The complexity of tobacco smoke leads to some confusion about the mechanisms by which it causes lung cancer. Among the multiple components of tobacco smoke, 20 carcinogens convincingly cause lung tumors in laboratory animals or humans and are, therefore, likely to be involved in lung cancer induction. Of these, polycyclic aromatic hydrocarbons and the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone are likely to play major roles. This review focuses on carcinogens in tobacco smoke as a means of simplifying and clarifying the relevant information that provides a mechanistic framework linking nicotine addiction with lung cancer through exposure to such compounds. Included is a discussion of the mechanisms by which tobacco smoke carcinogens interact with DNA and cause genetic changes--mechanisms that are reasonably well understood--and the less well defined relationship between exposure to specific tobacco smoke carcinogens and mutations in oncogenes and tumor suppressor genes. Molecular epidemiologic studies of gene-carcinogen interactions and lung cancer--an approach that has not yet reached its full potential--are also discussed, as are inhalation studies of tobacco smoke in laboratory animals and the potential role of free radicals and oxidative damage in tobacco-associated carcinogenesis. By focusing in this review on several important carcinogens in tobacco smoke, the complexities in understanding tobacco-induced cancer can be reduced, and new approaches for lung cancer prevention can be envisioned.

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Tobacco Smoke Carcinogens and Lung Cancer

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.

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

Chronic diseases are responsible for 7 in 10 deaths each year, and treating people with chronic diseases accounts for most of our nation’s health care costs. We know that many chronic diseases can be prevented by eating well, being physically active, avoiding tobacco and excessive drinking, and getting regular health screenings. CDC’s National Center for Chronic Disease Prevention and Health Promotion (NCCDPHP) helps people and communities prevent chronic disease and promotes health and wellness for all. National Center for Chronic Disease Prevention and Health Promotion

National Center For Chronic Disease Prevention and Health Promotion regions

pReVIously ClAssIfIed by IARC As “CARCInogenIC to humAns (gRoup 1)” And wAs deVeloped by sIx sepARAte woRkIng gRoups: phARmACeutICAls; bIologICAl Agents; ARsenIC, metAls, fIbRes, And dusts; RAdIAtIon; peRsonAl hAbIts And IndooR CombustIons; ChemICAl Agents And RelAted oCCupAtIons. thIs Volume 100f CoVeRs ChemICAl Agents And RelAted oCCupAtIons, speCIfICAlly 4-AmInobIphenyl, benzIdIne, dyes metAbolIzed to benzIdIne, 4,4’-methylenebIs(2-ChloRoAnIlIne), 2-nAphthylAmIne, oRtho-toluIdIne, AuRAmIne And AuRAmIne pRoduCtIon, mAgentA And mAgentA pRoduCtIon, benzo[A]pyRene, CoAl gAsIfICAtIon, oCCupAtIonAl exposuRes duRIng CoAl-tAR dIstIllAtIon, CoAl-tAR pItCh, Coke pRoduCtIon, untReAted oR mIldly tReAted mIneRAl oIls, shAle oIls, soot, As found In oCCupAtIonAl exposuRe of ChImney-sweeps, oCCupAtIonAl exposuRes duRIng AlumInIum pRoduCtIon, AflAtoxIns, benzene, bIs(ChloRomethyl)etheR And ChloRomethyl methyl etheR, 1,3-butAdIene, 2,3,7,8-tetRAChloRodIbenzo-pARA-dIoxIn, 2,3,4,7,8-pentAChloRodIbenzofuRAn, And 3,3’,4,4’,5-pentAChloRobIphenyl, ethylene oxIde, foRmAldehyde, sulfuR mustARd, VInyl ChloRIde, IsopRopyl AlCohol mAnufACtuRe by the stRong-ACId pRoCess, mIsts fRom stRong InoRgAnIC ACIds, oCCupAtIonAl exposuRes duRIng IRon And steel foundIng, oCCupAtIonAl exposuRe As A pAInteR, oCCupAtIonAl exposuRes In the RubbeR mAnufACtuRIng IndustRy. beCAuse the sCope of Volume 100 Is so bRoAd, Its monogRAphs ARe foCused on key InfoRmAtIon. eACh monogRAph pResents A desCRIptIon of A CARCInogenIC Agent And how people ARe exposed, CRItICAl oVeRVIews of the epIdemIologICAl studIes And AnImAl CAnCeR bIoAssAys, And A ConCIse ReVIew of the Agent’s toxICokInetICs, plAusIble meChAnIsms of CARCInogenesIs, And potentIAlly susCeptIble populAtIons, And lIfe-stAges. detAIls of the desIgn And Results of IndIVIduAl epIdemIologICAl studIes And AnImAl CAnCeR bIoAssAys ARe summARIzed In tAbles. shoRt tAbles thAt hIghlIght key Results ARe pRInted In Volume 100, And moRe extensIVe tAbles thAt InClude All studIes AppeAR on the monogRAphs pRogRAmme websIte (http://monogRAphs.IARC.fR). It Is hoped thAt thIs Volume, by CompIlIng the knowledge ACCumulAted thRough seVeRAl deCAdes of CAnCeR ReseARCh, wIll stImulAte CAnCeR pReVentIon ACtIVItIes woRldwIde, And wIll be A VAlued ResouRCe foR futuRe ReseARCh to IdentIfy otheR Agents suspeCted of CAusIng CAnCeR In humAns. D es ig n by A ude la d es m ot s

iArc monogrAphs on the evAluAtion oF cArcinogenic risks to humAns

Although smoking cessation is the primary goal for the control of cancer and other smoking-related diseases, chemoprevention provides a complementary approach applicable to high risk individuals such as current smokers and ex-smokers. The thiol N-acetylcysteine (NAC) works per se in the extracellular environment, and is a precursor of intracellular cysteine and glutathione (GSH). Almost 40 years of experience in the prophylaxis and therapy of a variety of clinical conditions, mostly involving GSH depletion and alterations of the redox status, have established the safety of this drug, even at very high doses and for long-term treatments. A number of studies performed since 1984 have indicated that NAC has the potential to prevent cancer and other mutation-related diseases. N-Acetylcysteine has an impressive array of mechanisms and protective effects towards DNA damage and carcinogenesis, which are related to its nucleophilicity, antioxidant activity, modulation of metabolism, effects in mitochondria, decrease of the biologically effective dose of carcinogens, modulation of DNA repair, inhibition of genotoxicity and cell transformation, modulation of gene expression and signal transduction pathways, regulation of cell survival and apoptosis, anti-inflammatory activity, anti-angiogenetic activity, immunological effects, inhibition of progression to malignancy, influence on cell cycle progression, inhibition of pre-neoplastic and neoplastic lesions, inhibition of invasion and metastasis, and protection towards adverse effects of other chemopreventive agents or chemotherapeutical agents. These mechanisms are herein reviewed and commented on with special reference to smoking-related end-points, as evaluated in in vitro test systems, experimental animals and clinical trials. It is important that all protective effects of NAC were observed under a range of conditions produced by a variety of treatments or imbalances of homeostasis. However, our recent data show that, at least in mouse lung, under physiological conditions NAC does not alter per se the expression of multiple genes detected by cDNA array technology. On the whole, there is overwhelming evidence that NAC has the ability to modulate a variety of DNA damage- and cancer-related end-points.

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Mechanisms of N-acetylcysteine in the prevention of DNA damage and cancer, with special reference to smoking-related end-points

In this paper, I review the results of a representative selection of chronic inhalation studies with rats and mice exposed to mainstream cigarette smoke and describe the inhalation exposures and the histopathological changes reported by various authors. Many of the studies used nose-only exposure systems, whereas others simply used large whole-body chambers. Smoke-induced epithelial hypertrophy, hyperplasia, and squamous metaplasia were reported in the conducting airways in most of the studies, along with increased numbers of intra-alveolar macrophages that were occasionally associated with alveolar metaplasia. Lung adenomas and adenocarcinomas were reported in only a few of the studies. No statistically significant increase in the incidence of malignant lung tumors was seen in either species as a result of smoke exposure, a finding that does not agree with the results of epidemiological studies in humans. Possible reasons for this lack of correlation are given.

https://journals.sagepub.com/doi/pdf/10.1177/019262339802600301

A Review of Chronic Inhalation Studies with Mainstream Cigarette Smoke in Rats and Mice

Rationale
Growing proportions of smokers in the USA do not smoke everyday and can be referred to as light and intermittent smokers (LITS). Despite a current prevalence of LITS in the USA estimated at 25–33% of all smokers, a systematic review of the literature on this group of smokers has yet to be written.

Light and intermittent cigarette smokers: a review (1989–2009)

Histologic changes in the respiratory tract induced by inhalation of xenobiotics: physiologic adaptation or toxicity?

In rodents, the larynx is a major site of histopathologic alteration following inhalation exposure to particulates, vapors, and aerosols. Specifically, the epithelial lining of a narrowly delineated region on the ventral floor of the larynges of rats and mice appears to be especially vulnerable to inhaled materials, and is recognized as a preferred site for histopathological evaluation in inhalation studies. This site is located at the base of the epiglottis, cranial to the ventral laryngeal diverticulum (ventral pouch). The presence of underlying seromucinous glands is critical for histologic identification of this site. We report a histologic sectioning technique, using the ventral laryngeal diverticulum as the anatomical landmark, to obtain tissue sections from this area of predilection in rats and in mice.

Christopher R. E. Coggins

Papers

A Review of Chronic Inhalation Studies with Mainstream Cigarette Smoke in Rats and Mice

Light and intermittent cigarette smokers: a review (1989–2009)

Histologic changes in the respiratory tract induced by inhalation of xenobiotics: physiologic adaptation or toxicity?

Histological sectioning of the rodent larynx for inhalation toxicity testing.

Ninety-day inhalation study in rats, comparing smoke from cigarettes that heat tobacco with those that burn tobacco.