Dose-Response Relationship of Diethylnitrosamine-Initiated Tumors in Neonatal Balb/c Mice: Effect of Phenobarbital Promotion

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Abstract
The dose-response of diethylnitrosamine (DENA) initiation of hepatocarcinogenesis was determined in infant Balb/c male mice with and without subsequent phenobarbital treatment. Male Balb/c mice received a single intraperitoneal injection of DENA (0, 2.5, 10.0, 25.0 or 50.0 μg/gbw) in saline on day 15 of age. Ninety mice were treated at each dose level. At weaning, mice received either deionized drinking water (45 mice per group) or deionized drinking water containing 500 mg/L sodium phenobarbital (PB) (45 mice per group). Mice from each group were sacrificed 12, 24, and 40 weeks post-weaning. Liver and lung tumors were found in DENA-only-treated and DENA + PB-treated mice. In DENA-only-treated mice, the incidence and number of hepatic adenomas were similar (not dose-dependent) at DENA doses of 10, 25, and 50 μg/gbw at each of the 3 sampling times. DENA-only-treated mice did display a time-related increase in hepatic adenoma incidence and number at each dose. In PB-treated mice, the hepatic adenoma number was dependent upon the dose of DENA between 2.5 and 50 μg/gbw. PB treatment following DENA administration resulted in a decrease in the time required for the detection of hepatic adenomas and increased the number of hepatic adenomas at most sampling times compared to the mice that received DENA only. Hepatocellular carcinomas (HPC) were detected in mice receiving the highest DENA doses (25 and 50 μg/gbw). PB treatment increased the number and incidence of HPC and decreased the time of first detection of HPC. The incidence and number of lung adenomas per mouse induced in DENA-treated mice was linearly proportional to the DENA dose. PB had no influence on the incidence or number of DENA-induced lung adenomas.