Carcinogenic effects of sequential administration of two nitrosamines in Fischer 344 rats

The carcinogenic effects of sequential treatment of female F344 rats with two nitrosamines were studied. The animals received either methylethylnitrosamine (NMEA), a strong liver carcinogen, N-nitrosomethylaniline (NMA), a moderately strong esophageal carcinogen, or N-nitrosopyrrolidine, (NPyr), a weaker liver carcinogen. The sequentially treated groups were given NMEA followed by NMA and vice versa, NPyr followed by NMEA and vice versa. The dose and duration for each chemical in the sequentially treated groups were identical for the individual treatments. The animals were allowed to die or were killed when moribund. The animals surviving longer than 110 weeks were sacrificed. The NMEA-NPyr and NPyr-NMEA groups had a tumor spectrum characteristic for NMEA alone (a mixture of hepatic carcinomas and sarcomas with extensive metastases to the lungs). The survival was reduced in the NMEA-NPyr group compared to the NMEA alone group. The time to death of the NMA-NMEA group was not affected by the NMA treatment, but many of the animals had esophageal neoplasms. The NMEA-NMA group survival was reduced when compared to the NMEA alone group but the tumor spectrum was dominated by NMEA. The data indicate that when the target organ is the same, the effect of two nitrosamines is additive with the stronger carcinogen dominating the tumor spectrum. When the target organs are different, the initial exposure influences the tumor spectrum, although the treatment with the second nitrosamine enhances the tumorigenicity of the initial nitrosamine.