ORGAN AND SPECIES SPECIFICITIES OF CHEMICAL CARCINOGENS

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The ability of human and rodent tissues to metabolize known or suspected chemical carcinogens is being investigated. The metabolic profile and genetic toxicity of the chemicals with human tissue activation are then being compared to the results from rodent tissues to aid the extrapolation of effects in rodents to potential effects in humans. Human and rodent liver and kidney cell metabolism of the model carcinogenic aromatic amine, acetylaminofluorene, has been completed. For human liver, nine individual tissue specimens have been investigated and a complex pattern of hydroxylated products observed with all cases. The same hydroxylated products were also observed with rat hepatocytes; however eight of the nine human samples were more active metabolizers than the rat hepatocytes. The interindividual variation in the overall human metabolism was about 4-fold; although variation in individual metabolites was as high as 35-fold. The ability of human hepatocytes to conjugate these hydroxylated products with sulfate or glucuronic acid was also greater than in rat hepatocytes and the human interindividual variation to conjugate was about 8-fold. Human hepatocytes were also more active that rat hepatocytes in producing metabolites which were mutagenic to Salmonella typhimurium. Studies with kidney tissues have also indicated that human cells are more active than rat kidney tissues have also indicated that human cells are more active that rat kidney cells in producing hydroxylated and mutagenic acetylaminofluorene metabolites; but kidney cells from both species are less active than hepatocytes. Again, about a 4-fold interindividual variation in human kidney metabolism was observed. The results of these studies are now being extended to other NTP chemicals to determine if these data when used in combination with pharmacodynamic and genetic toxicity data can aid in rodent to human extrapolation.