Epidemiological models of carcinogenesis: the example of bladder cancer

Epidemiological studies have clearly shown that smokers have an increased risk of bladder cancer. Chemical, biochemical, and molecular investigations indicate that such risk might be due to aromatic amines which are present in tobacco smoke. In particular, collaborative studies have shown that smokers have increased levels of hemoglobin-4-aminobiphenyl adducts in their blood and that these levels show a dose-response relationship and an association with the most carcinogenic variety of tobacco, air-cured or black tobacco. Adduct concentrations were also modulated by the genetically based slow acetylator phenotype. In addition, investigations in dogs and humans have described a DNA adduct in bladder biopsies and in exfoliated bladder cells that is a derivative of 4-aminobiphenyl. This paper summarizes the epidemiological, biochemical, and molecular evidence concerning the possible mechanisms of bladder cancer induction in smokers and in occupationally exposed workers. The case of bladder cancer is an example of integration between epidemiological studies, mathematical modeling, and laboratory investigations aiming at the elucidation of mechanisms of carcinogenesis.