A Study of the Carcinogenic Action of Urethan in Mice

Abstract

Urethan was given at 0.4 percent in the drinking water to 5-week old female and male CTM mice, an albino outbred strain: 2 groups were given urethan for one or two periods of 10 days, 3 other groups for one, two or three periods of 5 days, with intervals of 10 days. The treatment produced a toxic effect: 20 to 40 percent of the animals receiving urethan for the longer periods died with atrophy of the thymus, spleen, lymph nodes and bone marrow, and pulmonary congestion and hemorrhages. In addition, 2 groups of newborn mice received a single subcutaneous injection of either 1 mg or 3 mg of urethan within 24 hours after birth; about 10 percent of these mice died before weaning time. A group of 200 untreated animals was used as control. In all groups tumors were observed: 94.1 percent of all treated females, 88.7 percent of all treated males, 51.5 percent of control females and 17.1 percent of control males developed tumors. Lymphosarcomas were observed in 21.5 percent of the treated females and in 20.1 percent of the treated males, while among the controls the incidence was of 5.0 and 4.5 percent. The greatest incidence was found in the group given urethan for 2 periods of 10 days at 5 weeks of age, 27.0 percent for the females and 33.3 percent for the males, and in the group given 3 mg of urethan at birth, in which 35.3 percent of the females and 24.2 percent of the males developed lymphosarcomas. The latent period, calculated as the harmonic mean of the age at death, was of 31.9 weeks for all lymphosarcomas in treated mice, against 60.1 weeks for the lymphosarcomas in the controls; however, 7 lymphosarcomas which developed among an indeterminable number of female breeders, had a mean latent period of 29.9 weeks. Out of a total of 136 lymphosarcomas observed in all treated groups, 103 (75.7%) were thymic lymphosarcomas, while in the control group there were 2 thymic lymphosarcomas out of 9 lymphosarcomas; the others were generalized lymphosarcomas of indeterminate origin. Neither epithelial thymomas nor granulocytic leukemias were observed. A small number of reticulum-cell sarcomas were also observed in the control and in the treated group, with a mean latent period of 72.0 and 52.5 weeks respectively. Mammary adenocarcinomas developed in 31 percent control virgin females, in 38 percent females treated at 5 weeks, and in approximately 25 percent female breeders, with a mean latent period of 57.5, 37.3 and 40 weeks respectively. In the treated females, multiple mammary tumors were more frequent. Surprisingly, only 3 females out of 58 treated with urethan at birth had mammary carcinoma; in addition there were 2 sarcomas arising in the mammary tissue. On the contrary, there was a much higher incidence of hepatomas in the group treated at birth (33.3 percent in the females, 70.9 percent in the males) than in the animals treated as young adults (1.3 and 5.9 percent); in the control group, there were 4.5 percent hepatomas in the males and none in the females. Lung adenomas were seen in 42 to 84 percent of the treated animals, while in the control group there was an incidence of 7 percent in the females and of 2 percent in the males. Of the other tumors observed, liver angiomas and harderian glands tumors only had an incidence significantly higher than the controls. There was often coexistence of different tumors: in 12 cases the same animal had mammary adenocarcinoma and malignant lymphoma.