Factors involved in modulation effects of chemical carcinogens have been studied in several murine models. (1) Co-administration of ethanol has been found to have pronounced effects on the metabolism, distribution and toxic effects of the environmental carcinogen, N-nitrosodimethylamine (NDMA), including doses of NDMA giving blood levels comparable to those measured in many humans and causing, on the other hand, an increased incidence of lung tumors in mice. Ethanol given simultaneously with NDMA reduced the hepatotoxicity of the chemical, but caused a large increase in circulating levels of NDMA, presumably through competitive inhibition of NDMA metabolism. NDMA demethylase was not induced at the concentrations of ethanol used. A dose of 550 ppb NDMA resulted in an average blood steady-state level of 0.9 ppb, and also caused a significant doubling in incidence of lung tumors in strain A mice. This model system thus has considerable potential for mechanistic studies related to the metabolic epidemiology of cancer. (2) The induction of metabolism of NDMA in various mouse strains by acetone, pyrazole, and isopropanol is being systematically investigated with the intent to develop in vivo pharmacogenetic-pharmacokinetic models. Work is continuing on protection against polycyclic aromatic hydrocarbon carcinogenesis by enzyme induction. (3) Effects of N-nitrosocimetidine on tumor development are being studied with both skin and mammary tumor models, with several experiments nearing completion. (4) A project of tumorigenesis in athymic nude mouse skin, showing high incidence of squamous tumors in this model, has been completed and terminated.
