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Mutagenicity, Carcinogenicity and Teratogenicity of Germanium Compounds G.B

Mutagenicity, Carcinogenicity and Teratogenicity of Germanium Compounds G.B

Mutation Research 387Ž. 1997 141±146

Mutagenicity, carcinogenicity and teratogenicity of compounds G.B. Gerber, A. Leonard ) Teratogenicity and Mutagenicity Unit, Catholic UniÕersity of LouÕain, Brussels, Belgium Received 11 June 1997; accepted 13 August 1997

Abstract

The germanium has found widespread application in electronics, nuclear sciences and in medicine. General toxicity of germanium is low, except for the tetrahydride , and few observations on toxicity of germanium in man exist. Germanium is not carcinogenic and even appears to inhibit cancer development and, in the form of the organic germanium compound, spirogermanium, to destroy cancer cells. Germanium compounds have no mutagenic activity and may, under certain conditions, inhibit the mutagenic activity of other substances. High doses of germanium may result in an increased embryonic resorption, but possible malformations have been reported only after administration of dimethyl germanium to pregnant animals. Germanium may thus be considered an element of rather low risk to man. q 1997 Elsevier Science B.V.

Keywords: Germanium; Spirogermanium; Genotoxicity; Mutagenicity; Carcinogenicity; Teratogenicity; Metal

1. Introduction In view of its present and potential applications, we considered it useful to review the possible toxic, Germanium has been used extensively in the elec- mutagenic, carcinogenic and teratogenic properties tronic industry from then mid forties to the mid of germanium and its compounds. seventies. Indeed, the first transistor made by William Shockley in 1948 was based on germanium. Subse- quently, however, germanium has been largely re- 2. Occurrence, properties and use of germanium placed by silicium and other semi-conductor metal- loids. Today, germanium is still much used in For reviews on occurrence, properties and use of gamma-ray detectors and optical devices. Germa- germanium seewx 1±4 . nium incorporated into heterocyclic aromatic rings GermaniumŽ atomic number, 32; atomic weight, has also been used as an anticancer agent, although 72.59; , 937.48C; boiling point, 28308C,. its toxicity seems to be too high for widespread use. named after the country of its discoverer by Cl. A. Winkler, constitutes approximately 7 ppm of the earth's crust. This metalloid belongs to group IV of ) Corresponding author. Tel.: q32Ž. 2 764-7200; fax: q32 Ž. 2 elements in the periodic table with an electronic 764-7256; e-mail: [email protected] configuration intermediate between that of a metal

1383-5742r97r$17.00 q 1997 Elsevier Science B.V. All rights reserved. PII S1383-5742Ž. 97 00034-3 142 G.B. Gerber, A. Leonard rMutation Research 387() 1997 141±146 and a non-metal, a property that accounts for its i.e. a lower concentration at the surface increasing usefulness as material in electronic with depthwx 15 . In the ocean, the mean residence devices. Germanium exist in bivalent or tetrava- time of monomethyl germanium is about 4 million lent state, the latter being favoured under normal years and that of dimethyl germanium is about half a environmental conditionswx 5 . million years while that of inorganic germanium is Natural germanium is composed of 5 isotopes: much shorter, i.e. in the order of 10 000 yearswx 16 . 70 GeŽ. 20.55% ,72 GeŽ. 27.37% ,73 GeŽ. 7.67% ,74 Ge Coal contains relatively high concentrations of ger- Ž.36.74% ,76 GeŽ. 7.67% . Radioactive isotopes of maniumŽ coal ash as much as 20±280 mgrkgwx 17. , molecular weights of 65±69, 71, 75, 77 and 78 have although this does not seem to influence concentra- been artificially producedwx 6 . tions in the urban atmospherewx 18 .

Germanium is a constituent of argyroditeŽŽ Ag24 S . Most foods contain germanium at concentrations Ge Se, containing 5±7% of germanium. , germanite of about its natural abundance; higher values have r Ž.7CuS FeS GeS2 ; containing 8.7% of germanium , been reported for clamsŽ. 0.9±2.03 mg g , salmon renierite and enangite, a Cu±As sulphide which con- Ž.1.23 mgrg , canned tuna Ž.Ž 2.23 mgrg , milk 1.51 tains as much as 0.03% of germanium. . However, mgrg.Ž , butter 1.21 mgrg . , bran wheat Ž 1.41 mgrg, . most germanium is produced as a by-product of canned baked beansŽ. 4.67 mgrg and canned tomato refining, mainly in the United StatesŽ. 20% , Belgium juiceŽ. 5.76 mgrgwx 3,19 . Daily intake of germanium Ž.20% , Japan Ž. 12% , Germany Ž. 12% with some from food has been reported to vary between 367 production also in France, Italy, China and Eastern and 3700 mgwx 20,21 . European countrieswx 7 . Total annual production amounts to about 300 tons world wide. The semi-conductor revolution in the electronic 3. Biological functions, exposure, metabolism and industry would have been impossible without highly general toxicity of germanium[] 2,4,13,22 purified germanium being available. The use of ger- manium in transistors, diodes, rectifiers started in Uptake of germanium occurs through the diet and, 1945 and reached its peak in the mid seventies; in certain industrial environments, through inhala- afterwards germanium was progressively replaced by tion. Inorganic germanium compounds are readily silicium. Presently, germanium is applied for making absorbed and excreted mainly via the kidney and optic fibres, as a catalyst and to wx19,23,24 with half lives in the order of 1±4 days improve the resistance of some metal alloyswx 7 . wx25 . Germanium concentrates in liver, kidney, spleen Germanium± alloys maintain superconduc- and the gastrointestinal tract after i.v. injectionswx 23 . tive properties in strong magnetic fields up to a High germanium concentrations were seen, after oral temperature of 238K which makes them an interest- administration, in spleenwx 19 and, after i.p. injection, ing possibility for the construction of nuclear accel- in spleen and kidneywx 26 . Germanium becomes erators, electric power generators, etc. Germanium± widely distributed in the human body; the use of a detectors have a very high spectral resolution germanium application in a person who died from for gamma-rays thus allowing the simultaneous de- acute renal failure resulted in high concentrations in termination of many gamma-emitting radionuclides vertebrae, kidney, brain and skeletal musclewx 27 . wx8±12 . Some organo±germanium compounds, such Determination in hair and nails may allow excessive as spirogermanium and carboxyethylgermanium germanium uptake to be monitoredwx 28 . Spirogerma- sesquioxide, have anti-neoplastic properties in ani- nium is rapidly removed from the plasma and ap- mals and man. Several recent publicationsŽ for re- pears not to become accumulated in tissueswx 29 view seewx 13. suggest, however, that maximum tol- Germanium is not an essential element but, be- erable doses are too low to make such treatments cause it is a close relative of silicium, it mimics effective. pathways of silicium at low concentrations and in- Soil contains 0.6±1.0 ppm, water bodies less than hibits them at higher ones. This can affect minerali- 8 pptŽ. parts per trillionwx 5,14 . The distribution of sation in organisms such as sponges and limpets germanium in water bodies follows that of nutrients, wx30,31 . G.B. Gerber, A. Leonard rMutation Research 387() 1997 141±146 143

The gas germaneŽ. GeH4 is highly toxic at a level 4. Mutagenicity of germanium of 100 ppm and can cause death at 150 ppm from haemolysis and damage to the cardiovascular system, The mutation assay on hypoxanthine guanine the liver and kidneywx 13,32 . Symptoms are similar to phosphoribosyl transferaseŽ. HGPRT carried out with those observed after acute exposure to stibine, but dibutylgermanium dichloride on Chinese hamster germane is only half as toxic. Other inorganic ger- ovarianŽ. CHO cells yielded an LC50 of about 600 manium compounds show little toxicity with acute mgrmlŽ. 2.33 mM ; the incidence of mutants in- r r wx LD50 values in the order of 100±1000 mg kg for creased with dose up to 400 mg mlŽ. 1.55 mM 40 . parenteral and 500±5000 mgrkg for oral application The authors postulate that this electrophilic com- wx20,32 . At these doses, only general, but no charac- pound acts by binding to DNA bases, thereby form- teristic symptoms are found, such as hypothermia, ing penta- and hexa-coordination compounds. Li et diarrhoea, respiratory and cardiac failurewx 4,18 . al.wx 40 also evaluated the immunosuppressive poten- Chronic application of high doses of germanium tial of this compound in lymphocytes on the basis of dioxide in the dietŽ. 1000 ppm causes 50% mortality cytotoxicity and impairment of antibody formation. after a few weeks; 100 ppm of germanate in No toxic action was observed in lymphocytes at drinking water was also fatal, but lower doses had concentrations up to 64 mgrmlŽ. 0.25 mM , but the little influence and 10 ppm of GeO2 has been claimed number of antibody-producing cells was reduced to to stimulate growthŽ reviewed inwx 33. . However, one half of the control. several reports have appeared, many in Japanese Ge-132ŽŽ carboxyethylgermanium, O 3 journals dealing with people who had taken germa- Ž..GeCH22 CH COOH 2 is a potent antimutagen when nium preparation during a long period, e.g.wx 27 . added to agar at concentrations of 5±30 mgrml There have been 18 cases of acute renal dysfunction agar, markedly reducing the number of revertant or failure including two deaths linked to oral intake mutants induced by 10 kRad Ž.; 100 Gy of r y of such elixirs containing GeO2 or Ge-132 with gamma-rays in B r WP2 Trp Escherichia coli wx accumulated Ge intakes from 16 to 328 g over a 41 . Germanium oxideŽ. GeO2 has a dose-dependent period of 4±36 months or between 100 and 2000 antimutagenic activity for Trp-P-2 frameshift reverse times the average estimated dietary intake in hu- mutations induced by 3-amino-1-methyl-5H mans. While renal function improved in the surviv- pyridowx 4,3-6 indole in Salmonella typhimurium ing persons, recovery was not complete. strains TA98 and TA 1538wx 42 . The mutagenic wx Inhalation of GeCl4 causes necrosis of the tra- potential of benzo a pyrene was reduced by the 600 chea, bronchitis and interstitial pneumonia, but mgrplate of germanium dioxide in three of four S. chronic inhalation at 7 mgrm3 seems to be harmless typhimurium strains testedwx 43 . Žreviewed inwx 2. . Early in this century, it had been Similar antimutagenic effects of germanium oxide wx reported that germanium has erythropoietic effects Ž.GeO2 have been reported recently 44 after admin- wx wx 34,35 , but later studies 24 indicated that germa- istration of chlorideŽ. CdCl2 to laboratory nium is inert from a pharmacological point of view. mice. Application of 0.05 mgrkg germanium oxide Spirogermanium inhibits DNA, RNA and protein significantly reduced the action of 1.35 mg cadmium synthesis in vitrowx 36 and decreases cell survival chloride in the DNA synthesis inhibition test when m r wx after exposure to as little as 1.0 g ml for 24 h 37 . the CdCl2 was injected 1 h later; combinations of Quiescent cells seem more resistant. At higher con- other doses of the two compounds did not, however, centrations, cytolysis is observedwx 38 . Ge-132 yield such an antagonistic effect. Germanium dioxide Žcarboxethyl-Ge sesquioxide increases interferon ac- at doses of 0.1 or 0.5 mgrmlrkg decreased markedly tivity and NK cell activity of spleen cells in mice 24 the number of micronuclei or chromosome aberra- r h after oral administration and induces peritoneal tions induced by 0.7, 1.4 or 2.7 mg kg of CdCl2 in macrophage activitywx 39 . vivo in mouse bone marrow cells. Germanium diox-

Air standards exist only for GeH4 and were set at ide also protected in vivo against sperm head changes 0.2 ppmŽ 0.6 mgrm3. on the basis of acute toxicity in morphology and in vitro from the sister chromatid wx4. exchangesŽ. SCEs in human peripheral blood lym- 144 G.B. Gerber, A. Leonard rMutation Research 387() 1997 141±146 phocytes caused by CdCl2 . It should be noted that Synthetic amphibole asbestos, where silicium had GeO2 given alone had no effect whatsoever on all been replaced by Ge, produced less pleural mesothe- these tests. lioma and fibrosis in rats than did asbestos contain- ing siliciumwx 54 . To summarize this rather heteroge- neous and uncertain information, germanium cer- 5. Carcinogenicity of germanium tainly appears not to be carcinogenic; its anti- carcinogenic properties appear more doubtful and, Germanium compounds are not carcinogenic, and certainly, do not justify the fad of using germanium some, especially organic ones, have antineoplastic compounds as `bio-oxidative therapy'. properties in experimental animals and man. In a well-planned experiment where groups of 50 Long± Evans rats of each sex received sodium germanate in 6. Teratogenicity of germanium drinking water throughout their entire life time, start- ing from weaning, Kanisawa and Schroederwx 45 not The organic compound, dimethyl germanium ox- only found no increase in cancer rate, but also a ide, has been reported to be teratogenic in chick significantly lower incidence of tumours in animals embryos causing limb abnormalities, umbilical her- receiving 5 ppm of sodium germanate than in con- nias and anophthalmiawx 55 . Doses of 40 and 100 trols. A few inorganic and organic germanium com- mgrkg of germanium trioxideŽ sodium metager- P pounds have been reported to have anti-neoplastic manate; Na23 GeO 7H 2 O. injected intravenously activity in man. However, in a recent inorganic into pregnant hamsters on day 8 of gestation had germanium appeared not to alter the rate of dimeth- some embryopathic effects as indicated by an in- ylhydrazine-induced colon cancer in Western rats creased embryonic resorption rate, but did not pro- wx46 . duce obvious malformationswx 56 . Satohwx 47 described, in preliminary experiments, an antitumour activity of Ge-132Ž carboxy-ethyl ger- 7. Conclusions manium,ŽŽ O3222 GeCH CH COOH .. on mouse tu- mours which might be related to the ability of this compound to induce interferonwx 48 . Ge-132Ž 8 mgr The general toxicity of germanium is low, except day.Ž and natural organic germanium 70 mgrkgr for the tetrahydride germane, and few observations day. w an extract from the plant Hydrangea macro- on toxicity of germanium in man exist. Germanium phylla Ž.original content 600 ppm Gex significantly is not carcinogenic and even appears to inhibit can- decrease the incidence of intestinal cancer induced cer development and, in the form of the organic by of 1,2-dimethylhydrazine in male Sprague±Daw- germanium compound, spirogermanium, to destroy wx cancer cells. Germanium compounds have no muta- ley rats 49 ; inorganic germaniumŽ.Ž GeO2 27 mgrkgrday. had no such anticancer effect. Similar genic activity and may, under certain conditions, antitumour activities of germanium compounds have inhibit the mutagenic activity of other substances. also been reported for other systems, such as on High doses of germanium may result in an increased Lewis lung tumourwx 50 , murine ascites tumour wx 51 embryonic resorption, but possible malformations and the serum of mice given G-132 has been claimed have only been reported after administration of to possess some antitumour activity in an experimen- dimethyl germanium oxide to pregnant animals. Ger- tal tumourwx 51 . On the other hand, the number of manium may thus be considered an element of rather glutathione S-transferase P-positive rat hepatic foci low risk to man. induced by diethylnitrosamine after partial hepatec- tomy were reported to increase under chronic germa- nium administration compared to controlswx 52 . Later References studies by the same group suggested an inhibition of wx1 B.P. Fischer, P.L. Goering, Germanium, in: E. MerianŽ. Ed. , such hepatic foci, as well as of lung and thyroid Metals and Their Compounds in the Environment, VCH, adenomawx 53 . Weinheim, 1991, pp. 921±929. G.B. Gerber, A. Leonard rMutation Research 387() 1997 141±146 145

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