ReviewGenotoxicity of tobacco smoke and tobacco smoke condensate: a review
Introduction
Tobacco smoking ranks as a major public health problem whose negative impacts have spread around the world. Until recently, the health effects of tobacco smoking were confined largely to developed countries; however, the current promotion and adoption of this habit in developing countries is resulting in an enormous increase in smoking-associated disease and death of global dimensions [1], [2]. Worldwide, there is an estimated >1 billion smokers, and ∼3 million deaths per year are estimated to be attributable to smoking, with this number rising to ∼10 million per year in 30–40 years’ time [2]. Estimates suggest that of those people alive today, half a billion will die of tobacco-associated disease [1].
Tobacco smoking is the major risk factor associated with heart disease, which is the primary cause of death in developed countries [3], and smoking is the overwhelming cause of lung cancer, which is the leading cause of cancer deaths worldwide [4]. Currently, cigarette smoking is associated with ∼90% of lung cancer cases, resulting in ∼1.2 million deaths annually, and it accounts for ∼30% of all cancer cases in developed countries [2], [4], [5]. Recently, the International Agency for Research on Cancer [4] identified tobacco smoking as the cause of cancer at more organ sites than any other human carcinogen. These include cancers of the lung, oral cavity, naso−, oro−, and hypopharynx, nasal cavity and paranasal sinuses, larynx, esophagus, stomach, pancreas, liver, kidney, ureter, urinary bladder, uterine cervix, and bone marrow (myeloid leukemia). Thus, tobacco is the most extreme example of a systemic carcinogen, and, as this review documents, is must now be considered the most extreme example of a systemic human mutagen.
The mechanisms by which tobacco smoke causes these cancers and other health effects have been studied intensively during the past 20 years, and much has been learned. One mechanism involves the mutagenic activity of tobacco smoke, which has been demonstrated clearly and reviewed 2 decades ago [6], [7], [8]. Recent reviews have summarized the studies on smoking-related DNA and protein adducts in human tissues [9] as well as the chemical biomarkers associated with tobacco smoke exposure [10]. This review examines the literature on the genotoxicity of tobacco smoke and tobacco smoke condensate from 1985 onwards in experimental systems as well as the genotoxicity of active tobacco smoking in humans. In addition, some of the mutational mechanisms of tobacco smoke are reviewed within the context of the carcinogenic mechanisms associated with smoking-related tumors.
Section snippets
Mutagenicity, genotoxicity, and mutation spectra of cigarette smoke condensate (CSC)
As reviewed previously [6], [7], [8], CSC is mutagenic in a variety of systems. Most studies of CSC have used CSC generated from various reference cigarettes, such as K1R4F, which was developed jointly by the U.S. National Cancer Institute, the U.S. Department of Agriculture, and the University of Kentucky Tobacco and Health Research Institute [11]. The average mutagenicity of U.S. market and K1R4F mainstream CSCs in the Salmonella mutagenicity assay was not significantly different on a
HPRT mutations
The association between HPRT mutant frequencies in peripheral blood lymphocytes and smoking has been reviewed extensively [107], [108], [109], and this literature is not re-reviewed here. However, in general, studies show that smoking increases the HPRT mutant frequency in peripheral blood lymphocytes by ∼50%, but the increases did not reach statistical significance in some studies due to the large inter-individual variability. Using the autoradiographic HPRT assay, some portion of the HPRT
Note added in proof
After this paper was accepted for publication, several papers were published that should be noted. A set of studies showed that the presence of >400 tobacco ingredients (flavorings and other additives) has little influence on the mutagenicity, toxicity, or chemistry of the resulting smoke from CSCs containing various combinations of these ingredients [383], [384], [385]. Also, assays measuring hyperplasia and/or inflammation were capable of discriminating between CSCs with different
Acknowledgments
I thank R.J. Preston, R. Owen, R. Rogers, D. Shaughnessy, and L.D. Claxton for helpful comments on this review article. This manuscript has been reviewed by the National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.
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