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Hazard assessment of germanium supplements.
Tao SH, Bolger PM.
Center for Food Safety and Applied Nutrition, Food and Drug Administration, Washington, DC 20204, USA.
Germanium-containing dietary supplements became popular in the 1970s in Japan and later in other countries, as elixirs for certain diseases (e.g., cancer and AIDS). Germanium is not an essential element. Its acute toxicity is low. However, at least 31 reported human cases linked prolonged intake of germanium products with renal failure and even death. Signs of kidney dysfunction, kidney tubular degeneration, and germanium accumulation were observed. Other adverse effects were anemia, muscle weakness, and peripheral neuropathy. Recovery of renal function is slow and incomplete even long after germanium intake was stopped. The total dose of ingested germanium (as dioxide, carboxyethyl germanium sesquioxide, germanium-lactate-citrate, or unspecified forms) varied from 15 to over 300 g; the exposure duration varied from 2 to 36 months. In laboratory animals, elevated germanium in tissues and impaired kidney and liver function were observed in a life-time drinking water (5 ppm germanium) study. Other toxicities associated with ingested germanium products in human cases were also demonstrated in animal studies with germanium dioxide and sometimes other germanium compounds. Based on the evidence of persistent renal toxicity associated with germanium dioxide, the lack of conclusive findings of differential nephrotoxicity of organic germanium compounds, and the possibility of contamination of the organic germanium products with inorganic germanium, it is clear that germanium products present a potential human health hazard.
Complete remission of pulmonary spindle cell carcinoma after treatment with oral germanium sesquioxide.
Mainwaring MG, Poor C, Zander DS, Harman E.
Department of Medicine, Divisions of Hematology and Oncology, University of Florida College of Medicine and Veterinary Affairs Medical Center, Gainesville, FL 32610, USA. [email protected]
Spindle cell carcinoma (SCC) is a rare form of lung cancer representing 0.2 to 0.3% of all primary pulmonary malignancies. Even with combined surgery, chemotherapy, and radiation therapy, these tumors are associated with a poor prognosis and only 10% of patients survive 2 years after diagnosis. We describe a patient with an unresectable SCC who, following no response to conventional treatment with combined modality therapy, chose to medicate herself with daily doses of germanium obtained in a health food store. She noted prompt symptomatic improvement and remains clinically and radiographically free of disease 42 months after starting her alternative therapy.
Germanium is an elemental metal discovered in 1886 and was used primarily in transistor technology. Preclinical studies during the 1970s showed that two germanium compounds had antineoplastic activity: spirogermanium and germanium sesquioxide. Preclinical studies with germanium compounds revealed antitumor activity in several tissue culture cell lines, including Walker 256 carcinosarcoma,5 and promoted several phase I/II clinical studies on advanced malignancies including lung,6 breast,7 renal,8 and prostate cancers.9 10 Unfortunately germanium sesquioxide and spirogermanium showed extremely limited activity in these studies and significant dose-related nephrotoxicity and neurotoxicity.11
Nephrotoxicity and neurotoxicity in humans from organogermanium compounds and germanium dioxide.
Schauss AG.
Life Sciences Division, American Institute for Biosocial Research, Inc., Tacoma, WA 98401.
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 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 mumol/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 (greater than 3 mo) Ge supplementation at levels well above the estimated daily intake be medically supervised and monitored for potential renal-, pulmonary- or neurotoxicity. Further study regarding the mechanism of Ge-induced nephrotoxicity in human is warranted.
Nephrotoxicity in humans by the ultratrace element germanium.
Schauss AG.
Life Sciences Division, American Institute for Biosocial Research, Inc., Tacoma, Washington 98401.
Acute renal failure (ARF) or renal dysfunction (RD) associated with germanium-induced nephrotoxicity has been reported in 18 patients since 1982. In 2 of these cases the patients died of acute renal and cardiogenic failure. In 17 of 18 cases biopsies showed vacuolar degeneration in renal tubular epithelial cells in the absence of glomerular changes, without proteinuria or hematuria. Accumulated elemental Ge intake in 17 patients over a period of 4 to 36 months ranged between 16 and 328 g, or more than 100 to 2000 times the average estimated dietary intake of Ge for man (1.5 mg/d; range 0.40 to 3.40 mg/d). The biological half-life of Ge is 4.5 days for kidneys, the highest retention level of any organ. The mean concentration of Ge in healthy adult kidneys is 9.0 mg/kg wet weight. In 3 patients studied with Ge-induced RD or ARF, urinary Ge excretion was 9, 15, and 60 ng/mL, compared to greater than 5 ng/mL in healthy controls, and remained elevated even 12 months after discontinuing supplemental Ge intake. The mechanism for Ge-induced nephrotoxicity remains unknown, although the suspected cause is the inorganic Ge salts, such as germanium dioxide. Sufficient evidence for a role of organogermanium compounds, such as carboxyethyl germanium sesquioxide or citrate-lactate germanate, in Ge-induced nephrotoxicity remains lacking. The recent introduction of over-the-counter Ge "nutritional" supplements in some countries increases the risk of additional cases of Ge-induced nephrotoxicity, especially if appreciable levels of inorganic Ge salts are present and consumed for long periods (greater than 3 months) at levels above the average daily estimated dietary intake for Ge.
Tao SH, Bolger PM.
Center for Food Safety and Applied Nutrition, Food and Drug Administration, Washington, DC 20204, USA.
Germanium-containing dietary supplements became popular in the 1970s in Japan and later in other countries, as elixirs for certain diseases (e.g., cancer and AIDS). Germanium is not an essential element. Its acute toxicity is low. However, at least 31 reported human cases linked prolonged intake of germanium products with renal failure and even death. Signs of kidney dysfunction, kidney tubular degeneration, and germanium accumulation were observed. Other adverse effects were anemia, muscle weakness, and peripheral neuropathy. Recovery of renal function is slow and incomplete even long after germanium intake was stopped. The total dose of ingested germanium (as dioxide, carboxyethyl germanium sesquioxide, germanium-lactate-citrate, or unspecified forms) varied from 15 to over 300 g; the exposure duration varied from 2 to 36 months. In laboratory animals, elevated germanium in tissues and impaired kidney and liver function were observed in a life-time drinking water (5 ppm germanium) study. Other toxicities associated with ingested germanium products in human cases were also demonstrated in animal studies with germanium dioxide and sometimes other germanium compounds. Based on the evidence of persistent renal toxicity associated with germanium dioxide, the lack of conclusive findings of differential nephrotoxicity of organic germanium compounds, and the possibility of contamination of the organic germanium products with inorganic germanium, it is clear that germanium products present a potential human health hazard.
Complete remission of pulmonary spindle cell carcinoma after treatment with oral germanium sesquioxide.
Mainwaring MG, Poor C, Zander DS, Harman E.
Department of Medicine, Divisions of Hematology and Oncology, University of Florida College of Medicine and Veterinary Affairs Medical Center, Gainesville, FL 32610, USA. [email protected]
Spindle cell carcinoma (SCC) is a rare form of lung cancer representing 0.2 to 0.3% of all primary pulmonary malignancies. Even with combined surgery, chemotherapy, and radiation therapy, these tumors are associated with a poor prognosis and only 10% of patients survive 2 years after diagnosis. We describe a patient with an unresectable SCC who, following no response to conventional treatment with combined modality therapy, chose to medicate herself with daily doses of germanium obtained in a health food store. She noted prompt symptomatic improvement and remains clinically and radiographically free of disease 42 months after starting her alternative therapy.
Germanium is an elemental metal discovered in 1886 and was used primarily in transistor technology. Preclinical studies during the 1970s showed that two germanium compounds had antineoplastic activity: spirogermanium and germanium sesquioxide. Preclinical studies with germanium compounds revealed antitumor activity in several tissue culture cell lines, including Walker 256 carcinosarcoma,5 and promoted several phase I/II clinical studies on advanced malignancies including lung,6 breast,7 renal,8 and prostate cancers.9 10 Unfortunately germanium sesquioxide and spirogermanium showed extremely limited activity in these studies and significant dose-related nephrotoxicity and neurotoxicity.11
Nephrotoxicity and neurotoxicity in humans from organogermanium compounds and germanium dioxide.
Schauss AG.
Life Sciences Division, American Institute for Biosocial Research, Inc., Tacoma, WA 98401.
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 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 mumol/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 (greater than 3 mo) Ge supplementation at levels well above the estimated daily intake be medically supervised and monitored for potential renal-, pulmonary- or neurotoxicity. Further study regarding the mechanism of Ge-induced nephrotoxicity in human is warranted.
Nephrotoxicity in humans by the ultratrace element germanium.
Schauss AG.
Life Sciences Division, American Institute for Biosocial Research, Inc., Tacoma, Washington 98401.
Acute renal failure (ARF) or renal dysfunction (RD) associated with germanium-induced nephrotoxicity has been reported in 18 patients since 1982. In 2 of these cases the patients died of acute renal and cardiogenic failure. In 17 of 18 cases biopsies showed vacuolar degeneration in renal tubular epithelial cells in the absence of glomerular changes, without proteinuria or hematuria. Accumulated elemental Ge intake in 17 patients over a period of 4 to 36 months ranged between 16 and 328 g, or more than 100 to 2000 times the average estimated dietary intake of Ge for man (1.5 mg/d; range 0.40 to 3.40 mg/d). The biological half-life of Ge is 4.5 days for kidneys, the highest retention level of any organ. The mean concentration of Ge in healthy adult kidneys is 9.0 mg/kg wet weight. In 3 patients studied with Ge-induced RD or ARF, urinary Ge excretion was 9, 15, and 60 ng/mL, compared to greater than 5 ng/mL in healthy controls, and remained elevated even 12 months after discontinuing supplemental Ge intake. The mechanism for Ge-induced nephrotoxicity remains unknown, although the suspected cause is the inorganic Ge salts, such as germanium dioxide. Sufficient evidence for a role of organogermanium compounds, such as carboxyethyl germanium sesquioxide or citrate-lactate germanate, in Ge-induced nephrotoxicity remains lacking. The recent introduction of over-the-counter Ge "nutritional" supplements in some countries increases the risk of additional cases of Ge-induced nephrotoxicity, especially if appreciable levels of inorganic Ge salts are present and consumed for long periods (greater than 3 months) at levels above the average daily estimated dietary intake for Ge.
