Genetic variability and extrapolation from animals to man: some perspectives on susceptibility to chemical carcinogenesis from aromatic amines.

I would like to consider the problem of chemical carcinogenesis arising from exposure to certain aromatic amines as a basis for my remarks about the predictive value for man of data obtained in other species and biological systems. This example was chosen because it illustrates the complexity of extrapolation very well, and there is new knowledge derived from a variety of disciplines including biochemistry, molecular biology, microbial and human genetics and pharmacology and from various levels of biological organization which must be brought together to enable us to predict the risks to man from exposure to these environmental agents. Aromatic amines are one of the principal groups of chemical carcinogens. They were first discovered to be carcinogenic in man as a result of industrial exposure followed by a 15-20 year latent period. Aromatic amines which produce tumors in animals are not in themselves carcinogenic, but they become so after they have been converted in vivo to more reactive substances. Metabolism of carcinogenic arylamines is complex and may include ring hydroxylation, N-hydroxylation, conjugation of the ring and N-hydroxyl metabolites, and Nacylation of the amine function. Deacylation of N-acylated arylamines is also observed. The major route for metabolism of carcinogenic arylamines in many species involves N-acetylation of the amine group (1).