium(VI), as positive controls, the same genotoxicity biomarkers were evidently affected. Thus, consistently with the knowledge accumulated in 50 years of research on chromium(VI) kinetics and metabolism, oral chromium(VI) appears to be devoid of genotoxicity in the gastrointestinal tract. After 9 months, we did not observe any variation of tumor yield in skin, lung, forestomach, glandular stomach, and duodenum of chromium(VI)-treated mice. These results are discussed in the light of literature data, also including a recent 2-year carcinogenicity study performed by the National Toxicology Program.
六价铬在体外进行测试或以能避开解毒机制的方式经肠外注射时具有基因毒性。然而，由于体液和非靶细胞中的有效还原作用，根据剂量和给药途径的不同，其基因毒性和潜在致癌性会消失。六价铬是国际癌症研究机构（IARC）第1组致癌物，但仅在呼吸道以及涉及大量暴露的明确职业环境中如此。最近，有人担心口服六价铬可能是一种胃癌致癌物。我们证明，给成年小鼠及其胎儿饮用含极高剂量六价铬的水，不会在其造血细胞中诱导任何致断裂效应。此后，我们研究了给小鼠饮用含六价铬的水是否会在胃肠道中诱导局部基因毒性效应。将二水合重铬酸钠连续9个月给予小鼠，剂量分别相当于5和20毫克六价铬/升，这分别比饮用水标准高出100倍和400倍。在这些条件下，六价铬未能提高DNA-蛋白质交联的频率，也未在森林胃、腺胃和十二指肠中造成以8-氧代-2'-脱氧鸟苷衡量的氧化性DNA损伤。当从相同器官分离细胞并在体外以六价铬进行攻击作为阳性对照时，相同的基因毒性生物标志物明显受到影响。因此，与50年关于六价铬动力学和代谢的研究所积累的知识一致，口服六价铬在胃肠道中似乎没有基因毒性。9个月后，我们在接受六价铬处理的小鼠的皮肤、肺、森林胃、腺胃和十二指肠中未观察到肿瘤发生率有任何变化。我们根据文献数据，包括美国国家毒理学计划最近进行的一项为期两年的致癌性研究，对这些结果进行了讨论。
