Nephrotoxicity and neurotoxicity in humans from organogermanium compounds and germanium dioxide
- Alexander G. Schauss
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There is no known biological requirement for germanium (Ge), germanates, or any organogermanium compound. Ge deficiency has not been demonstrated in any animal. The estimated average dietary intake of Ge in humans is 1.5 mg/d. Ge is widely distributed in edible foods, all of which, with few exceptions, contain less than 5 ppm Ge, since higher levels are toxic to most plants. Ingestion of Ge compounds has been shown to produce toxic effects in experimental animals.
In recent years inorganic germanium salts and novel organogermanium compounds, such as carboxyethyl germanium sesquioxide (Ge-132) and lactate-citrate-germanate (Ge lactate citrate) have been sold as “nutritional supplements” in some countries for their purported immunomodulatory effects or as health-producing elixirs, resulting sulting in intakes of Ge significantly exceeding the estimated average dietary intake. Since 1982, there have been 18 reported cases of acute renal dysfunction or failure, including two deaths, linked to oral intake of Ge elixirs containing germanium dioxide (GeO2) or Ge-132. In these cases, biopsies show vacuolar degeneration in renal tubular epithelial cells, without proteinuria or hematuria, in the absence of glomerular changes. Serum creatinine levels have been well above 400 μmol/L in such patients. In 17 of 18 cases, accumulated elemental Ge intakes reportedly ranged between 16 to 328 g over a 4–36 mo period, or between 100 to 2000 times the average estimated dietary intake for human. In surviving patients, renal function improved after discontinuation of Ge supplementation. However, in no case was recovery complete.
One organogermanium compound, an azaspiran organogermanium compound, 2-aza-8-germanspiro[4,5] decane-2-propamine-8,8-diethyl-N,N-dimethyl dichloride (spirogermanium), has been found to cause both neurotoxicity and pulmonary toxicity in phase I and II studies examining its chemotherapeutic potential as an antitumor drug in the treatment of various malignancies. In cancer patients given the drug spirogermanium, 40% experienced marked, yet transient neurotoxicity. Two patients suffered from pulmonary toxicity. Results of phases I and II human cancer trials for spirogermanium have not been favorable, with the exception of moderate benefits for three types of malignancies.
It is recommended that patients exposed to long-term (>3 mo) Ge supplementation at levels well above the estimated daily intake be medically supervised and monitored for potential renal-, pulmonaryor neurotoxicity. Further study regarding the mechanism of Geinduced nephrotoxicity in human is warranted.
E. S. Dana,A Textbook of Mineralogy, 4th Ed., Wiley & Sons, New York, 1944.
W. L. Roberts, G. R. J. Rapp, and J. Weber,Encyclopedia of Minerals, Van Nostrand Reinhold, New York, 1974.
R. Schwarz and H. Scholz,Berichte d D Chem. Ges. 74, 1676–1679 (1941).CrossRef
E. I. Hamilton and M. J. Minski,Sci. Total. Environ. 1, 341–374 (1972/1973).CrossRef
W. S. Snyder, M. J. Cook, E. S. Nasset, L. R. Karhausen, G. P. Howells, and I. H. Tipton, inInternational Commission on Radiological Protection, ICRP, New York, 1975.
C. Reilly,Metal Contamination of Food, Applied Science Publishers, London, UK, 1980.
H. Matsumoto, S. Syo, and E. Takahasi,Soil Sci. Plant Nutr. 21, 273–280 (1975).
M._-K. Park and D._-S. Han,Soul Taehakkyo Yahhak Nonmunjip 4, 100–108 (1979).
M. Staufer,Erfahrungsheilkunde 29, 646–647 (1980).
P. D. Whanger inNutrition and Basic and Applied Science, J. N. Hatchcook, ed., Academic, New York, 1982, pp. 163–208.
G. Rosenfeld and E. J. Wallace,Arch. Indust. Hyg. Occup. Med. 8, 466–479 (1953).
V. Vouk, inHandbook on the Toxicology of Metals, L. Friberg, G. F. Nordberg, and V. Vouk, eds., Elsevier Science, Amsterdam, 1979, pp. 421–428.
V. Vouk, inHandbook on the Toxicology of Metals, 2nd Ed., L. Friberg, G. F. Nordberg, and V. Vouk, eds., Elsevier Science, Amsterdam, 1986, pp. 255–266.
M. Hatano, K. Ishimura, and K. Fuchigami,Oyo Yakuri 21, 793–796 (1981).
O. Mogilevskaja, inProblems of Industial Hygiene and Occupational Pathology in Work with Rare Metals. Z. I. Israel’son, O. Mogilevsskaja, and S. V. Suvorov, eds., Medicina, Moscow, 1973, pp. 227–239.
H. C. Dudley and E. J. Wallace,Arch. Ind. Hyg. Occup. Med. 6, 263–270 (1952).
L. M. Rice, J. M. Wheeler, and C. F. Geschickter,J. Heterocyl. Chem. 11, 1041–1047 (1974).CrossRef
K. Pinnamaneni, H._-Y. Yap, S. S. Legha, G. R. Blumenschein, and G. P. Bodey,Cancer Treat. Rep. 68, 1197–1198 (1984).PubMed
N.J. Volgelzang, D. H. Gesme, and B. J. Kennedy,Am. J. Clin. Oncol. 8, 341–344 (1985).CrossRef
P. Schulman, R. B. Davis, S. Rafla, M. Green, and E. Henderson,Cancer Treat. Rep. 68, 1305, 1306 (1984).PubMed
D. E. Brenner, N. B. Rosenshein, M. Dillon, H. W. Jones, A. Forastiere, S. Tipping, L. S. Burnett, F. A. Greco, and P. H. Wiernik,Cancer Treat. Rep. 69, 457, 458 (1985).PubMed
K. Asai,Miracle Cure Organic Germanium, K. Asai Japan Publications, Tokyo, 1980.
M. Tsutsui, D. Kakimoto, D. Axtell, H. Oikawa, and K. Asai,J. Am. Chem. Soc. 98, 8287–8289 (1976).CrossRef
N. Kumano, Y. Nakai, T. Kshikawa, S. Koinumaru, S. Suzuki, and K. Konno,Sci. Rep. Res. Inst. Tohoku Univ. 25, 89–95 (1978).
H. Sato and T. Iwaguchi,Gan To Kagaku Ryoho (Japan J. Cancer Chemotherapy) 6, 79–83 (1979).
H. Aso, Y. Hayashi, F. Suzuki, and N. Ishida,Proc. Jap. Cancer Assn. 38, 112–115 (1979).
T. Suzuki. S. Ishikawa, T. Motoyama, and Oboshi,Acta. Pathol. Jap. 30, 557–564 (1980).
K. Shimpo and N. Mori,Phamacometrics (Japan) 20, 675–679 (1980).
K. Miyao, inImmunomodulation by Microbial Products and Related Synthetic Compounds, Y. Yamamura, and S. Kotani, eds., Elsevier, Amsterdam, 1981, pp. 536–539.
N. Kumano, Y. Nakai, T. Ishikawa, S. Koinumaru, S. Suzuki, T. Kikumoto, S. Takizawa, K. Miyao, and K. Konno,Sci. Rep. Res. Inst. Tohoku Univ. 25, 89–95 (1978).
F. Suzuki,Gan to Kagaku Ryoho (Japan J. Cancer Chemotherapy) 12, 2122–2188 (1985).
I. Sato, B. Yuan, T. Nishimua, and N. Tanaka,J. Bio. Response Modifiers 4, 159–168 (1985).
H. Aso, E. Shibuya, F. Susuki, T. Nakamurea, H. Inoue, T. Ebina, and N. Ishida,Gan To Kagaku Ryoho (Japan J. Cancer Chemotherapy) 12, 2345–2351 (1985).
F. Suzuki, R. R. Brutkiewicz, and R. B. Pollard,Brit. J. Cancer 52, 757–764 (1985).PubMed
H. Kobayashi, T. Komuro, and H. Furue,Gan To Kagaku Ryoho (Japan J. Cancer Chemotherapy) 13, 2588–2593 (1986).
F. Susuki, R. R. Brutkiewicz, and R. B. Pollard,Anticancer Res. 6, 177–182 (1986).
F. Susuki,Gan To Kagaku Ryoho (Japan J. Cancer Chemotherapy) 14, 127–134 (1987).
P. S. Schein, M. Slavik, T. Smythe, D. Hoth, F. Smith, J. S. Macdonald, and P. V. Woolley,Cancer Treat. Rep. 64, 1051–1056 (1980).PubMed
S. S. Legha, J. A. Ajani, and G. P. Bodey,J. Clin. Oncol. 1, 331–336 (1983).PubMed
C. Trope, W. Mattsson, I. Gynning, J.-E. Johnson, K. Sigurdsson, and B. Orbert,Cancer Treat. Rep. 65, 119, 120 (1981).PubMed
G. Falkson and H. C. Falkson,Cancer Treat. Rep. 67, 189, 190 (1983).PubMed
J. P. Kuebler, D. C. Tormey, G. R. Harper, Y.-C. Chang, J. D. Khandekar, and G. Falkson,Cancer Treat. Rep. 68, 1515, 1516 (1984).PubMed
J. J. Kavanagh, P. B. Saul, L. J. Copeland, D. M. Gershenson, and I. H. Krakoff,Cancer Treat. Rep. 69, 139, 140 (1985).PubMed
C. Dixon, F. Hegemeister, S. Legha, and G. Bodey,Cancer Treat. Rep. 68, 907, 908 (1984).PubMed
B. T. Hill, S. A. Whatley, A. S. Bellamy, L. Y. Jenkins, and R. D. H. Whelan,Cancer Res. 42, 2852–2856 (1982).PubMed
D. R. Budman, P. Schulman, V. Vinciguerra, and T. J. Degnan,Cancer Treat. Rep. 66, 173–175 (1982).PubMed
K. Loren,The Report on Germanium, Life Extension Educational Service, Glendale, CA, 1987.
B. Kamen,Germanium, A New Approach to Immunity, Nutrition Encounter, Larkspur, CA, 1987.
Y. Mizushima, Y. Shoji, and K. Kaneko,Int. Arch. Allergy Appl. Immunol. 63, 338, 339 (1980).PubMed
N. J. Vagelzang, D. H. Gesme, and B. J. Kennedy,Am J. Clin. Oncol. 8, 341–344 (1985).CrossRef
H. A. Schroeder, M. Kanisawa, D. V. Frost, and M. Mitchener,J. Nutr. 96, 37–45 (1968).
I. Yoneyama,Nippon Jinzo Gakkaishi 24, 1355, 1356 (1982).
N. Nagata, T. Yoneyama, K. Yanagida, K. Ushio, S. Yanagihara, O. Matsubara, and Y. Eishi,J. Toxicol. Sci. 10, 333–341 (1985).PubMed
M. Omata, M. Kikuchi, C. Higuchi, S. Sanaka, T. Takuma, N. Sugino, and Y. Mori, inNephrotoxicity of Antibiotics and Immunosuppressants, T. Tanabe, J. B. Hook, and H. Endou, eds., Elsevier, Amsterdam, 1986, pp. 15–20.
K. Okagawa, M. Kosaka, T. Sakikawa, M. Hiasa, H. Sato, K. Morizumi, H. Morita, S. Simomura, and S. Saito,Naika (Japan Arch. Int. Med.) 58, 1211–1214 (1986).
S. Okuda, S. Kiyama, Y. Oh, K. Simamatsu, N. Oochi, K. Kobayashi, F. Nanishi, S. Fujimi, K. Onoyama, and M. Fujishima,Curr. Ther. Res. 41, 265–275 (1987).
T. Matsusaki, M. Fujii, T. Nakano, T. Terai, A. Kurata, M. Imaizumi, and and H. Abe,Clin. Nephrol. 30, 341–345 (1988).
T. Nakano, M. Fuki, T. Terai, T. Matsuzaka, M. Kimura, and T. Toyomasu,J. Clin. Electron Microscopy 20, 850, 851 (1987).
R. Muller and Iszard,Am. J. Med. Sci. 163, 364–372 (1922).CrossRef
W. C. Hueper,Am. J. Med. Sci. 181, 820–830 (1931).CrossRef
K. Okada, K. Okagawa, K. Kawadami, Y. Kuroda, K. Morizumi, H. Sato, H. Morita, S. Shimomura, and S. Saito,Clin. Nephrol. 31, 219–224 (1989).PubMed
J. I. Van der Spoel, B. H. Stricker, M. R. Esseveld, and M. E. I. Schipper,Lancet ii, 117 (1990).
E. Browning,Toxicity of Industrial Metals, 2nd Ed., Butterworths, London, UK, 1969.
K. Asai, Asai Germanium Research Institute, 1984, pp. 1–17.
S. Tomizawa, N. Suguro, and M. Kagoshima,Oyo Yakuri (Japan J. Appl. Pharmacol.) 16, 671–682 (1978).
K. Miyao, T. Onishi, K. Asai, S. Tomizawa, and F. Suziki, inProceedings of the 11th ICC and the 19th ICAAC, American Society of Microbiology, 1980, pp. 1527–1529.
H. E. Stokinger, inPatty’s Industrial Hygiene and Toxicology, G. D. Clayton and F. E. Clayton, eds., John Wiley, New York, 1981, p. 1493.
Seizure actions.FDA Consumer 24, 37, 1990.
Seizure actions.FDA Consumer 24, 45, 1990.
R. Krapf,Schweiz Apoth Ztg 129, 10 (1991).
- Nephrotoxicity and neurotoxicity in humans from organogermanium compounds and germanium dioxide
Biological Trace Element Research
Volume 29, Issue 3 , pp 267-280
- Cover Date
- Print ISSN
- Online ISSN
- Humana Press
- Additional Links
- germanium toxicity—humans
- germanium dioxide
- organogermanium compounds
- carboxyethyl germanium sesquioxide (Germanium-132 or Ge-132)
- germanium lactate citrate
- acute renal failure resulting from germanium toxicity
- germanium-induced nephrotoxicity
- germanium neurotoxicity
- Industry Sectors
- Author Affiliations
- 1. Life Sciences Division, American Institute for Biosocial Research, Inc., PO Box 1174, 98401, Tacoma, WA