ABSTRACT About 11-24% of smokers will develop lung tumors over their lifetime, with a greater cancer incidence in African American and Native Hawaiian cigarette smokers as compared with Whites, Japanese Americans, and Latinos. These differences persist even after adjusting for smoking amounts. Cigarette smoke is a complex mixture of chemicals including at least 70 known carcinogens, procarcinogens, and inflammatory agents. Smokers belonging to different ethnic groups may have variable responses towards cigarette smoke due to inherent genetic and epigenetic differences and ethnicity-related lifestyle factors such as diet, exercise, alcohol consumption, and environmental exposures. These factors can lead to differing amounts of DNA and protein adducts in smokers, mediating their sensitivity to smoking-induced mutations and cancer. Recent development in analytical methodologies and bioinformatics have made it possible to characterize the totality of human exposures from both external and internal sources (the exposome) using untargeted or multifaceted analyses of hemoglobin adducts. Hemoglobin is the most abundant protein in human blood with a relatively long half-life, and hemoglobin adducts reflect cumulative exposures to electrophiles. The adductomics approach is analogous to other -omics methodologies such as genomics, transcriptomics, and metabolomics, which are making it possible to understand and view complex human diseases such as cancer from a global perspective. Adductomics studies in smokers will capture individual physiological responses to smoking, potentially uncovering new factors that contribute to lung cancer risk. We hypothesize that due to genetic differences and ethnic variations in diet, lifestyle, and environmental exposures, human populations of different ethnicity/race form variable numbers of protein and DNA adducts, which contributes to ethnic disparities in lung cancer risk following exposure to tobacco smoke. The objective of this application is to characterize the exposomes of smokers, former smokers, and never smokers, to investigate inter-individual and inter-ethnic/racial differences in formation of hemoglobin adducts in African American, Native Hawaiian, White, Japanese American, and Latino smokers from the Multiethic Cohort (MEC), and to establish the role of the exposome in modifying lung cancer risk. Our approach is innovative because we will, for the first time, characterize the totality of external and internal exposures using hemoglobin adductomics in a large multiethnic group of smokers. Expected outcomes: Our studies will help provide insight into the origins of ethnic variability in sensitivity to smoking-mediated lung cancer and help identify specific risk factors that play the greatest role in modifying lung cancer risk. An increased understanding of such risk factors may lead to preventative strategies that will help overcome ethnic/racial disparities in lung cancer risk and improve human health.