1: Introduction, evaluation of evidence on mechanisms of disease production, and summary. Introduction ; Evaluation of evidence on mechanisms of disease production ; Mechanisms of action: necessary, sufficient, or neither ; Description of evidence on mechanisms of disease production ; Scientific basis of the report ; Development of the report ; Major conclusions ; Chapter conclusions ; References -- 2: The changing cigarette. Introduction ; Cigarette design changes over the years ; New cigarette products ; Low-nicotine cigarettes ; Cigarette-like products ; Evaluation of new cigarette products ; New oversight of tobacco products ; Summary ; Conclusions ; References -- 3: Chemistry and toxicology of cigarette smoke and biomarkers of exposure and harm. Introduction ; Chemistry ; Biomarkers ; Summary ; Conclusions ; References -- 4: Nicotine addiction : past and present. Introduction ; Definition of nicotine addiction ; Tobacco constituents and pharmacokinetics ; Components of nicotine addiction ; Pathophysiology of nicotine addiction ; Genetics ; Prevalence and trajectory toward nicotine dependence ; Epidemiology of tobacco use and nicotine dependence in adults ; Trajectory of recovery or relapse ; Evidence summary ; Conclusion ; References -- 5: Cancer. Introduction ; Carcinogen exposure, metabolism, and DNA adducts ; DNA repair and conversion of adducts to mutations ; Gene mutations in tobacco-induced cancer ; Loss of mechanisms for growth control ; Other aspects ; Evidence summary ; Conclusions ; References -- 6: Cardiovascular diseases. Introduction ; Tobacco use and cardiovascular disease ; Secondhand tobacco smoke and cardiovascular disease ; Pathophysiology ; Hemodynamic effects ; Smoking and the endothelium ; Thrombogenic effects ; Inflammation ; Smoking and diabetes ; Lipid abnormalities ; Cardiovascular biomarkers ; Smoking cessation and cardiovascular disease ; Methods to reduce exposure ; Evidence summary ; Conclusions ; References. 7: Pulmonary diseases. Introduction ; Smoking and respiratory defense mechanisms ; Oxidative stress ; Oxidative stress in chronic obstructive pulmonary disease ; Genetics of pulmonary disease and susceptibility to tobacco smoke ; Pathogenesis of emphysema ; Summary ; Evidence summary ; Conclusions ; Implications ; References -- 8: Reproductive and developmental effects. Introduction ; Review of epidemiologic literature on smoking ; Pathophysiological and cellular and molecular mechanisms of smoking ; Implications ; Evidence summary ; Conclusions ; References -- 9: A vision for the future. The global tobacco epidemic ; Reducing the risks from smoking ; Ending the tobacco epidemic ; Concluding remarks ; Appendix 9-1. Recommendations for future research ; Appendix 9-2. Ending the tobacco problem : a blueprint for the nation ; Appendix 9-3. Promoting healthy lifestyles : policy, program, and personal recommendations for reducing cancer risk ; References -- List of abbreviations -- List of tables and figures -- Definitions and alternative nomenclature of genetic symbols used in this report -- Index. This report considers the biological and behavioral mechanisms that may underlie the pathogenicity of tobacco smoke. Many Surgeon General's reports have considered research findings on mechanisms in assessing the biological plausibility of associations observed in epidemiologic studies. Mechanisms of disease are important because they may provide plausibility, which is one of the guideline criteria for assessing evidence on causation. This report specifically reviews the evidence on the potential mechanisms by which smoking causes diseases and considers whether a mechanism is likely to be operative in the production of human disease by tobacco smoke. This evidence is relevant to understanding how smoking causes disease, to identifying those who may be particularly susceptible, and to assessing the potential risks of tobacco products.