title: Bioassay of ICRF-159 for possible carcinogenicity.
abstract: A bioassay of the experimental anticancer drug ICRF-159 for possible carcinogenicity was conducted by administering the compound by intraperitoneal injection to Sprague-Dawley rats and B6C3F1 mice. Groups of 35 rats and 35 mice were injected three times per week with ICRF-159 in buffered saline at one of the following doses, either 48 or 96 mg/kg body weight for the rats and either 40 or 80 mg/kg body weight for the mice. Both rats and mice were dosed for 52 weeks, then observed for 29-34 additional weeks. Untreated-control and vehicle-control groups each consisted of 10 rats and 15 mice of each sex; pooled-control groups consisted of the 10 vehicle controls of each sex of the rats combined with 30 vehicle controls of each sex of rats from similar bioassays of three other chemicals and the 15 vehicle controls of each sex of the mice combined with 30 vehicle controls of each sex of mice from similar bioassays of two other chemicals. All surviving rats were killed at 81-86 weeks; all surviving mice, at 86 weeks. Mean body weights were depressed in rats and mice administered ICRF-159, and mortality was dose related among male and female rats and male mice. The high mortality among the male rats may have been associated with inflammatory lesions observed in the lungs, the liver, and the pleural and peritoneal cavities. Sufficient numbers of female rats and of both male and female mice were at risk for development of late-appearing tumors. In the male rats, time-adjusted analysis of the incidence of tumors was used for determining statistical significance. In female rats, the incidence of uterine adenocarcinomas was higher in the low- and high-dose groups (P>0.001) than in the pooled controls (controls 0/38, low-dose 10/33, high-dose 11/32); the incidence was also dose related (P<0.001). In male rats, no tumors occurred in the dosed groups in a significantly increased incidence. In female mice, the incidence of all hematopoietic neoplasms (histiocytic lymphomas, lymphocytic lymphomas, or lymphocytic leukemias), taken together, was higher in the low-dose group (P=0.038) and in the high-dose group (P=0.002) than in the pooled controls (controls 1/45, low-dose 5/31, high-dose 9/34); the incidence was also dose related (P=0.002). In addition, the incidence of these tumors in the high-dose group was higher (P=0.026) than that in the vehicle controls (0/15), and the incidence was dose related (P=0.021) using the vehicle controls. In male mice, lymphocytic neoplasms occurred only in two low-dose and two high-dose animals. It is concluded that under the conditions of this bioassay, ICRF-159 was carcinogenic for female Sprague-Dawley rats, producing uterine adenocarcinomas, and was also carcinogenic for female B6C3F1 mice, producing lymphomas.