Ethanol has a strong influence on the risk of several types of human cancer, especially in synergism with tobacco use, even though it is itself not carcinogenic or genotoxic. A likely mechanism of its action is through potentiation of the genotoxic effects of carcinogens present in environmental sources such as cigarette smoke. Interaction of ethanol with these carcinogens, especially nitrosamines, is therefore being studied in mice and in nonhuman primates. In a study of the enhancement of N-nitrosodimethylamine (NDMA) tumorigenesis by ethanol in mice, (1) an ethanol concentration as low as 1% in the drinking water was sufficient to give a maximal, 4-fold increase in lung tumorigenesis; (2) with chronic exposure to 1 ppm over 18 months, there was a cumulative enhancing effect, and kidney tumors were also significantly increased; and (3) no enhancing effect occurred when the NDMA and ethanol were not given simultaneously and by the same oral route. These results illustrate the efficacy of this synergistic action of ethanol and support inhibition of first-pass hepatic cytochrome P450 2E1-dependent clearance of NDMA by ethanol as the mechanism of effect. The latter phenomenon was investigated in a toxicokinetic study with nonhuman primates (patas monkeys), to begin to extend the concept to humans. Co-administration of NDMA with ethanol or other inhibitors of P450 2E1 resulted in large increases in area under the blood concentration vs time curves, mean residence times, and amounts excreted in urine (see ZO1CP05092).
