Bad Science Dies Hard
Good science is vital to progress and true learning. Contrastingly, sloppy science casts a shadow on even the most meticulous studies and leads to contradictions and confusion. Upon scrutiny, there is always a logical explanation for an apparent contradiction but once in the public domain it is nearly impossible to entirely remove the effects of bad science. The following are examples of sloppy science that have helped foster over-generalized concerns regarding the safety of all germanium containing compounds.
A report issued in 1987 by Okuda et al. damaged the reputation of germanium sesquioxide considerably. Two cases of renal compromise were attributed to germanium sesquioxide 14. The discussion section of this report suggested possible GeO2 contamination but still attributed the toxicity to germanium sesquioxide. The presence of GeO2 contamination in the Okuda et al. report was proven conclusively in a paper published the following year by Matsusaka. et al. 15. Two years later, Okuda revised his earlier position on germanium sesquioxide by demonstrating the safety of chronic high doses of germanium sesquioxide (240 mg/kg/day) and the toxic effects of GeO2 at 150 mg/kg/day 16.
Unfortunately, the damage had already been done. The original Okuda error of 1987 has been cited for nearly twenty years as the greatest evidence of germanium sesquioxide toxicity. In fact, it has been cited in so many articles that a false perception of a larger body of evidence against germanium sesquioxide resulted. Subsequent authors of scientific publications 30, 32, 34, 38, 39seem unaware that a correction was made in 1988 36 and that the subject of germanium sesquioxide toxicity was fully explored again in 1990 37. This was a simple mistake that the perpetrator attempted to correct. Imagine the impact of scientists who are unaware of or refuse to acknowledged their errors
1. Anger F, Anger JP, Guillou L, Papillon A. Subchronic oral toxicity (six months) of carboxyethylgermanium sesquioxide in rats. Applied Organometallic Chemistry 1992;6(3):267-72.
Analysis: This rat study was conducted with extremely high dosages of germanium sesquioxide (1,000 mg/kg/day) for six months produced no detectable toxic effects. The summary reports mild kidney dysfunction but this claim appears biased toward the negative perceptions of germanium sesquioxide. The data presented in table 3 of this paper, in fact, shows all kidney parameters to be normal and unchanged in spite of such a large dose.
2. Krapf R, Schaffner T, Iten PX. Abuse of germanium associated with fatal lactic acidosis. Nephron 1992;62:351-356.
Analysis:This paper reports a death associated with a high dosage of Ge-lac-cit (2g/day). Neither the title nor the abstract correctly distinguishes this as an inorganic form.
3. Luck BE, Mann H, Melzer H, Dunemann L, Begerow J. Renal and other organ failure caused by germanium intoxication. Nephrology Dialysis Transplantation 1999(14):2464-2468.
Analysis: Once again the culprit in this study is the inorganic form of Ge-lac-cit in excess of 2 g/day . This is the same group who has incorrectly classified this form as “organic” on previous occasions. The general mention of germanium in the title implies a hazard associated with all germanium compounds.
4. Okada K, Okagawa K, Kawakami K, et al. Renal failure caused by long-term use of a germanium preparation as an elixir. Clinical Nephrology 1989;31:219-224.
Analysis:This report fails to place adequate emphasis on the fact that all three cases of renal failure were caused by high doses of an inorganic germanium form. The fact that no organic forms were ingested was determined with 13C-NMR. This information, however, is only mentioned deep within the text.
5. Omata M, Kikuchi M, Higuchi C, et al. Drug-induced nephropathy: Our recent clinical experience. In: Tanabe T, Hook JB, Endow H, eds. Nephrotoxicity of Antibiotics and Immunosuppressants. Amsterdam: Elsevier Science Publishers B.V., 1986: 15-20.
Analysis: This study mentions three cases of renal damage attributed to germanium but no effort is made to determine the form of germanium ingested.
6. Raisin J, Hess B, M. B, et al. Toxicity of an organic germanium compound: deleterious consequences of a "natural remedy". Schweiz Med Wochenschr 1992;122(1-2):11-13.
Analysis: This article incorrectly classifies Ge-lac-cit as an organic form thereby furthering the perception that organic forms are also hazardous.
7. Takeuchi A, Yoshizawa N, Oshima S, et al. Nephrotoxicity of germanium compounds: Report of a case and review of the literature. Nephron 1992;60:436-442.
Analysis: This review reports a single fatality attributed to germanium. The NMR data, however, suggests a mixture of several compounds. Admittedly the true composition was never determined
8. Taylor A, Dickson F, Dobrota M. Effects of germanium health supplements in the rat. Clinical Chemistry 1991;37(6):985.
Analysis: This study fails to establish whether the supplement ingested was in fact a pure form of germanium sesquioxide. The reported toxicity at low doses is more congruent with an inorganic form and it is clear from published literature that adulterated material has skewed test results in the past.
9. Van der Spoel JI, Sticker BHC, Esseveld MR, Schipper MEI. Dangers of dietary germanium supplements. The Lancet 1990;336:117.
Analysis:The very title of this letter strikes out at all germanium supplements. Nowhere is there a distinction between organic forms and the toxic inorganic form of Ge-lac-cit reported to cause the problem.
1. Massey P. Dietary supplements. Medical Clinics of North America 2002;86:127-147.
2. Maskarinec G, Murphy S, Shumay DM, Kakai H. Dietary changes among cancer survivors. Eur J Cancer Care 2001;10:12-20.
3. Gerber GB, Leonard A. Mutagenicity, carcinogenicity and teratogenicity of germanium compounds. Mutation Research 1997;387(3):141-146.
4. Jao S-W, Lee W, Ho Y-S. Effect of germanium on 1, 2-dimethylhydrazine-induced intestinal cancer in rats. Diseases of the Colon and Rectum 1990;33:99-104.
5. Sato I, Yuan BD, Nishimura T, Tanaka N. Inhibition of tumor growth and metastasis in association with modification of immune response by novel organic germanium compounds. Journal of Biological Response Modifiers 1985;4(2):159-168.
6. Komuro T, Kakimoto N, Katayama T, Hazato T. Inhibitory effects of Ge-132 (carboxyethyl germanium sesquioxide) derivatives on enkephalin-degrading enzymes. Biotechnology and Applied Biochemistry 1986;8(5):379-386.
7. Miyao K, Onishi T, Asai K, Tomizawa S, Suzuki F. Toxicology and Phase I studies on a novel organogermanium compound, Ge-132. In: Nelson JD, Grassi C, eds. Current Chemotherapy and Infectious Diseases. Washington, D.C.: American Society of Microbiology, 1980: 1527-1529.
8. Fujita H, Seto Y. Antiviral activity of 3-oxygermylpropionic acid polymer (SK-818). Pharmacometrics 1990;39(4):385-388.
9. Asano K, Yamano M, Haruyama K, et al. Influence of propagermanium (SK-818) on chemically induced renal lesions in rats. The Journal of Toxicological Sciences 1994;19:131-143.
10. Hess B, Raisin J, Zimmermann A, et al. Tubulointerstitial nephropathy persisting 20 months after discontinuation of chronic intake of germanium lactate citrate. American Journal of Kidney Diseases 1993;21:548-552.
11. Krapf R, Schaffner T, Iten PX. Abuse of germanium associated with fatal lactic acidosis. Nephron 1992;62:351-356.
12. Luck BE, Mann H, Melzer H, Dunemann L, Begerow J. Renal and other organ failure caused by germanium intoxication. Nephrology Dialysis Transplantation 1999(14):2464-2468.
13. Schauss AG. Nephrotoxicity in humans by the ultratrace element germanium. Renal Failure 1991;13(1):1-4.
14. Okuda S, Kiyama S, Oh Y, et al. Persistent renal dysfunction induced by chronic intake of germanium-containing compounds. Current Therapeutic Research 1987;41:265-275.
15. Matsusaka T, Fujii M, Nakano T, et al. Germanium-induced nephropathy: report of two cases and review of the literature. Clinical Nephrology 1988;30(6 - 1988):341-345.
16. Sanai T, Okuda S, Onoyama K, et al. Germanium dioxide-induced nephropathy: A new type of renal disease. Nephron 1990;54:53-60.
17. Tao SH, Bolger PM. Hazard assessment of germanium supplements. Regulatory Toxicology and Pharmacology 1997;25(3):211-219.
18. Takeuchi A, Yoshizawa N, Oshima S, et al. Nephrotoxicity of germanium compounds: Report of a case and review of the literature. Nephron 1992;60:436-442.
19. Schauss A, G. Nephrotoxicity and neurotoxicity in humans from organogermanium compounds and germanium dioxide. Biological Trace Element Research 1991;29(3):267-280.
20. Anger F, Anger JP, Guillou L, Papillon A. Subchronic oral toxicity (six months) of carboxyethylgermanium sesquioxide in rats. Applied Organometallic Chemistry 1992;6(3):267-272.
21. van der Spoel JI, Sticker BHC, Esseveld MR, Schipper MEI. Dangers of dietary germanium supplements. The Lancet 1990;336:117.
22. Raisin J, Hess B, M. B, et al. Toxicity of an organic germanium compound: deleterious consequences of a "natural remedy". Schweiz Med Wochenschr 1992;122(1-2):11-13.
23. Omata M, Kikuchi M, Higuchi C, et al. Durg-induced nephropathy: Our recent clinical experience. In: Tanabe T, Hook JB, Endow H, eds. Nephrotixicity of Antibiotics and Immunosuppressants. Amsterdam: Elsevier Science Publishers B.V., 1986: 15-20.
24. Okada K, Okagawa K, Kawakami K, et al. Renal failure caused by long-term use of a germanium preparation as an elixir. Clinical Nephrology 1989;31:219-224.
25. Taylor A, Dickson F, Dobrota M. Effects of germanium health supplements in the rat. Clinical Chemistry 1991;37(6):985.
26. Nagata N, Yoneyama T, Yanagida K. Accumulation of germanium in the tissues of a long-term user of germanium preparation dead of acute renal failure. J Toxicol Sci 1985;10:333-341.
27. Obara K, Saito T, Sato H, et al. Germanium poisoning: Clinical symptoms and renal damage caused by long-term intake of germanium. Japanese Journal of Medicine 1991;30:67-72.
28. Shinogi M, Masaki T, Mori I. Determination and biokinetics of germanium in mouse tissues by atomic absorption spectrometry with electrothermal atomization. J Trace Elem Electrolytes Health Dis 1989;3:25-28
29. Sanai T, Onoyama K, Osato S, et al. Dose dependency of germanium dioxide-induced nephrotoxicity in rats. Nephron 1991;57(3):349-354.
30. Sanai T, Okuda S, Onoyama K, et al. Chronic tubulointerstitial changes induced by germanium dioxide in comparison with carboxyethylgermanium sesquioxide. Kidney International 1991;40:882-890.
31. Masaki Y, Kumano K, Iwamura M, et al. Protective effect of an organic germanium compound on warm ischemia and prolonged kidney preservation. Transplanatation Proceedings 1989;21:1250-1251.
32. Wakabayashi Y. Effect of germanium-132 on low-density lipoprotein oxidation and atherosclerosis in Kurosawa and Kusanagi hypercholesterolemic rabbits. Biosci Biotechnol Biochem 2001;65(8):1893-1896.
33. Yang MK, Kim YG. Protective role of germanium-132 against paraquat-induced oxidative stress in the livers of senescence-accelerated mice. Journal of Toxicology and Environmental Health 1999;12(58):289-297.
34. Unakar NJ, Tsui J, Johnson M. Effect of pretreatment of germanium-132 on Na(+)-K(+)-ATPase and galactose cataracts. Current Eye Research 1997;16(8):832-837.
35. Fujii A, Kuboyama N, Yamane J, Nakao S, Furukawa Y. Effect of organic germanium compound (Ge-132) on experimental osteoporosis in rats. General Pharmacology 1993;24(6):1527-1532.
36. Fujita H, Kurono M, Toyoshima S. Effect of 3-oxygermylpropionic acid polymer (SK-818) on the incidence of spontaneous leukemia in AKR mice. Pharmacometrics 1990;39(4):389-395.
37. Aso H, Suzuki F, Ebina T, Ishida N. Antiviral activity of carboxyethylgermanium sesquioxide (Ge-132) in mice infected with influenza virus. Journal of Biological Response Modifiers 1989;8(2):180-189.
38. Aso H, Shibuya E, Suzuki F, et al. Antitumor effect in mice of an organic germanium compound (Ge-132) when different administration methods are used. Gan To Kagaku Ryoho 1985;12(12):2345-2351.
39. Kumano N, Ishikawa T, Koinumaru S, et al. Antitumor effect of the organogermanium compound Ge-132 on the Lewis lung carcinoma (3LL) in C57BL/6 (B6) mice. Tohoku Journal of Experimental Medicine 1985;146(1):97-104.
40. Kobayashi H, Komuro T, Furue H. Effect of combination immunochemotherapy with an organogermanium compound, Ge-132, and antitumor agents on C57BL/6 mice bearing Lewis lung carcinoma (3LL). Gan To Kagaku Ryoho 1986;13(8):2588-2593.
41. Chen F, Zhang Q. Inhibitive effects of spirulina on aberrant crypts in colon induced by dimethylhydrazine. Zhonghua Yu Fang Yi Xue Za Zhi 1995;29(1):13-17.
42. Song WS. Experimental study on prevention of the colorectal cancer by China medical stone and the organogermanium compound. Zhonghua Yu Fang Yi Xue Za Zhi 1993;27(5):286-289.
43. Jang JJ, Cho KJ, Lee YS, Bae JH. Modifying responses of allyl sulfide, indole-3-carbinol and germanium in a rat multi-organ carcinogenesis model. Carcinogenesis 1991;4:691-695.
44. Ono M, Oka T, Yoshihara H, et al. Effect of NK-421 (bestatin) and Ge-132 on the cytotoxicity of spleen cells obtained from the tumor-bearing mice. Gan To Kangaku Ryoho 1982;9(10):1771-1777.
45. Aso H, Suzuki F, Yamaguchi T, Hayashi Y, Ebina T, Ishida N. Induction of interferon and activation of NK cells and macrophages in mice by oral administration of Ge-132, an organic germanium compound. Microbiology and Immunology 1985;29(1):65-74.
46. Nakada Y, Kosaka T, Kuwabara M, Tanaka S, Sato K, Koide F. Effects of 2-carboxyethylgermanium sesquioxide (Ge-132) as an immunological modifier of post-surgical immunosuppression in dogs. Journal of Veterinary Medical Science 1993;55(5):795-799.
47. Suzuki F, Brutkiewicz RR, Pollard RB. Ability of sera from mice treated with Ge-132, an organic germanium compound, to inhibit experimental murine ascites tumours. British Journal of Cancer 1985;52(5):757-763.
48. Suzuki F, Brutkiewicz RR, Pollard RB. Importance ot T-cells and macrophages in the antitumor activity of carboxyethylgermanium sesquioxide (Ge-132). Anticancer Research 1985;5(5):479-483.
49. Suzuki F, Pollard RB. Prevention of suppressed interferon gamma production in thermally injured mice by administration of a novel organogermanium compound, Ge-132. Journal of Interferon Research 1984;4(2):223-233.
50. Suzuki F. Suppression of tumor growth by peritoneal macrophages isolated from mice treated with carboxyethylgermanium sesquioxide (Ge-132). Gan To Kagaku Ryoho 1985;12(11):2122-2128.
51. Suzuki F, Brutkiewicz RR, Pollard RB. Cooperation of lymphokine(s) and macrophages in expression of antitumor activity of carboxyethylgermanium sesquioxide (Ge-132). Anticancer Research 1986;6(2):177-182.
52. Suzuki F. Antitumor mechanisms of carboxyethyl-germanium sesquioxide (Ge-132) in mice bearing Ehrlich ascites tumors. Gan To Kagaku Ryoho 1987;14(1):127-134.
53. Ming X, Yin H, Zhu Z. Effect of dietary selenium and germanium on the precancerous lesion in rat glandular stomach induced by N-methyl-N'-nitro-N-nitrosoguanidine. Zhonghua Wai Ke Za Zhi 1996;34(4):221-223.
54. Ikemoto K, Kobayashi M, Fukimoto T, Morimatsu M, Pollard RB, Suzuki F. 2-carboxyethylgermanium sesquioxide, a synthetic organogermanium compound, as an inducer of contrasuppressor T cells. Experientia 1996;15(52):159-166.
55. Sato I, Nishimura T, Kakimoto N, Suzuki H, Tanaka N. Prevention of pulmonary metastasis of Lewis lung carcinoma and activation of murine macrophages by a novel organic germanium compound, PCAGeS. Biological Response Modifiers 1988;7(1):1-5.
56. Tanaka N, Ohida J, Ono M, et al. Augmentation of NK activity in peripheral blood lymphocytes of cancer patients by intermittent Ge-132 administration. Gan To Kagaku Ryoho 1984;11(6):1303-1306.
57. Mainwaring MG, Poor C, Zander DS, Harman E. Complete remission of pulmonary spindle cell carcinoma after treatment with oral germanium sesquioxide. Chest 2000;117:591-593.
58. Saiers JH, Slavik M, Stephens RL, Crawford ED. Therapy for advanced renal cell cancer with spirogermanium: A Southwest Oncology Group study. Cancer Treatment Reports 1987;71(2):207-208.
59. Falkson G, Falkson HC. Phase II trial of spirogermanium for treatment of advanced breast cancer. Cancer Treatment Reports 1983;67(2):189-190.
60. Eisenhauer E, Quirt I, Connors JM, Maroun J, Skillings J. A phase II study of spirogermanium as second line therapy in patients with poor prognosis lymphoma: An NCI Canada Clinical Trials Group study. Investigational New Drugs 1985;3(3):307-310.
61. Eisenhauer E, Kerr I, Bodurtha A, et al. A phase II study of spirogermanium in patients with metastatic malignant melanoma.: An NCI Canada Clinical Trials Group study. Investigational New Drugs 1985;3(3):303-305.
62. Goodwin JW, Crowley J, Tranum B, et al. Phase II trial of spirogermanium in central nervous system tumors: A Southwest Oncology Group study. Cancer Treatment Reports 1987;71(1):99 100.
63. Ettinger DS, Finkelstein DM, Donehower RC, et al. Phase II study of N-methylformamide, spirogermanium, and 4-demethoxydaunorubicin in the treatment of non-small cell lung cancer (EST 3583): An Eastern Cooperative Oncology Group study. Med Pediatr Oncol 1989;17(3):197-201.
64. Vogelzang NJ, Gesme DH, Kennedy BJ. A phase II study of spirogermanium in advanced human malignancy. American Journal of Clinical Oncology 1985;8(4):341-344
65. McMaster M, Greco F, Johnson D, Hainsworth J. An evaluation of combination 5-fluorouracil and spirogermanium in the treatment of advanced colorectal carcinoma. Investigational New Drugs 1990;8:87-92.
66. Mirabelli C, Badger A, Sung C, et al. Pharmacological activities of spirogermanium and other structurally related azaspiranes: Effects on tumor cell and macrophage functions. Anticancer Drug Design 1989;3:231-242.
67. Import Alert IA #54-07. Germanium Products Rev. September 13, 1995.
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