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The epidemiologic investigation has successively delineated associations of air pollution exposure with non-malignant and malignant lung disease, cardiovascular disease, cerebrovascular disease, pregnancy outcomes, perinatal effects and other extra-pulmonary disease including diabetes. Defining these relationships between air pollution exposure and human health closely parallels results of an earlier epidemiologic investigation into cigarette smoking and environmental tobacco smoke (ETS), two other particle-related exposures. Humic-like substances (HULIS) have been identified as a chemical component common to cigarette smoke and air pollution particles. Toxicology studies provide evidence that a disruption of iron homeostasis with sequestration of host metal by HULIS is a fundamental mechanistic pathway through which biological effects are initiated by cigarette smoke and air pollution particles. As a result of a common chemical component and a shared mechanistic pathway, it should be possible to extrapolate from the epidemiology of cigarette smoking and ETS to predict associations of air pollution exposure with human disease, which are currently unrecognized. Accordingly, it is anticipated that the forthcoming epidemiologic investigation will demonstrate relationships of air pollution with COPD causation, peripheral vascular disease, hypertension, renal disease, digestive disease, loss of bone mass/risk of fractures, dental disease, eye disease, fertility problems, and extrapulmonary malignancies.