ⅥTrace Elements

Trace Elements and

JMAJ 47(8): 391–395, 2004

Hiroyuki FUKUDA*1†, Masaaki EBARA*2†, Hiroyuki YAMADA†, Manaka ARIMOTO†, Shinichiro OKABE†, Masamichi OBU†, Masaharu YOSHIKAWA*1†, Nobuyuki SUGIURA*3† and Hiromitsu SAISHO*4†

*1†Research Associate, *2†Assistant Professor, *3† Lecturer, *4† Professor, † Department of Medicine and Clinical , Graduate School of Medicine, Chiba University

Abstract: In regard to iron, malignant are often seen in various organs in idiopathic hemochromatosis, and complication by lung cancer is especially common. In regard to the carcinogenicity of copper, large amounts of copper and iron have been reported to accumulate in the liver and spleen of patients with cancer of the respiratory tract, urinary tract, and thorax. Increases in skin and pulmonary epithelial cancer, and the precancerous condition cutaneous keratosis (Bowen’s ) are seen as a result of chronic oral or airway exposure to arsenic. In addition, there is a report that has been observed in aplastic anemia and a report that arsenic causes cancer of the bladder, kidney, digestive tract, and liver, etc. Lung cancer is cited in associations between chromium and . Nickel has been reported to be associated with lung cancer and nasal cavity cancer. High mortality from lung cancer in factories handling beryllium and increased tumors of the central nervous system have also been suggested. Key words: Trace element; Cancer; Metal carcinogenicity

Introduction Carcinogenicity of Metals

Arsenic, chromium, and nickel are said to 1. Iron contribute to the development of cancer based and skin have been reported on the epidemiologic evidence, and beryllium, to have developed when animals were intra- cadmium, chromium, cobalt, lead, nickel, zinc, muscularly injected with iron dextran.1) Boyd and iron have been found to be carcinogenic in et al.2) reported an association between iron experimental animals. In this paper, we will ore miners and the incidence of lung cancer, describe the carcinogenicity of a variety of but it also appeared that they may have been metals. exposed to radon, which was also present, and

This article is a revised English version of a paper originally published in the Journal of the Japan Medical Association (Vol. 129, No. 5, 2003, pages 646–648).

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smoking. gel-filtration method, the increased copper in Various malignant neoplasms of different hepatocellular also appears to exist organs are often seen in idiopathic hemo- in the form of Cu-MT and hydroxyl radicals are chromatosis, but liver cancer is an especially generated by a Fenton-like reaction, and simi- common complication.3) The mechanisms of larities to LEC rats have been found. Hydroxyl the hepatocarcinogenesis are thought to be radicals form the DNA damage marker 8- that iron bound to low-molecular protein in OHdG (hydroxydeoxyguanosine), and tissue the liver generates hydroxyl radicals via the 8-OHdG levels have been shown to be high in Fenton reaction that damage DNA, and a chronic hepatitis, liver cirrhosis, and hepato- direct action of iron on the replication process cellular carcinoma.9) of the DNA. In a study of iron deposits in the surrounding liver parenchyma in a group of 3. Zinc HCV-positive liver cirrhosis patients with liver Zinc deficiency causes dermatitis, alopecia, cancer and a group without liver cancer, the and taste disorders, and excessive intake can iron deposits were reported to be clearly more cause acute poisoning. In experimental models, common in the group with liver cancer.4) development of teratomas and cancers were observed when zinc chloride was injected into 2. Copper the testes of chicks and rats.10) Accumulation of large amounts of copper No epidemiologic evidence of any type of and iron has been reported in the liver and increased cancer incidence has yet been obtained spleen of patients with cancer of the respira- in zinc factory workers or ordinary popula- tory tract, urinary tract, and thorax,5) and the tions. Zinc is a component of SOD (superoxide copper content of benign tumors of the esoph- dismutase), an enzyme that removes free radi- agus, bronchi, and intestine is said to be lower cals, and since it is also necessary for activation than in cancers. of DNA repair enzymes, zinc has the opposite LEC rats (Long-Evans rats with cinnamon- effect and protects against carcinogenesis. like color) are animal models of Wilson disease, in which copper accumulates in liver tissue. The 4. Arsenic animals develop hepatitis at 4 months of age In a study in which carcinogenesis was and approximately 40% die, and at approxi- observed when animals were exposed to arsenic, mately 1 year of age those that survive develop Yamamoto11) et al. reported that bladder, kidney, liver cancer via cirrhotic change. Gel-filtration liver, and thyroid tumors were induced when analyses have shown that the majority of the rats were given another initiator at the same increased copper exists in the form of Cu-MT time as a dimethylarsinic acid solution, and the (copper-metallothionein),6) and it is thought development of skin, lung, and bladder tumors that hydroxyl radicals are generated in the was later reported in mice and rats. Increases presence of hydrogen peroxide as a result of a in skin and pulmonary epithelial cancer,12) and Fenton-like reaction and cause hepatitis and the development of precancerous cutaneous hepatocarcinogenesis. keratosis (Bowen’s disease) are seen when Liver tissue copper content increases in chronically exposed orally or via the airway. human chronic hepatitis C and liver cirrhosis In addition, there have been reports of as the liver disease progresses,7) and the copper leukemia in aplastic anemia and of arsenic content of well differentiated hepatocellular causing cancer of the bladder, kidney, digestive carcinoma becomes significantly greater than tract, liver, etc. The carcinogenetic mechanism that of moderately or poorly differentiated is unknown, but there have been reports that hepatocellular carcinoma.8) According to the arsenic compounds inhibit methyl thymidine

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uptake by human skin cells in vitro and inhibit kinase phosphorylation, and is said to possibly DNA synthesis. Chromosome abnormalities exert an effect on . Since it also inter- have been observed when human leukocytes or feres with proper chromosome arrangement cutaneous fibroblasts were exposed, and there during cell division, the risk of carcinogenicity is a report that it is due to DNA binding becom- cannot be ruled out. An association is also said ing weaker as a result of substitution for phos- to exist between the vanadium concentration in phorus in DNA. air and lung cancer, but no clear causality has been established.15) 5. Chromium An association between chromium and car- 8. Beryllium cinogenesis has been pointed out in regard to Lung tumors have been observed in carcino- lung cancer. A high incidence of lung cancer genesis experiments in response to intratra- has been demonstrated as an occupational cheal administration, inhalation exposure, and disease among workers engaged in the chro- intraperitoneal administration, and develop- mate production process in Germany and the ment of osteosarcoma has been reported after United States.13) The risk of lung cancer among intravenous administration. Carcinogenicity in chromium workers compared to an ordinary humans has been suggested by high mortality population is very high, with a lung cancer from lung cancer in factories handling beryl- prevalence rate 100,000 versus 578, and the lium16) and by increases in tumors of the central relative risk from the standpoint of lung cancer nervous system. deaths has reached from 3.6 to 29.1. Histo- The carcinogenetic mechanism is thought to pathologically, the most common chromium- be inhibition of the enzymes required for DNA related lung cancers are squamous cell carcino- synthesis, such as thymidine kinase, thymidine mas and small cell cancers. synthase, and DNA polymerase.

6. Nickel 9. Lead In experiments on rats, induction of rhabdo- Renal cancer has been reported in rats and myosarcoma was reported as a result of intra- mice subcutaneously injected with lead phos- muscular injection of nickel subsulfate, and phate.17) There are also reports of lung cancer development of in various organs has in hamsters after simultaneous intratracheal been reported as a result of intravenous injec- administration of lead oxide and benzpyrene, tion of nickel carbon. Lung cancer developed and of development of brain tumors when lead when cats were allowed to inhale nickel dust, acetate was orally administered to rats. A slight and high rates of lung cancer and cancer of association with the development of lung can- the nasal cavity have been found in nickel cer, stomach cancer, and brain tumors has been refinery workers.14) The principal reported in workers in a lead smelter, and in are thought to be inhaled nickel particles and lead poisoning,18) but lead has not been defi- nickel oxide. nitely concluded to be carcinogenic in humans. The carcinogenetic mechanism is assumed to 7. Vanadium be interference with the DNA repair process, Vanadium has been negative in many bacte- but the details are currently unknown. rial tests for mutagenicity. It is not recognized as possessing carcinogenic activity, and no asso- 10. Cadmium ciation has been found with cancer in humans DNA fragmentation and chromosome muta- or animals. Nevertheless, vanadium promotes tions have been reported in cultured human cell mutation in some cells, causes tyrosine cells, sarcoma and testicular interstitial cell

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tumors have been reported as a result of injec- metabolism in hemochromatosis. Medicine tions in rats, and an association with prostate (Baltimore) 1955; 34: 381–430. cancer has been reported in humans, but ques- 4) Chapoutot, C., Esslimani, M., Joomaye, Z. et tions about the carcinogenicity of cadmium al.: Liver iron excess in patients with hepato- cellular carcinoma developed on viral C cir- have arisen based on recent epidemiologic 19) rhosis. Gut 2000; 46: 711–714. research. 5) Sandberg, M., Gross, H. and Holly, O.M.: Changes in retention of copper and iron in 11. Cobalt liver and spleen in chronic accom- The mechanism of gene mutations by cobalt panied by secondary anemia. Arch Path 1942; is known to be DNA breaks and inhibition of 33: 834–844. DNA repair by cobalt, and gene mutations 6) Sakurai, H., Nakajima, K., Kamada, H. et al.: and carcinogenicity have been reported in cells Coppermetallothionein distribution in the liver and in experimental animals. However, no evi- of Long-Evans Cinnamon rats: Studies on immunohistochemical staining, metal deter- dence is yet available in humans.20) mination, gel filtration and electron spin resonance spectroscopy. Biochem Biophys Conclusion Res Commun 1993; 192: 893–898. 7) Hatano, R., Ebara, M., Fukuda, H. et al.: Metal carcinogenesis has recently been Accumulation of copper in the liver and attracting attention not only in terms of occu- hepatic injury in chronic hepatitis C. J Gastro- pational diseases but in ordinary environments. enterol Hepatol 2000; 1: 786–791. In humans, iron is said to cause liver cancer in 8) Tashiro-Itoh, T., Ichida, T., Matsuda, Y. et al.: Metallothionein expression and concentra- hemochromatosis, copper to cause liver cancer, tions of copper and zinc are associated with respiratory tract cancer, urinary tract cancer, tumor differentiation in hepatocellular carci- and thoracic cancer, arsenic to cause skin noma. Liver 1997; 17: 300–306. cancer, liver cancer, respiratory tract cancer, 9) Shimoda, R., Nagashima, M., Sakamoto, M. and urinary tract cancer, chromium to cause et al.: Increased formation of oxidative DNA lung cancer, nickel to cause lung cancer and damage, 8-hydroxydeoxyguanosine, in human cancer of the nasal cavity, beryllium to cause livers with chronic hepatitis. Cancer Res 1994; lung cancer and central nervous system tumors, 54: 3171–3172. 10) Platz, E.A., Helzlsouer, K.J., Hoffmann, S.C. lead to cause lung cancer, stomach cancer, and et al.: Prediagnostic toenail cadmium and zinc central nervous system tumors, and cadmium and subsequent prostate cancer risk. Prostate to cause prostate cancer, but many aspects of 2002; 52: 288–296. their carcinogenetic mechanisms are unknown. 11) Yamamoto, S., Konishi, Y., Matsuda, T. et al.: Cancer induction by an organic arsenic com- REFERENCES pound, dimethylarsenic acid (cacodylic acid) in F344/DuCrj rats after pretreatment with 1) Rezazadeh, H., Nayebi, A.R. and Athar, M.: five carcinogens. Cancer Res 1995; 55: 1271– Role of iron-dextran on 7, 12-dimethylbenz(a) 1276. anthracene-initiated and croton oil-promoted 12) Ott, M., Holder, B.B., Gordon, H.L. et al.: cutaneous tumorigenesis in normal and preg- Respiratory cancer and occupational expo- nant mice. Hum Exp Toxicol 2001; 20: 471– sure to arsenicals. Arch Environ Health 1974; 476. 29: 250–255. 2) Boyd, J.T., Doll, R., Faulds, J.S. et al.: Cancer of 13) Pfeil, E.: Lungentumoren als Berufserkrankung the lung in iron ore (haematite) miners. Brit J in Chromatbetrieben. Dtsch Med Wochenshr Ind Med 1970; 27: 97–105. 1935; 61: 1197–1200. 3) Finch, S.C. and Finch, C.A.: Idiopathic hemo- 14) Heuper, W.C.: Occupational and environ- chromatosis, an iron storage disease. A. Iron mental cancers of the respiratory system.

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