Toxicology and carcinogenesis study of glycidol (CAS No. 556-52-5) in genetically modified haploinsufficient p16(Ink4a)/p19(Arf) mice (gavage study).

Abstract

Unlabelled: Glycidol is used as a chemical intermediate in the pharmaceutical industry, as a stabilizer in the manufacture of vinyl polymers, and as an intermediate in the synthesis of glycerol, glycidyl ethers, and amines. Glycidol was nominated for carcinogenicity study by the United States Environmental Protection Agency. Glycidol was selected for study in the haploinsufficient p16(Ink4a)/p19(Arf) mouse because it was found to be carcinogenic in rats and mice in conventional 2-year rodent studies (NTP, 1990), but was negative in a study in p53+/- mice (Tennant et al., 1999). Male and female haploinsufficient p16(Ink4a)/p19(Arf) mice received glycidol (greater than 95% pure) by gavage for 40 weeks. Genetic toxicology studies were conducted in mouse peripheral blood erythrocytes. 40-WEEK STUDY IN MICE: Groups of 15 male and 15 female haploinsufficient p16(Ink4a)/p19(Arf) mice were administered 0, 25, 50, 100, or 200 mg glycidol/kg body weight in deionized water by gavage, 5 days per week for 40 weeks. Survival of 200 mg/kg male and female mice was less than that of the vehicle control groups, but the differences were not significant. Mean body weights of 200 mg/kg male mice and 50, 100, and 200 mg/kg female mice were less than those of the vehicle controls. The left testis, left epididymis, and left cauda epididymis weights were significantly decreased in 200 mg/kg males; the number of sperm heads per cauda epididymis were also significantly decreased in this group. Enlarged spleen and foci of discolored liver were observed in 200 mg/kg male mice at necropsy. These findings corresponded to infiltration by histocytic sarcoma or extramedullary hematopoiesis. The incidences of histiocytic sarcoma were increased in dosed groups of males and in females administered 50 mg/kg or greater, and the incidences in 50 and 200 mg/kg males were significantly greater than that in the vehicle control group. In the lung, incidences of alveolar/bronchiolar adenoma were significantly increased in 100 mg/kg males and 200 mg/kg females; multiple adenomas were seen in some dosed males. Squamous cell papillomas of the forestomach were seen in one 200 mg/kg male, one 100 mg/kg female, and three 200 mg/kg females. Significantly increased incidences of epithelial hyperplasia occurred in the forestomach of 200 mg/kg males and females. Neuronopathy, gliosis, and hemorrhage of the brain were observed at various sites in a few 200 mg/kg males and 100 and/or 200 mg/kg females.

Genetic toxicology: The frequency of micronucleated erythrocytes was monitored in peripheral blood of male and female haploinsufficient p16(Ink4a)/p19(Arf) mice in the 40-week study. No significant increases were observed at 6.5, 13, or 19.5 weeks; small but statistically significant increases were seen in both male and female mice sampled at 26 and 40 weeks.

Conclusions: Under the conditions of this 40-week gavage study, there was clear evidence of carcinogenic activity of glycidol in male haploinsufficient p16(Ink4a)/p19(Arf) mice based on the occurrence of histiocytic sarcomas. The increased incidences of alveolar/bronchiolar adenomas in male mice were also considered to be related to glycidol administration. There was some evidence of carcinogenic activity of glycidol in haploinsufficient p16(Ink4a)/p19(Arf) female mice based on the occurrence of alveolar/bronchiolar adenoma. The occurrence of forestomach papillomas in female mice may also have been related to glycidol administration. Treatment of male and female haploinsufficient p16(Ink4a)/p19(Arf) mice with glycidol was associated with forestomach hyperplasia and neuronopathy in the and brain.