Review
Genotoxicity of tobacco smoke and tobacco smoke condensate: a review

https://doi.org/10.1016/j.mrrev.2004.02.001Get rights and content

Abstract

This report reviews the literature on the genotoxicity of mainstream tobacco smoke and cigarette smoke condensate (CSC) published since 1985. CSC is genotoxic in nearly all systems in which it has been tested, with the base/neutral fractions being the most mutagenic. In rodents, cigarette smoke induces sister chromatid exchanges (SCEs) and micronuclei in bone marrow and lung cells. In humans, newborns of smoking mothers have elevated frequencies of HPRT mutants, translocations, and DNA strand breaks. Sperm of smokers have elevated frequencies of aneuploidy, DNA adducts, strand breaks, and oxidative damage. Smoking also produces mutagenic cervical mucus, micronuclei in cervical epithelial cells, and genotoxic amniotic fluid. These data suggest that tobacco smoke may be a human germ-cell mutagen. Tobacco smoke produces mutagenic urine, and it is a human somatic-cell mutagen, producing HPRT mutations, SCEs, microsatellite instability, and DNA damage in a variety of tissues. Of the 11 organ sites at which smoking causes cancer in humans, smoking-associated genotoxic effects have been found in all eight that have been examined thus far: oral/nasal, esophagus, pharynx/larynx, lung, pancreas, myeoloid organs, bladder/ureter, uterine cervix. Lung tumors of smokers contain a high frequency and unique spectrum of TP53 and KRAS mutations, reflective of the PAH (and possibly other) compounds in the smoke. Further studies are needed to clarify the modulation of the genotoxicity of tobacco smoke by various genetic polymorphisms. These data support a model of tobacco smoke carcinogenesis in which the components of tobacco smoke induce mutations that accumulate in a field of tissue that, through selection, drive the carcinogenic process. Most of the data reviewed here are from studies of human smokers. Thus, their relevance to humans cannot be denied, and their explanatory powers not easily dismissed. Tobacco smoke is now the most extreme example of a systemic human mutagen.

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.

References (386)

  • G. Krause et al.

    Spontaneous and chemically induced point mutations in HPRT cDNA of the metabolically competent human lymphoblastoid cell line, MCL-5

    Mutat. Res.

    (1999)
  • K.P. Putnam et al.

    Comparison of the cytotoxic and mutagenic potential of liquid smoke food flavourings, cigarette smoke condensate and wood smoke condensate

    Food Chem. Toxicol.

    (1999)
  • J.J. Fitzgerald

    Cigarette smoke comparative toxicology

    Food Chem. Toxicol.

    (2001)
  • C.J. Smith et al.

    Response to cigarette smoke comparative toxicology

    Food Chem. Toxicol.

    (2001)
  • M. Curvall et al.

    In vitro studies of biological effects of cigarette smoke condensate. I. genotoxic and cytotoxic effects of neutral, semivolatile constituents

    Mutat. Res.

    (1985)
  • S. Salomaa et al.

    Genotoxicity and PAC analysis of particulate and vapour phases of environmental tobacco smoke

    Mutat. Res.

    (1988)
  • A.O. Asita et al.

    Mutagenicity of wood smoke condensates in the Salmonella/microsome assay

    Mutat. Res.

    (1991)
  • D.J. Doolittle et al.

    The genotoxic potential of nicotine and its major metabolites

    Mutat. Res.

    (1995)
  • D.J. Doolittle et al.

    The effect of exposure to nicotine, carbon monoxide, cigarette smoke or cigarette smoke condensate on the mutagenicity of rat urine

    Mutat. Res.

    (1991)
  • C.J. Smith et al.

    The relative toxicity of compounds in mainstream cigarette smoke condensate

    Food Chem. Toxicol.

    (2000)
  • E.L. Carmines

    Evaluation of the potential effects of ingredients added to cigarettes. Part 1: cigarette design, testing approach, and review of results

    Food Chem. Toxicol.

    (2002)
  • E. Roemer et al.

    Evaluation of the potential effects of ingredients added to cigarettes. Part 3: In vitro genotoxicity and cytotoxicity

    Food Chem. Toxicol.

    (2002)
  • W.L. Clapp et al.

    Reduction in Ames Salmonella mutagenicity of mainstream cigarette smoke condensate by tobacco protein removal

    Mutat. Res.

    (1999)
  • J.L. White et al.

    Effect of pyrolysis temperature on the mutagenicity of tobacco smoke condensate

    Food Chem. Toxicol.

    (2001)
  • Y. Mori et al.

    Effect of cigarette smoke on the mutagenic activation of various carcinogens in hamster

    Mutat. Res.

    (1995)
  • A.A.J.J.L. Rutten et al.

    Effect of cigarette-smoke condensate and norharman on the induction of SCEs by direct and indirect mutagens in CHO cells

    Mutat. Res.

    (1986)
  • A. Lafi et al.

    Cytogenetic activities of tobacco particulate matter (TPM) derived from a low to middle tar British cigarette

    Mutat. Res.

    (1988)
  • T. Jansson et al.

    In vitro studies of biological effects of cigarette smoke condensate. II. Induction of sister-chromatid exchanges in human lymphocytes by weakly acidic, semivolatile constituents

    Mutat. Res.

    (1986)
  • T. Jansson et al.

    In vitro studies of the biological effects of cigarette smoke condensate. III. Induction of SCE by some phenolic and related constituents derived from cigarette smoke. A study of structure-activity relationships

    Mutat. Res.

    (1988)
  • D. Veltel et al.

    Characterization of cigarette smoke-induced micronuclei in vitro

    Exp. Toxicol. Pathol.

    (1996)
  • C.K. Lee et al.

    Ninety-day inhalation study in rats, using aged and diluted sidestream smoke from a reference cigarette: DNA adducts and alveolar macrophage cytogenetics

    Fundam. Appl. Toxicol.

    (1993)
  • C.K. Lee et al.

    Fourteen-day inhalation study in rats, using aged and diluted sidestream smoke from a reference cigarette

    Fundam. Appl. Toxicol.

    (1992)
  • R. Balansky et al.

    Investigation of the mutagenic activity of tobacco smoke

    Mutat. Res.

    (1987)
  • R.M. Balansky et al.

    The mutagenic and clastogenic activity of tobacco smoke

    Mutat. Res.

    (1988)
  • E. Mohtashamipur et al.

    Clastogenic effect of passive smoking on bone marrow polychromatic erythrocytes of NMRI mice

    Toxicol. Lett.

    (1987)
  • I.I. Stoichev et al.

    Dominant-lethal mutations and micronucleus inductionin male BALB/c, BDF1 and H mice by tobacco smoke

    Mutat. Res.

    (1993)
  • A.K. Nersessian et al.

    The comparative clastogenic activity of mainstream tobacco smoke from cigarettes widely consumed in Armenia

    Mutat. Res.

    (1994)
  • S. Fielding et al.

    Studies on the ability of smoke from different types of cigarettes to induce single-strand breaks in cultured human cells

    Mutat. Res.

    (1989)
  • P. Leanderson et al.

    Cigarette smoke-induced DNA-damage: role of hydroquinone and catechol in the formation of the oxidative DNA-adduct, 8-hydroxydeoxyguanosine

    Chem. Biol. Interact.

    (1990)
  • P. Leanderson et al.

    Cigarette smoke-induced DNA damage in cultured human cells: role of hydroxyl radicals and endonuclease activation

    Chem. Biol. Interact.

    (1992)
  • P. Leanderson et al.

    Cigarette tar promotes neutrophil-induced DNA damage in cultured lung cells

    Environ. Res.

    (1994)
  • J.P.E. Spencer et al.

    DNA damage in human respiratory tract epithelial cells: damage by gas phase cigarette smoke apparently involves attack by reactive nitrogen species in addition to oxygen radicals

    FEBS Lett.

    (1995)
  • X. Liu et al.

    Synergistic induction of hydroxyl radical-induced DNA single-strand breaks by chromium (VI) compound and cigarette smoke solution

    Mutat. Res.

    (1999)
  • R.D. Hess et al.

    DNA damage by filtered, tar-and aerosol-free cigarette smoke in rodent cells: a novel evaluation

    Toxicol. Lett.

    (1996)
  • M.F. Borgerding et al.

    Chemical and biological studies of a new cigarette that primarily heats tobacco. Part 1. Chemical composition of mainstream smoke

    Food Chem. Toxicol.

    (1998)
  • D.J. Doolittle et al.

    Human urine mutagenicity study comparing cigarettes which burn or only heat tobacco

    Mutat. Res.

    (1989)
  • C.K. Lee et al.

    Analysis of cytogenetic effects in bone-marrow cells of rats subchronically exposed to smoke from cigarettes which burn or only heat tobacco

    Mutat. Res.

    (1990)
  • C.K. Lee et al.

    Comparative genotoxicity testing of mainstream whole smoke from cigarettes which burn or heat tobacco

    Mutat. Res.

    (1990)
  • D.W. Bombick et al.

    Chemical and biological studies of a new cigarette that primarily heats tobacco. Part 3. In vitro toxicity of whole smoke

    Food Chem. Toxicol.

    (1998)
  • D.J. Doolittle et al.

    Comparative studies of the mutagenicity of urine from smokers and non-smokers on a controlled non-mutagenic diet

    Food Chem. Toxicol.

    (1990)
  • Cited by (425)

    • Herbal Remedies

      2023, Haschek and Rousseaux's Handbook of Toxicologic Pathology, Volume 3: Environmental Toxicologic Pathology and Major Toxicant Classes
    • On-site detection of pyrene from mixture with ppb level sensitivity by plasmonic TLC-DSERS

      2022, Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy
    View all citing articles on Scopus
    View full text