DESCRIPTION: (Applicant's Description) This project emphasizes the concept of smoke dosage as a determinant of cancer susceptibility. We hypothesize that changes in smoking behavior, which paralleled changes of cigarette design, have affected the delivered doses of nicotine as well as of other carcinogenic compounds which govern the risk for tobacco-related cancers. Lung cancer, the foremost cause of deaths in the United States for both men and women, has long been known to be caused by smoking, as has bladder cancer, but important etiologic and mechanistic questions have yet to be resolved. A major scientific and public concern is that lower-yield cigarettes may not confer lower risks to all smokers. The long-term increase in adenocarcinoma relative to squamous cell lung cancer has coincided with a greater than 60 percent decrease in "tar" (which produces squamous tumors in laboratory animals) and nicotine in mainstream smoke (MS), while MS nitrosamines, such as NNK (which elicits adenocarcinomas in rodents), have increased. The purpose of this project is to expand our studies of the relationship between smoking behavior, dosage of nicotine, and carcinogens delivered to the smoker in the MS, and metabolic products of carcinogens measured in blood or urine of smokers of cigarette brands with the full market range of nicotine, and to study how these relationships vary with race and gender. We utilize a unique laboratory system in which a volunteer's smoking topography (puff volume, frequency, etc.) is measured with a PC-controlled pressure transducer. These parameters are then programmed into a piston-driven smoking machine which captures the MS of the smoker's usual cigarette on a Cambridge filter for subsequent chemical analysis of the "delivered dose" presented to the smoker. We utilize a factorial design to enroll asymptomatic male, female, African American and Caucasian smokers of different types of cigarettes from the surrounding community. In a sub-project we will also evaluate whether, in addition to differences in metabolism, the smoking behavior and delivered dose of 4-aminobiphenyl, a bladder carcinogen, are responsible for the differences in risk for cancer of the urinary bladder among African American and Caucasian men. In the proposed work period, we will complete recruitment of African American smokers of low-yield cigarettes, and expand our study to smokers of the increasingly popular "ultra-low" (0.5 mg nicotine/cigarette) and high yield cigarettes (1.3 mg per cigarette) with the following aims: 1)To compare the effect of smoking topography on dosage of MS nicotine and lung/bladder carcinogens delivered to smokers of ultra-low-, low-, medium-, and high-yield cigarettes; 2) To compare levels of biomarkers of nicotine and lung/bladder carcinogens between smokers of low- vs medium-yield cigarettes, and the relationship between these levels and delivered dosage of mainstream smoke nicotine and carcinogens.