Mutagen-induced chromatid breakage as a marker of cancer risk

Risk assessment is now recognized as a multidisciplinary process, extending beyond the scope of traditional epidemiologic methodology to include biological evaluation of interindividual differences in carcinogenic susceptibility. Modulation of environmental exposures by host genetic factors may explain much of the observed interindividual variation in susceptibility to carcinogenesis. These genetic factors include, but are not limited to, carcinogen metabolism and DNA repair capacity. This chapter describes a standardized method for the functional assessment of mutagen sensitivity. This in vitro assay measures the frequency of mutagen-induced breaks in peripheral lymphocytes. Mutagen sensitivity assessed by this method has been shown to be a significant risk factor for tobacco-related malignancies, especially those of the upper aerodigestive tract. Mutagen sensitivity may therefore be a useful member of a panel of susceptibility markers for defining high-risk subgroups for chemoprevention trials. This chapter describes methods for and discusses results from studies of mutagen sensitivity as measured by quantifying chromatid breaks induced by chromosome breaking agents, such as the gamma-radiation radiomimetic DNA crosslinking agent bleomycin and chemicals that form so-called bulky DNA adducts, such as 4-NQO and the tobacco smoke constituent, benzo[a]pyrene, in short-term cultured peripheral blood lymphocytes.