Species differences in carcinogen metabolism and interspecies extrapolation

Many carcinogens demonstrate both qualitative and quantitative species differences in activity. Since many carcinogens must be metabolized to reactive electrophiles to elicit their tumorigenic effects, the observed species differences may have a metabolic basis. A number of examples exist that support the concept that metabolic differences are the underlying cause of species variation in carcinogenicity. Such differences are most often of a quantitative nature, but qualitative differences in carcinogenicity may also be due to differences in rates and/or pathways between species. There are also many instances in which there is no clear evidence that metabolism explains species differences in carcinogenicity. Carcinogenicity studies are often performed at much higher doses than those encountered by humans. Since metabolic processes may become saturated at high tissue concentrations, the rates and pathways of metabolic activation and detoxication may be different at high doses from those at lower doses. Such metabolic variation can lead to differences in target tissue doses, resulting in altered tissue responses at high doses in relation to lower doses. In situations in which no saturation of the metabolic pathways occurs, tissue concentrations are proportional to the administered dose. Scaling of doses from those used in experimental animals to those experienced by humans has often involved simple conversion factors, such as body weight or surface area. Since the reactions involved in carcinogen metabolism may differ both for high and low doses and for various species, much more realistic extrapolations from animal to human can be obtained using physiologically based kinetic modelling. The metabolism of carcinogens in humans shows large interindividual variation, which in turn may be reflected in differences in individual risks. The occurrence of genetic polymorphisms in carcinogen metabolizing enzymes indicates that subgroups of the population may experience carcinogenic risks distinctly different from those of the rest of the population.