The sensitivity of experimental animals and humans to chemical carcinogens may be greatly influenced by coexposure to other environmental chemicals. We have been examining, as a model for such interactions, the influence of ethanol on metabolism of nitrosamines as influencing tumor initiation. Ethanol cotreatment of mice with N-nitrosodimethylamine (NDMA) potentiated lung tumorigenesis only if given orally and simultaneously. The effect of exposure to the carcinogen by other routes, including i.v., s.c., or i.p., was not altered by ethanol in the drinking water. A concentration of ethanol as low as 1% in the drinking water resulted in a fourfold increase in average number of lung tumors. These findings are all consistent with ethanol acting primarily via competitive inhibition of NDMA metabolism during first-pass clearance in the liver by cytochrome P450 IIE1. A prediction of this hypothesis was that lung tumors should be increased by ethanol cotreatment with other nitrosamines metabolized by P450 IIE1, such as N-nitrosodiethylamine (NDEA) and N-nitrosopyrollidine (NPy), and experimental test of this prediction gave affirmative results. Ethanol cotreatment increased lung tumorigenesis by 6.8 ppm NDEA to about the same extent as for equimolar NDMA, and 40 ppm NPy was not carcinogenic in the lung unless ethanol was coadministered. Extension of this work to include ethanol at a higher dosing level in liquid diet and immunohistochemical localization is in progress in collaboration with Dr. P.G. Forkert. NDMA toxicokinetics and ethanol effects have also been studied in the patas monkey (see Project Z01CP05092). An interspecies scaling effort involving mouse, patas monkey, and four other species, with Drs. C. Gombar and G. Harrington, has confirmed the usefulness of animal determination for prediction of human toxicokinetic parameters, and raised an interesting possibility of increasing involvement of extrahepatic metabolism in clearance of NDMA in larger animals.
