Study design and genetic susceptibility factors in the risk assessment of chemical carcinogens

Molecular epidemiology approaches are being employed to examine the validity and elucidate the basis for hypothesized associations of genetic susceptibility factors with common malignancies due to carcinogen exposure. This approach integrates traditional epidemiologic study designs with state-of-the-art laboratory assays. Advantages of this strategy include the possibility of gaining insight into mechanisms and better exposure assessment. Disadvantages include added complexity and cost. Three examples of pharmacogenetic risk factors are discussed: the first two are p450 enzymes whose activity has been associated with susceptibility to lung cancer (debrisoquine hydroxylase, aryl hydrocarbon hydroxylase), and the last, N-acetyltransferase, a non-p450 enzyme, has been associated with bladder cancer susceptibility. In this context, a case-control study which examined the hypothesis of an association between the debrisoquine metabolic phenotype and lung cancer is discussed. While various studies from the molecular to the population level provide evidence to support each of these associations, methodologic problems exist and a causal association remains to be decisively demonstrated. New epidemiologic studies, the application of improved DNA based tests for the genotype, and further basic investigations regarding the mechanisms of the proposed associations continue, and progress is anticipated in the resolution of these questions with important consequences for our understanding of chemical carcinogenesis in these common malignancies. While these associations remain controversial, the existence of wide interindividual variation in the population in the ability to metabolize certain chemical carcinogens is certain and this argues for a conservative approach in the regulation of chemical carcinogens.