Hemoglobin-carcinogen adducts as molecular biomarkers in epidemiology.

The goal of our work is to determine the exposure of people to the ultimate form of both environmental and endogenous mutagens and carcinogens. The scientific approach is to develop methods of analysis of chemically-defined adducts of protein and DNA. Our research to date has encompassed a wide variety of compounds known or suspected to cause cancer in people: aromatic amines, heterocyclic amines, polycyclic aromatic hydrocarbons (PAH), aflatoxins, N-nitroso compounds, and urethane. The most advanced of those problems is that of aromatic amines in which several different types of studies on human populations have already been completed using hemoglobin (Hb) adducts of 4-amino-biophenyl (ABP) as the biomarker. These studies have revealed a correlation between the level of amine adduct and risk of bladder cancer, and most important, the role of a metabolic polymorphism, the acetylator phenotype, as an important determinant of adduct level. In the case of PAH we have developed a useful human dosimeter based upon release of bay region tetrols from Hb esters. This method is now being applied to analyze the internal dose of benzo[a]pyrene (BaP) diolepoxide and to determine the range of PAH structures subject to conversion to ultimate carcinogenic forms. Together, these studies open the door to a new era in which we will be able to examine the overall influence of metabolic polymorphisms on the internal dose of many carcinogens in individuals.