Epidemiological and experimental data suggest that exposure to environmental carcinogens plays a substantial role in the causation of human cancers. The majority of environmental carcinogens including aromatic amines, polycyclic aromatic hydrocarbons, heterocyclic amines, and cigarette smoke constituents need to be metabolized before they elicit biological responses. Electrophilic metabolites generated during bioactivation of toxicants interact with cellular macromolecules, such as DNA and proteins, forming adducts.

Endogenously formed reactive oxygen species and other electrophiles provide additional threat to the genome integrity. Efficient repair systems are operative in all living organisms to cope with such damage.

However, if not repaired before the onset of DNA replication, or repaired erroneously, these DNA lesions can promote genetic alterations (e.g. mutations) that may be linked to an altered phenotype. If such alterations occur in growth-controlling genes, these mutations can lead to cell transformations and development of cancer.

Therefore, progressive accumulation of both pre-mutational DNA lesions and genetic mutations are central to the disease process. The damage to macromolecules is generally accompanied with changes in activities and levels of the metabolizing enzymes, and genes associated with the bioactivation pathways and DNA repair processes also are modulated.

Due to susceptibility differences (gene expression, genetic polymorphisms, DNA repair capacity), certain individuals may accumulate more DNA damage, resulting in higher levels of gene mutations, and are at higher risk of developing cancer. These molecular events can be used as early biomarkers to investigate etiology of cancer development, as well as to identify efficacious agents to inhibit DNA damage and mutations, which may ultimately inhibit cancer development.

Using cell-free, cell culture and animal models, and human-derived tissues/cells, various laboratories are defining the metabolic pathways involved in the disposition of carcinogens, monitoring DNA adduct formation and repair, and characterizing nature of metabolites and DNA adducts formed. Other laboratories are studying the effects of polymorphisms in genes for xenobiotic-metabolizing enzymes and DNA repair proteins to cancer risk. Still other laboratories are using burden of DNA adducts and protein adducts to define environmental exposure, as well as to understand the mechanisms of action of the toxicants.

Modulation of gene expression and proteins by the emerging microarray and proteomics technologies, respectively, in some other laboratories complement the other intermediate biomarkers. These studies encompass the many molecular events involved in the initiation and progression of cancer development, with emphasis on tobacco-related cancers.