Potential effect of germanium exposure on the risk of influenza-like illness in housewives in Shanxi Province, China.

Few studies have examined the relationship between exposure to germanium (Ge) and the risk of influenza-like illness (ILI). Therefore, we investigated the association of Ge exposure and its interaction with single nucleotide polymorphisms (SNPs) related to Phase II metabolism on ILI risk among housewives in Shanxi Province, northern China. This cross-sectional study enrolled 373 housewives. Information on the housewives' characteristics and the frequency of ILI was collected by questionnaire. We analyzed the Ge concentrations in hair samples taken from near the scalp at the back of the head. Blood samples were used to identify SNPs related to Phase II metabolism. The results suggested that the hair Ge concentration was associated with ILI risk with an adjusted odds ratio and 95% confidence interval of 2.59 (1.61-4.19). A significant dose-response relationship was observed without or with adjusting for confounders. We did not observe any interaction effect between the hair Ge concentration and the SNPs on ILI risk. We found that high dietary consumption of meat and fried foods was positively correlated with the hair Ge concentration. Therefore, chronic Ge exposure may be a risk factor for an increased frequency of ILI in housewives.

Epidemiological survey of workers exposed to inorganic germanium compounds.

OBJECTIVES: To assess occupational exposure to inorganic germanium (Ge) in workers from a producing plant, and to assess the health of these workers, with a special focus on respiratory, kidney, and liver functions. METHODS: Cross sectional study of 75 workers exposed to Ge and 79 matched referents. Exposure was characterised by measuring air and urine concentrations of the element during a typical working week, and health was assessed by a questionnaire, clinical examination, lung function testing, chest radiography, and clinical chemistry in serum and urine, including high and low molecular weight urinary proteins. RESULTS: Airborne concentrations of Ge (inhalable fraction) ranged from 0.03 to 300 micrograms/m, which was reflected by increased urinary excretion of Ge (0.12-200 micrograms/g creatinine, after the shift at the end of the working week). Lung, liver, and haematological variables were not significantly different between referents and workers exposed to Ge. A slightly higher urinary concentration of high molecular weight proteins (albumin and transferrin) was found in workers exposed to Ge, possibly reflecting subclinical glomerular changes. No relation was found between the intensity or duration of exposure and the urinary concentration of albumin. No difference between referents and workers exposed to Ge was found for other renal variables. CONCLUSIONS: Measurement of urinary Ge can detect occupational exposure to inorganic Ge and its compounds. It is prudent to recommend the monitoring of renal variables in workers exposed to Ge.

Hazard assessment of germanium supplements.

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.

[Fatal multiple organ system dysfunction associated with germanium metal used in complementary therapy].

The element germanium is widely distributed in nature. It is used in industry as a semiconductor and there have been a few attempts to use it in medicine. In the past few years 20 patients have been described in the literature as suffering from germanium overdosage. Like laboratory animals affected by the element, they suffer from renal failure and injury to other organs. We describe a 52-year old man given germanium to prevent recurrence of a brain tumor. He developed multiple organ dysfunction syndrome and died of intractable hyperdynamic shock. We call for caution regarding morbidity resulting from treatments believed safe.

Tubulointerstitial nephropathy persisting 20 months after discontinuation of chronic intake of germanium lactate citrate.

Two young human immunodeficiency virus (HIV)-infected patients, a 25-year-old woman and a 26-year-old man, consumed large amounts of germanium lactate citrate 18% as an "immunostimulant" for 9 months. The woman, who had stage II HIV infection, developed severe renal dysfunction (creatinine clearance, 7 mL/min/1.73 m2) and slight proteinuria (0.28 g/d) after ingesting 260 g germanium lactate citrate 18%. Hepatomegaly with liver dysfunction (SGOT, 102 U/L; gamma-glutamyl transferase (GT), 159 U/L) and lactic acidosis (plasma lactate, 7.3 mmol/L) developed simultaneously. Renal biopsy revealed tubulointerstitial nephropathy with vacuolar cell degeneration and periodic acid-Schiff-positive intracellular deposits mainly in distal tubules. Liver biopsy disclosed severe hepatic steatosis; liver function tests returned to normal within 5 weeks. Since renal failure persisted for 2 years after ingestion of germanium (creatinine clearance, 14 mL/min/1.73 m2; proteinuria, 0.84 g/d), a second renal biopsy was performed, which showed marked but focal distal tubular atrophy and slight interstitial fibrosis. The male patient, who had stage III HIV infection, had ingested the same compound; he presented with a creatinine clearance of 43 mL/min/m2 and proteinuria of 0.36 g/d. Renal biopsy disclosed tubulointerstitial changes similar to those found in the female patient. After 9 months off germanium, creatinine clearance remained unchanged. Neutron activation analysis of all biopsy specimens in both cases documented germanium concentrations 10 to 70 times normal in renal tissue and 140 times normal in liver tissue.

[A patient with liver cirrhosis manifesting various symptoms including cerebellar ataxia due to germanium intoxication].

A patient with hepatitis B virus-associated cirrhosis manifested various symptoms such as anemia, renal damage and neurological signs including cerebellar ataxia due to long-term administration of germanium-containing food. The patient was a 40-year-old male who had taken germanium containing mineral cheese for 26 months after he was diagnosed as having cirrhosis. Twenty four months after beginning to take the mineral cheese, he began manifesting paresthesia of the extremities, dysarthria and gait ataxia. Laboratory findings revealed anemia and renal damage. Biopsy of the peripheral nerve revealed loss of the large sheathed nerve, a characteristic feature of germanium intoxication. A high concentration of germanium (GeO2) was detected in patient's hair and urine. Cerebellar ataxia was characteristic in this patient, which was not reported in the previous papers.

[Toxicity of an organic Germanium compound: deleterious consequences of a "natural remedy"]. / Toxizität einer organischen Germanium-Verbindung: Deletäre Folgen eines "Naturheilmittels"

Reports mainly from Japan, recommend germanium (Ge)-containing compounds as "anti-cancer" and "immunostimulatory" remedies. We report on a 25-tear-old woman with stage II HIV disease who consumed a total of 47 g Ge as Ge-lactate-citrate 18%. She developed severe renal insufficiency (creatinine clearance 7 ml/min/1.73 m2, proteinuria 0.28 g/d) and hepatomegaly. Biopsies revealed tubulointerstitial nephropathy with vacuolar degeneration, mainly of distal tubular epithelia, and severe liver steatosis. Tissue Ge content in kidney and liver biopsy specimens was increased 68-and 140 fold respectively. In agreement with previous reports, renal dysfunction persisted 9 months later (creatinine clearance 11 ml/min/1.73 m2).

[Toxic damage of kidney, liver and muscle attributed to the administration of germanium-lactate-citrate]. / Toxische beschadiging van nier, lever en spier toegeschreven aan het gebruik van germanium-lactaat-citraat.

The case history is described of a woman aged 57 years with renal, hepatic and muscular damage attributed to intake of germanium lactate-citrate (a cumulative dose of 32.1 g germanium) over at least one year, as alternative treatment of metastatic breast cancer. Histological examination of biopsies showed highly vacuolated cytoplasm of the epithelial cells of the distal renal tubules and micro- and macrovesicular steatosis of centrilobular hepatocytes. After discontinuation of the germanium, serum aminotransferases and creatine kinase values returned to normal, but moderately severe renal impairment persisted.

Nephrotoxicity in humans by the ultratrace element germanium.

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.(ABSTRACT TRUNCATED AT 250 WORDS)

Germanium dioxide-induced nephropathy: a new type of renal disease.

Chronic renal failure developed in 5 patients who were taking germanium dioxide (GeO2)-containing compounds. Renal functional deterioration was slow but progressive and dialysis treatment was necessitated temporarily in 2 patients. After the discontinuation of GeO2, the impaired renal function tended to improve but remained abnormal for an observation period of 10-40 months. The lack of proteinuria and hematuria was characterized as the clinical manifestations. Renal biopsy specimens revealed the tubular epithelial cell degeneration containing hematoxylin-positive fine granules on light microscopy, and electron-dense inclusions in the swollen mitochondria on electron microscopy. These findings localized mainly in distal segment of the tubules. In the rats given GeO2 orally for 10 weeks, similar histological lesions were evident, as manifested by marked weight loss, anemia, azotemia, and negative proteinuria. In the rats given carboxyethylgermanium sesquioxide, these changes were not observed and Ge concentration of kidney was significantly lower than in the rats given GeO2. The present study indicates that chronic GeO2 intake causes progressive renal dysfunction characterized by the degeneration of distal tubules.

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.

One hundred forty-four patients with non-small cell lung cancer, the majority (72%) of whom had received previous chemotherapy, were evaluable in this randomized phase II study of N-methylformamide (N-MF), spirogermanium, and 4-demethoxydaunorubicin. There were two partial responses, one each with spirogermanium and 4-demethoxydaunorubicin. There were eight life-threatening complications (mostly hematologic) and two lethal complications (N-MF, hematologic; 4-demethoxydaunorubicin, gastrointestinal). The overall survival ranged from 9 days to 533 days with a median of 17.6 weeks. The following factors were associated with poor survival: Poor initial performance status, prior weight loss, presence of liver or subcutaneous metastases.

Germanium myopathy: clinical and experimental pathological studies.

Pathological examinations were carried out on the skeletal muscle of a patient with germanium intoxication. The prominent histochemical finding was vacuolar myopathy with lipid excess, increased acid phosphatase activity and decreased cytochrome c oxidase activity. Ultrastructural lesions revealed a mitochondrial abnormality, autophagic vacuoles and accumulation of high electron-dense materials in deformed mitochondria and at the periphery of lipid droplets. Furthermore, the toxic effect of germanium on skeletal muscle was confirmed by the experimentally induced germanium myopathy, which showed autophagic degeneration, decreased cytochrome c oxidase activity and a mitochondrial abnormality with high electron-dense materials.

Germanium-induced nephropathy: report of two cases and review of the literature.

We report two cases of renal failure following long-term ingestion of germanium dioxide (GeO2) and comment on eight other cases reported in Japan. Ge-induced nephropathy is characterized by insidious onset of renal failure without proteinuria or hematuria after oral intake of Ge-containing compounds for more than several months, and by degeneration of renal tubular cells with minor glomerular abnormality in histology. When patients ceased to ingest Ge compounds, renal function gradually recovered but never returned to the normal range. Serious extrarenal complication can contribute to an unfavorable prognosis.