Carcinogenicity study of poly-<i>trans</i>-[(2-carboxyethyl)germasesquioxane] (Ge-132) in F344 rats

Abstract

There were no adverse effects on survival rate, food consumption or hematology data, although diarrhea and bodyweight retardation were observed in the male and female 2.5% groups. Significant increases of kidney and adrenal weights were noted in both male and female 2.5% group. Macroscopically, dilatation of the cecum was observed in both male and female 2.5% group, and enlargement of the adrenals was observed in the male of 2.5% group. Significantly higher incidences of benign or malignant pheochromocytoma were observed in the male 1.3% group and both male and female 2.5% groups. Significantly positive trends were noted in the incidences of kidney pelvic and papilla mineralization in both sexes and cortico-medullary junction in females. To investigate possible mechanisms underlying Ge-132-associated development of pheochromocytoma, male F344 rats were administered diets containing 0, 0.6, or 2.5% Ge-132 for 4 or 13 weeks. Although loose stools and increasing water consumption were observed in treated groups, there were no bodyweight retardation. Significant elevation of inorganic phosphorus in the serum was found in the 2.5% group at week 13. Dilatation of the cecum and increased cecum weight were evident macroscopically in the 2.5% group. Significant elevation of Ki-67 positive ratio in adrenal medullary cells was also found in the 2.5% group. These data indicated that Ge-132 ingestion induced disturbance in calcium/phosphorus homeostasis, and secondarily induced the development of benign or malignant pheochromocytoma in rats. Such secondary pheochromocytomas are considered to be not relevant for human risk assessment.

Organogermanium THGP Induces Differentiation into M1 Macrophages and Suppresses the Proliferation of Melanoma Cells via Phagocytosis

“…In animal experiments, administration of 0.05% Ge-132 (40-70 mg/kg) for 30 days did not lead to signs of toxicity in mice, such as weight loss. In previous studies, the toxicity of Ge-132 has been investigated in various animal species (mouse, rat and dog), and its safety (extremely low toxicity) has been documented [60][61][62]. The LD50 was also determined in experiments using mice or rats, and its concentration was confirmed to be greater than 11 g/kg following oral administration [63].…”

The Organogermanium Compound 3-(Trihydroxygermyl) Propanoic Acid (THGP) Suppresses Inflammasome Activation Via Complexation with ATP

“…In another study, daily administration of 5000 mg/kg Ge-132 did not cause any of the rats to die, and the maximum safe dose was estimated to be 1667 mg/kg [ 43 , 44 ]. Furthermore, it has been reported that oral Ge-132 is noncarcinogenic in mice and rats up to a concentration of 1,500 mg/kg/day [ 45 , 46 ]. A phase I study in Japan showed that in humans, Ge-132 is nontoxic up to a concentration of 75 mg/kg [ 47 ].…”

Physiological Activity of Trace Element Germanium Including Anticancer Properties

“…Regarding concerns over the alleged high toxicity of Ge-132 (see Chapter 2), its toxicity [56][57][58] and possible carcinogenicity [81,82] have been studied many times over the past 10 years. The results of the research once again confirmed the complete safety of Ge-132.…”