Fundamental Toxicological Sciences

Paper Details

Fundamental Toxicological Sciences
Vol. 5 No. 4 July 10, 2018 p.127-140
Original Article
Carcinogenicity study of poly-trans-[(2-carboxyethyl)germasesquioxane] (Ge-132) in F344 rats
  • Katsuharu Iwadate (Central Institute, New Drug Research Center, Inc. /
Katsuharu Iwadate 1) , Yukari Yamaguchi 1) , Mai Sasaki 1) , Mikiya Nakatani 1) , Yuko Doi 2) , Norio Imai 2) , Seiko Tamano 2) , Yorifumi Nishihori 1)
1) Central Institute, New Drug Research Center, Inc. , 2) DIMS Institute of Medical Science, Inc.
Keywords: Poly-trans-[(2-carboxyethyl)germasesquioxane], Carcinogenicity study, Rat, Pheochromocytoma, Hypercalcemia, Ge-132

Ge-132 was administered to both sexes of F344 rats at dietary levels of 0, 0.6, 1.3, and 2.5% for 2 years. There were no adverse effects on survival rate, food consumption or hematology data, although diarrhea and body-weight 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 body-weight 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.