Abstract for TR-238

A carcinogenesis bioassay of ziram (89% pure, with 6.5% thiram), a fungicide and a rubber vulcanization accelerator, was conducted in F344/N rats and in B6C3F1 mice. Groups of 50 rats of each sex received diets containing 300 or 600 ppm of commercial grade ziram for 103 weeks; groups of 49 or 50 mice of each sex received diets containing 600 or 1,200 ppm ziram; and groups of 50 rats and 50 mice of each sex served as untreated controls.

The average daily consumption of ziram by low-and high-dose rats, through the majority of the study, was about 11 and 22 mg/kg for males and 13 and 26 for females. The average daily consumption of ziram by low-and high-dose mice, through the majority of the study, was 122 and 196 mg/kg for males and about 131 and 248 mg/kg for females.

Survival and feed consumption and mean body weights of rats of each sex were not adversely affected by ziram; rats of each sex could have tolerated higher doses.

C-Cell carcinomas of the thyroid in male rats occurred with a statistically significant positive trend (P<0.01) and the incidence in the high-dose group was significantly higher (P<0.05) than that in the controls (control, 0/50, 0%; low-dose, 2/49, 4%; high-dose, 7/49, 14%) and higher than that previously observed in control male rats at the same laboratory (18/584, 3%; range 0% to 8%). The combined incidence of males with either C-cell adenoma or carcinoma also showed a statistically significant (P<0.05) positive trend (control, 4/50, 8%; low-dose, 9/49, 18%; high-dose, 12/49, 24%). There were no significant histopathologic changes noted in the follicular cells.

Survival of male and female mice was not adversely affected by ziram in feed; mean body weight gain by dosed male mice throughout the study and by high-dose female mice after week 80 was depressed by 15% to 20% relative to the controls. Average daily feed consumption by high-dose males and high-dose females was, respectively, 78% and 85% that of the controls. Mice probably could not have tolerated higher doses.

The incidence of alveolar/bronchiolar adenomas was significantly (P<0.05) increased in female mice (control, 2/50, 4%; low-dose, 5/49, 10%; high-dose, 10/50, 20%). The combined incidence of alveolar/bronchiolar adenomas or carcinomas in female mice showed a statistically significant (P<0.05) positive trend. The incidence in the high-dose group was significantly (P<0.05) higher than that in the controls (control, 4/50, 8%; low-dose, 6/49, 12%; high-dose, 11/50, 22%). Pulmonary adenomatous hyperplasia consistent with chronic Sendai virus infection (confirmed by serologic analysis performed on untreated animals from the same animal shipment and present in the same room) was observed in control and dosed male mice (control, 15/49, 31%; low-dose, 19/50, 38%; high-dose, 16/49, 33%) as well as in control and dosed female mice (control, 18/50, 36%; low-dose, 27/49, 55%; high-dose, 26/50, 52%). Six of the 26 high-dose females without pulmonary adenomatous hyperplasia had pulmonary tumors, whereas 4 of the 24 high-dose females without pulmonary adenomatous hyperplasia also had pulmonary tumors. Only 1 of 27 low-dose females with adenomatous hyperplasia had a pulmonary tumor.

There was a significant decrease in the incidence of mammary fibroadenomas in high-dose female rats (control, 16/50, 32%; low-dose, 17/50, 34%; high-dose, 8/50, 16%). Significant dose-related decreased incidences of liver carcinomas in male mice (control, 13/49, 27%; low-dose, 8/50, 16%; high-dose, 1/49, 2%) and of liver adenomas in female mice (control, 7/50, 14%; low-dose, 2/50, 4%; high-dose, 0/50, 0%) were observed.

Under the conditions of these studies, ziram was carcinogenic for male F344/N rats, causing increased incidences of C-cell carcinomas of the thyroid gland. Ziram was not carcinogenic for either female F344/N rats or for male B6C3F1 mice. Increased incidences of alveolar/bronchiolar adenomas and of combined alveolar/bronchiolar adenomas or carcinomas occurred in female B6C3F1 mice. However, the interpretation of this increase in lung tumors is complicated by an intercurrent Sendai virus infection.