:Germanium:

:During the 1980s germanium was listed as a possible anti-cancer drug, and sold as either germanium sesquioxide (Ge-132) or spirogermanium. However, a decade of human clinical trials has failed to conclusively show such a benefit (1A). There was a recently published report of a complete remission following germanium sesquioxide use by a patient with a rare type of lung cancer. This tumor, a pulmonary spindle cell carcinoma, is usually associated with a poor prognosis and this patient had not responded to conventional chemotherapy (2A). The report was accompanied by an editorial calling for rigorous research on alternative therapies (3B).

Claims of beneficial effects on galactose-induced cataracts and perhaps glycation of proteins have been reported (4A, 5A)) as well as analgesic (6A) and anti-viral (7A, 8A) activities, all observed in studies with animals. A germanium compound, propagermanium (3-oxygermylpropionic acid polymer) has been reported to act as an immune system activator in mice and in that species provides protection against liver damage caused by herpes virus or chemicals (9A, 10A, 11A).

Chemistry: The concern with use of Ge-132 is not primarily the organic compound itself, but rather the potential for contamination of a product with the toxic inorganic forms of various germanium salts, such as the highly toxic germanium dioxide.

Toxicity: The toxicity of germanium dioxide has been well documented in animal studies and in humans. In humans, the use of germanium dioxide has been associated with nervous system pathology and kidney damage (12A, 13A, 14A, 15A, 16A,), muscle damage (13A, 14A, 15A) and anemia (15A). Irreversible changes, and several deaths, are included among these cases. The progressive kidney failure caused by germanium dioxide (GeO2) is associated with a characteristic pathology that persists even after use of GeO2 is stopped. This pathology involves white blood cell invasion, formation of collagen and fibrosis of parts of the kidney. Treatment of rats with L-arginine can prevent this terminal effect of GeO2 (17A).

Germanium dioxide was shown to prevent changes in gap junctional intercellular communication (GJIC) caused by tumor promoters. GJIC depends on channels that connect neighboring cells and is believed to be important in controlling cell functioning, growth and differentiation. This study indicated an anticarcinogenic role for GeO2, but the report made no mention of its toxicity or of any similar work planned with Ge-132 (18A).
Human toxicity has also been reported for germanium-lactate-citrate, including kidney, liver and nervous system effects and several deaths (16A, 19A, 20A, 21A). One case history reported multi-organ pathology in a man after consumption of 426g of germanium-lactate-citrate over a six month period. Nausea, vomiting, kidney dysfunction and peripheral neuropathy persisted six months after discontinuation of germanium (22A).

There are few adverse effects reported for germanium sesquioxide (Ge-132, prosigermanium, carboxyethyl germanium sesquioxide) (23B, 24A).
Reviews of germanium toxicity (exclusive of industrial health studies relating mainly to germanium metal) include articles by Tao and Bolger (1A) and Schauss (25A, 26A).

Conclusion: Scientific data and information published to date do not at this time substantiate widespread use of Germanium as a dietary supplement. In the absence of evidence that germanium is an essential nutrient for humans (1A, 25A) the known toxicity of germanium dioxide makes the purity of Ge-132 a critical factor in determining propriety of its use as a dietary supplement. Existing evidence for the value of germanium is not adequate to overcome the burden of the possible toxicity of Ge-132 itself or, what is more likely, the possibility of contamination with germanium dioxide.

A recent article in Archives of Family Medicine reported on a survey of health food store personnel as sources of recommended products for breast cancer patients. In 36 of the 40 stores involved, a total of 38 products were recommended. Germanium was mentioned in four stores. (28A)

Consult with your health care practitioner before taking Germanium.

References:*

1A Tao, SH & PM Bolger. Hazard assessment of germanium supplements. Regul Toxicol Pharmacol 25, 211-9 (1997)
2A Mainwaring, MG et al. Complete remission of pulmonary spindle cell carcinoma after treatment with oral germanium sesquioxide. Chest 117, 591-3 (2000)
3B Ernst, E. Unconventional cancer therapies. What we need is rigorous research, not closed minds. Chest 117, 307-8 (2000)
4A Unakar, NJ et al. Effect of pretreatment of germanium-132 on Na(+)-K(+)-ATPase and galactose cataracts. Curr Eye Res 16, 832-7 (1997)
5A Unakar, NJ et al. Effect of germanium-132 on galactose cataracts and glycation in rats. Exp Eye Res 61, 155-64 (1995)
6A Hachisu, M et al. Analgesic effect of novel organogermanium compound, Ge-132. J Pharmacobiodyn 11, 814-20 (1983)
7A Aso, H et al. Antiviral activity of carboxyethylgermanium sesquioxide (Ge-132) in mice infected with influenza virus. J Biol Response Mod 8, 180-9 (1989)
8A Ishiwata, Y et al. Effects of proxigermanium on interferon production and 2',5'-oligoadenylate synthetase activity in the lung of influenza virus-infected mice and in virus-infected human peripheral blood mononuclar cell cultures. Arzneimittelforschung 40, 896-9 (1990)
9A Ishiwata, Y et al. Studies on the antiviral activity of propagermanium with immuno-stimulating action. Arzneimittelforschung 44, 357-61 (1994)
10A Ishiwata, Y el al. Protection against concanavalin A-induced murine liver injury by the organic germanium compound, propagermanium. Scand J Immunol 48, 605-14 (1998)
11A Yokochi, S et al. Hepatoprotective effect of propagermanium on Corynebacterium parvum and lipopolysaccharide-induced liver injury in mice. Scand J Immunol 48, 183-91 (1998)
12A Fujimoto, M. A patient with liver cirrhosis manifesting various symptoms including cerebellar ataxia due to germanium intoxication. Fukuoka Igaku Zasshi 83, 139-43 (1992) (in Japanese)
13A Obara, K. Germanium poisoning: clinical symptoms and renal damage caused by long-term intake of germanium. Jpn J Med 30, 67-72 (1991)
14A Kamijo, M et al. An autopsy case of chronic germanium intoxication presenting peripheral neuropathy, spinal ataxia, and chronic renal failure. Rinsho Shinkeigaku 31, 191-6 (1991) (in Japanese)
15A Iijima, M et al. A case of inorganic germanium poisoning with peripheral and cranial neuropathy, myopathy and autonomic dysfunction. No To Shinkei 42, 851-6 (1990)
16A Asaka, T et al. Germanium intoxication with sensory ataxia. J Neurol Sci 130, 220-3 (1995)
17A Yanagisawa, H et al. L-Arginine treatment may prevent tubulointerstitial nephropathy caused by germanium dioxide. Kidney Intl 57, 2275-84 (2000)
18A Kany, K-A et al. Preventive effect of germanium dioxide on the inhibition of gap junctional intercellular communication by TPA. Cancer Letters 166, 147-53 (2001)
19A Krapf, R et al. Abuse of germanium associated with fatal lactic acidosis. Nephron 62, 351-6 (1992)
20A Raisin, J et al. Toxicity of an organic germanium compound: deleterious consequences of a "natural remedy". Schweiz Med Wochenschr 122, 11-13 (1992) (in German)
21A Van der Spoel, JR et al. Toxic damage of kidney, liver and muscle attributed to the administration of germanium-lactate-citrate. Ned Tijdschr Geneeskd 135, 1134-7 (1991) (in Dutch)
22A Luck, BE et al. Renal and other organ failure caused by germanium intoxication. Nephrol Dial Transplant 14, 2464-8 (1999)
23B Stricker, BH. Dietary germanium supplements. Lancet 336, 117 (1990); 337, 864 (1991) (Letters)
24A Anger, F et al. Subacute and subchronic oral toxicity of beta-bis carboxyethyl sesquioxide of germanium in the rat. J Toxicol Clin Exp 11, 421-36 (1991) (in French)
25A Schauss, AG. Nephrotoxicy and neurotoxicity in humans from organogermanium compounds and germanium dioxide. Biol Trace Elem Res 29, 267-80 (1991)
26A Schauss, AG. Nephrotoxicity in humans by the ultratrace element germanium. Renal Failure 13, 1-4 (1991)
27A Nielsen, FH. How should dietary guidance be given for mineral elements with beneficial actions or suspected of being essential? J Nutr 126 (Suppl), 2377S-2385S (1996)
28A Gotay, CC & D Dumitriu. Health food store recommendations for breast cancer patients. Arch Fam Med 9, 692-8 (2000)
*Key:
A reference: research article or editorial comment in peer-reviewed journal
B reference: letters to the editor, professional personal communications, meeting/conference abstracts (NOT usually peer reviewed), and pending reviewed publications
C reference: lay/trade press publications, interviews, patents and Web site material

The main nutritional supplement form of germanium is known as Ge-132, Germanium-132, germanium sesquioxide or bis-carboxyethyl germanium sesquioxide. This is a synthetic organic product. It has not been found naturally. Noteworthy is that many of the clinical trials studying the effect of germanium on subjects with various cancers used another synthetic germanium compound, spirogermanium or 8,8-diethyl-N,N-dimethyl-2-aza-8-germaspiro (4,5) decane-2-propranamine dihydrochloride. Spirogermanium has great toxicity, especially neurotoxicity. Spirogermanium is not sold as a nutritional supplement.

Topical products containing inorganic germanium are marketed in Japan for relief of pain and swelling.

Like many minerals, germanium exists in numerous forms. The form of a mineral greatly affects its biological activity and safety. Minerals like chromium, sodium, potassium, phosphorus and selenium are essential to health and wellness or even life itself. However, they also exist in forms that can be deadly. Understanding the difference between safe and dangerous forms, and the ability to positively discriminate between them, is vital to the safe use of germanium supplements.

Germanium sesquioxide contains a germanium carbon bond and is therefore correctly classified as an organic form. Indistinguishable from germanium sesquioxide in appearance, germanium dioxide lacks a germanium carbon bond and is therefore correctly classified as inorganic.
GeO2 contamination has tainted the reputation of the germanium supplement market considerably.26, 27, 28 However, contamination of germanium sesquioxide with dangerous levels of inorganic germanium occurs only as a result of extreme carelessness or a wanton act. Analytical testing is capable of detecting levels of contamination far below anything considered dangerous 29. Common sense dictates that careful processing and quality controls are necessary to insure the safety of germanium or any other supplement.

The image of germanium sesquioxide was tainted by the actions of a few reckless and unscrupled profiteers over a decade ago. Asian material, grossly contaminated with GeO2, caused numerous cases of renal compromise and some fatalities 30-33. This, combined with the failure of "scientists" to correctly classify the different forms, generated considerable fear and confusion and fostered overgeneralized statements on the dangers of all germanium-containing products. 26, 27, 28, 31, 34 A report issued in 1987 by Okuda, et al, further compounded the misunderstanding. Two cases of renal toxicity were attributed to germanium sesquioxide 35. The discussion section of this publication suggested possible product contamination but still attributed the toxicity to germanium sesquioxide. However, the presence of GeO2 contamination in the Okuda, et al, study was proven conclusively in a paper published the following year by Matsusaka, et al. 36. Two years later, Okuda revised his position on germanium sesquioxide by demonstrating the inherent safety of chronic high doses of germanium sesquioxide (240 mg/kg/day) and the toxic effects of GeO2 at 150 g/kg/day 37.

The original Okuda error of 1987 has been cited for 15 years as evidence of germanium sesquioxide toxicity. This creates a false perception of a larger body of evidence against germanium sesquioxide. Subsequent authors of scientific publications 30, 32, 34, 38, 39 seem unaware that a correction was made in 1988 36 and that the subject of germanium sesquioxide toxicity was fully explored again in 1990 37.

Safety: Overwhelming evidence supports the safety of pure germanium sesquioxide. Acute and chronic exposure to extremely high doses demonstrates a margin of safety difficult to surpass 38, 40, 41, 42, 43, 44, 45, 46. Relatively speaking, germanium sesquioxide is at least 1.5 times safer than calcium carbonate 47, three times safer than table salt 48, four times safer than potassium chloride 48, and 23 times safer than chromium picolinate 49.

I also think it is important to note that contamination problems occurred with Asian material. However, there has never been a problem with U.S.-manufactured germanium sesquioxide.

by David Parish

References:

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29. Designed Nutritional Products analytical method archives (available upon request).
30. Krapf R, et al. Nephron 1992;62:351-356.
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47. Fisher Scientific North Carolina catalog; Calcium Carbonate MSDS.
48. Sigma Chemical MSDS database.
49. Expert Group on Vitamins and Minerals Secretariat Review of Chromium January 2000.
50. Import Alert IA #54-07 Germanium Products 1995 revision.