The role of inflammation in promotion of tumor development in response to chemical carcinogens is important but incompletely understood. One current hypothesis is that leukocytes when stimulated with phorbol esters release free radicals which may cause genomic changes. We have found that the release of reactive oxygen intermediates (ROI) from macrophages is regulated at multiple molecular levels and that model xenobiotics can alter the release of ROI. We have further established that macrophages can initiate DNA damage in cocultivated eukaryotic cells. We here propose to analyze in molecular terms how the potential for secretion of ROI is altered in macrophages from animals exposed to model xenobiotics; to define the precise conditions under which macrophages cause alterations in DNA in cocultivated cells; and to establish the role of ROI and other compounds such as lipid peroxides in DNA damage. Our long range goal is to study the role of macrophages and their secreted products in potentiating chemical carcinogenesis.