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Tobacco Smoke and Its Constituents Stephen S part 1 . PART 1 concordance between cancer in humans and in experimental CHAPTER 5 animals chapter 5. Tobacco smoke and its constituents Stephen S. Hecht and David M. DeMarini This chapter addresses the con- Coherence: carcinogenicity the induction of lung tumours, both cordance in studies of carcinogen- of tobacco smoke in humans benign and malignant, by cigarette icity and mechanisms between versus experimental animals smoke. experimental animals and humans Although these studies have Volume 100E and previous IARC established animal models for the for tobacco smoke and its constit- Monographs and certain reviews on study of tobacco smoke carcino- uents. Volume 100E of the IARC tobacco smoke have summarized genesis and, in aggregate, support Monographs updated the literature the literature on animal studies of the the epidemiological findings that on tobacco smoke and the evalua- carcinogenicity of tobacco smoke smoking is a cause of cancers of the tions of its carcinogenicity (IARC, (IARC, 1986, 2004, 2012b; Hecht, lung and larynx in humans, specif- 2012b). It concluded that there was 2005). These studies demonstrated ic problems associated with animal sufficient evidence that tobacco that cigarette smoke can induce tu- studies of tobacco smoke expo- smoking causes multiple types of mours of the lung and nasal cavity in sure have been recognized. Many cancer in humans, including (to var- mice and rats and tumours of the lar- of these issues result from the fact ying extents) cancers of the lung, ynx in hamsters. Some recent stud- that most laboratory animals are ob- oral cavity, pharynx, oesophagus, ies not included in the evaluations ligate nose breathers and, thus, do in Volume 100E have consistently stomach, colorectum, liver, pancre- not inhale tobacco smoke voluntari- established the carcinogenicity of ly and habitually in the same way in as, nasal cavity and paranasal si- cigarette smoke to the lung in the which humans smoke tobacco prod- nuses, larynx, uterine cervix, ovary A/J mouse, where it produces ade- ucts (Wynder and Hoffman, 1967). (mucinous), urinary bladder, kidney, noma and adenocarcinoma, as well Constant whole-body exposure of ureter, and bone marrow (myeloid as causing emphysema (Stinn et al., rodents to cigarette smoke, often at leukaemia). 2010, 2013). The A/J mouse, which relatively high concentrations, pro- is highly susceptible to lung tumour duces avoidance reactions, stress, development, appears to present weight loss, and other indicators of a relatively reproducible system for toxicity that are widely different from Part 1 • Chapter 5. Tobacco smoke and its constituents 47 the human responses to voluntary imals (IARC, 2010). Similarly, NNK is in urine, collected years before di- inhalation driven by the desire for re- a powerful lung carcinogen, inducing agnosis, and oesophageal cancer, curring small doses of nicotine. adenocarcinoma of the lung in rats, but not lung cancer, in smokers, after There are some mechanistic dif- mice, and hamsters independent of correction for duration and intensity ferences as well. For example, muta- the route of administration and fre- of smoking (Yuan et al., 2011). This tions in the KRAS gene are frequent- quently at very low doses (Hecht, indicates considerable concordance ly observed in lung adenocarcinoma 1998). Thus, PAHs and NNK are between target tissues of NNN and in humans, as are K-ras mutations in widely considered to be causes of NNK in rats and observations of can- lung adenocarcinoma in mice; how- lung cancer in smokers. PAHs – cer incidence in smokers (Stepanov ever, the mutation frequency is not and their diol epoxide metabolites et al., 2014). increased and the mutation spec- in particular – produce mutations in Carcinogenicity studies in lab- trum is not altered in mice exposed TP53 and KRAS that are similar to oratory animals and studies in hu- to cigarette smoke (Hutt et al., 2005; those observed in lung tumours from mans exposed occupationally have DHHS, 2010; Stinn et al., 2013). smokers (DHHS, 2010). In recent established aromatic amines such Taken together, there is only moder- nested case–control studies within as 4-aminobiphenyl and 2-naphthyl- ate concordance between the carci- prospective cohorts, biomarkers of amine as human bladder carcino- nogenic and mechanistic effects of PAH and NNK exposure were asso- gens (IARC, 1987, 2012a). These tobacco smoke evident in laboratory ciated with risk of lung cancer, after and other aromatic amines are com- animals and epidemiological obser- correction for duration and intensity ponents of mainstream cigarette vations in humans (Witschi, 2007). of smoking (Hecht et al., 2013). smoke (Xie et al., 2013). There is 1,3-Butadiene is another com- also considerable mechanistic evi- Concordance: carcinogenicity pound likely to be involved in the dence from studies of haemoglobin of tobacco smoke in humans etiology of lung cancer in smokers. It adducts consistent with the propos- versus carcinogenicity of is found in relatively high concentra- al that 4-aminobiphenyl is respon- tobacco smoke constituents in experimental animals tions in tobacco smoke and is a pow- sible for bladder cancer in smokers erful lung carcinogen in mice, but not (Castelao et al., 2001; IARC, 2012a). There is considerable concordance in rats (IARC, 2008). Benzene is a leukaemogen in hu- between the known carcinogenic Other tobacco smoke compounds mans, and it occurs in considerable properties of many tobacco smoke with the lung as a target tissue/organ quantities in cigarette smoke (IARC, constituents and the multiple target in some animal studies include iso- 1987, 2012a). The uptake of benzene tissues of tobacco smoke as demon- prene, ethylene oxide, ethyl carba- by smokers has been demonstrated strated in epidemiological studies mate, benzene, and various metals conclusively by biomarker studies (IARC, 2012b). (Hecht, 2011). (Hecht et al., 2010). Thus, it is like- It should be noted that carcino- The oral cavity, pharynx, and ly that benzene is responsible for genicity assays of pure compounds oesophagus of rats are established leukaemia in smokers, although it generally do not suffer from the target tissues of the tobacco-specif- does not cause leukaemia in rodents above-mentioned operational dif- ic nitrosamine N′-nitrosonornicotine (IARC, 2012a). ficulties with respect to tobacco (NNN), and in particular its (S) enan- Multiple tobacco smoke carcino- smoke (Witschi, 2007). tiomer (Hecht, 1998; Balbo et al., gens have produced tumours of the With respect to lung cancer, 2013). NNN is found in the smoke of upper respiratory tract. Tumours of multiple polycyclic aromatic hy- all tobacco products (IARC, 2007). the larynx, nose, and trachea as well drocarbons (PAHs) and the tobac- N-nitrosodiethylamine is another as of the pharynx and oesophagus co-specific nitrosamine 4-(methylni- tobacco smoke constituent that in- were induced in inhalation studies trosamino)-1-(3-pyridyl)-1-butanone duces oesophageal tumours in rats, with benzo[a]pyrene, an archetyp- (NNK) are found in the smoke of although its levels in smoke are con- al PAH, in hamsters (IARC, 2010). all cigarettes tested to date (IARC, siderably lower than those of NNN. Tumours of the nose have also been 2004). There is abundant evidence One nested case–control study observed in rats treated with tobac- attesting to the ability of PAHs to found a strong relationship between co-specific nitrosamines (Hecht, induce lung cancer in laboratory an- levels of NNN and its glucuronides 1998; Balbo et al., 2013). Inhalation 48 studies with formaldehyde and ac- lead to the eventual development of and cause DNA replication errors etaldehyde produced nasal tumours lung cancer (IARC, 2004; DHHS, that may lead to mutations. If these (IARC, 1985, 2006, 2012a). 2010, 2014). This scheme is for lung mutations occur in important regions Tobacco smoke contains com- cancer because it is for this disease of critical growth control genes, such PART 1 pounds that are carcinogenic to that the most data are available. as the oncogene KRAS or the tu- CHAPTER 5 the colorectum in rats, most nota- The central pathway of Fig. 5.1 mour suppressor gene TP53, cellular bly certain heterocyclic aromatic in particular shows great coherence growth processes become severely amines (IARC, 2004, 2012b; Hecht, with established genotoxic mecha- dysregulated, resulting in uncon- 2012). With respect to induction nisms by which many carcinogens, trolled cell proliferation and cancer. of liver cancer by tobacco smoke, including most of the more than 70 There are convincing data from there is coherence with furan and established carcinogens in cigarette studies of smokers and lung cancer N-nitrosodimethylamine, which are smoke, drive the process of cancer patients that illustrate coherence of liver carcinogens in rats (Peto et al., induction. Thus, exhaustive mecha- these observations in humans with 1991; NTP, 19 93), whereas NNK nistic studies carried out both in vitro the results observed in the plethora and its major metabolite 4-(methyl- and in laboratory animals since the of mechanistic studies noted above. nitrosamino)-1-(3-pyridyl)-1-butanol middle of the 20th century and con- Carcinogen uptake by smokers has (NNAL) induce pancreatic cancer in tinuing today provide solid evidence been unequivocally demonstrated rats (Hecht, 1998). that most carcinogens, either direct- by biomarker studies that compare Collectively, there is considerable ly or after metabolism catalysed by levels of carcinogens and their me- concordance between established multiple cytochrome P450 enzymes, tabolites in the urine of smokers sites of tobacco smoke carcinogen- react with nucleophilic sites in DNA and non-smokers (Hecht et al., icity in humans and target tissues to form covalent binding products 2010). These studies leave no doubt in experimental animals of individ- called DNA adducts. that exposure to multiple carcino- ual carcinogens present in tobacco There are cellular repair systems gens, including tobacco-specific ni- smoke. that have evolved to repair these trosamines, PAHs, aromatic amines, DNA adducts and restore the nor- and various volatile compounds in- Concordance: overall mechanism of cancer mal structure of DNA.
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