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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction 12 Cancer Around 1950, Doll and Hill (Doll and Hill, 1950), Wynder and Graham (Wynder and Graham, 1950), and others reported the extremely high incidence of smoking in lung cancer patients. In fact, lung cancer was a rare disease before smoking (Doll and Hill, 1950). If one employs almost any method to assess causality, such as that proposed in the first Surgeon General’s report on smoking (U.S. PHS, 1964) and later articulated in more detail by Sir Austin Bradford Hill (Hill, 1965), then clearly the use of tobacco products causes cancer. This conclusion comes from substantial epidemiology, laboratory animal, and in vitro studies. Tobacco smoke contains more than 100 carcinogens and mutagens, many of which are classified as carcinogens based upon human and animal studies (IARC, 1986), the latter include lung tumors in the same organs as cancers occur in humans. It is estimated that 20% of all cancers worldwide are attributable to smoking (Parkin et al., 1999). If a regular smoker successfully quits, then the risk of cancer decreases, but the risk of cancer in former smokers does not decrease to the level of “never smokers.” Thus, the concept of harm reduction by reducing exposure to tobacco carcinogens might be plausible if the exposure is significantly reduced, but the reduction in risk could not be more than that for a former smoker and would probably be less. Therefore, the most beneficial harm reduction strategy in smokers is to stop smoking. The assessment of cancer risk from potential reduced-exposure agents (PREPs) must consider mechanisms of mutagenesis and carcinogenesis. This chapter will focus on only four types of cancer caused by cigarettes
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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction and tobacco-containing products, although smoking causes other cancers as well (Doll, 1996); two of these are examples of the most common cancers related to tobacco (lung and oropharyngeal), and one is an example of a cancer that occurs remotely from the site of entry of the carcinogen into the body (bladder). The fourth cancer is one in which tobacco is believed to reduce risk (endometrial). In this chapter, a mutagen is defined as a compound that causes DNA damage of any sort. A carcinogen is defined as a compound that contributes to cancer, independent of the mechanism. A tobacco constituent is any compound from a tobacco-containing product, used in an intended or unintended fashion, which results in human exposure. MUTAGENESIS AND DNA DAMAGE Cancers result from an accumulated amount of mutations (changes in nucleotide sequence) or gross chromosomal damage. There are several pathways to such DNA damage. Genetic damage occurs because a mutagen, or its activated metabolite, binds to or otherwise interacts with DNA. This mutagen can then cause a promutagenic lesion or in some other way perturb the genetic structure resulting in a gross chromosomal alteration (aneuploidy, break, translocation, amplification, deletion). The genetic damage follows a failure of several protective mechanisms. The first line of defense against chemical insult involves metabolizing enzymes that are intended to aid excretion of potentially damaging chemicals in the body (produced endogenously or coming from exogenous sources; Guengerich, 2000). For tobacco constituents, this “excretory” process gone wrong is a multistep pathway simplistically described as (1) entry of the mutagen into the body (i.e., oral, respiratory, and gastrointestinal mucosa) and its distribution throughout the body; followed by (2) recognition by an organ that this is a foreign substance in need of excretion (e.g., lung, liver, bladder); (3) use of enzymes for metabolic conversion of the chemical so that it can be bound to an excretory conjugate (Guengerich, 2000); (4) binding to DNA rather than an excretory conjugate; and (5) formation of a DNA adduct or a lesion that then results in DNA damage. A mutagen might be made more water soluble or able to bind an excretory conjugate (e.g., glutathione) through several chemical reactions catalyzed by cytochrome P-450 (CYP) and other enzymes, followed by conjugation catalyzed by enzymes (e.g., glutathione S-transferases, glucuronyl transferases, sulfuronyl transferases). Every one of these steps can influence cancer risk (Hecht, 1999a; Perera, 1997; Van Delft et al., 1998), where greater activity increases the risk of DNA damage, while greater conjugation and excretory capacity could reduce risk. Metabolic conversion and conjugate binding is a complex pathway that differs
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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction for different classes of mutagens, and there are redundant pathways (Anttila et al., 1992, 1993, 1995; Brennan, 1998; Grundy et al., 1998; Guengerich, 2000; Nakajima et al., 1995). Different parts of an organ such as the lung may have different capacities for activation and detoxification (Anttila et al., 1993; Bartsch et al., 1991; Geneste, 1991; Petruzzelli et al., 1989; Rojas et al., 1992; Shimada et al., 1996b). Enzymes that are responsible for metabolic activation and detoxification can be induced by exposures, which could further affect the level of subsequent DNA damage (Bartsch et al., 1995; Ciruzzi et al., 1998; Guengerich, 2000; McLemore et al., 1990; Nakajima et al., 1995). Thus, when manipulating the levels of carcinogens in tobacco products, it is important to consider how these changes might affect any of the above steps. Separately, it is well known that people have different heritable abilities for these steps, so manipulating the level of one or more tobacco product constituents might affect people differently. If a mutagen binds to DNA, additional processes must fail before a mutagenic event occurs, and this takes place more often for some mutagens than for others. Thus, not all mutagens are human carcinogens. One form of DNA damage is a DNA adduct, which is a nucleotide with a chemically bound mutagen or some part of the mutagen. There may be some specificity for the sites of DNA adducts to occur within the genome, but adducts can form anywhere in the genome (La and Swenberg, 1996). Importantly, for the DNA adduct to contribute to the carcinogenic process, it must lead to a mutation and that mutation has to occur in a critical part of a critical gene. Chemicals within the same class can have different capacities to form reactive intermediates and cause DNA-adduct formation in different parts of a gene. Therefore, simply altering the levels of a specific class in a harm reduction strategy might not affect the important chemical within that class, and the formation of a new adduct due to changes in chemical constituents might result in greater degrees of mutagenicity. The chemical binding to DNA through the formation of adducts, for example, can lead to nucleotide sequence changes (insertions, deletions, or substitutions). It also can lead to gross chromosomal aberrations such as breaks, deletions, or translocations. These events occur when the mutagen causes errors during DNA replication or mitosis. However, there are protective mechanisms should any of these types of DNA damage occur and cancer develop due to the imbalance of DNA damage and DNA repair (Loeb and Loeb, 2000). Individual adducts may be repaired by excision repair pathways, while chromosomal aberrations are repaired by recombination repair pathways. In addition to DNA repair, other protective mechanisms can reduce the harmful effects of DNA damage, such as lengthening the G1 or G2 checkpoints to allow more time for DNA
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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction repair or triggering cell death (apoptosis). Unfortunately, some mutations might block the entry into these checkpoints or evade cell death processes. In addition to repair pathways that remove adducts, there are other control methods if these mechanisms or pathways fail. There are DNA repair enzymes that recognize and repair mismatch damage, and if this does not occur, cell death may be triggered. The combination of repair and cell turnover leads to a half-life of carcinogen-DNA adducts. To date, the effects of chemicals on these repair and control pathways, and interindividual differences in DNA repair, cell-cycle control, and cell death have only recently received some attention (Sumida et al., 1998). The relationship between a mutagen and mutation is complex and may depend on the dose of the mutagen (La and Swenberg 1996; Van Delft et al., 1998). Low-dose exposures are often difficult to evaluate in vitro or in vivo because of mutational background rates, and extrapolation of mutation rates from high-dose to low-dose exposures depends on assumptions that may not be true (Liber et al., 1985). Mutation rates for exposures that switch from high dose to low dose and how the mutational spectra changes have not been studied. In summary, for a tobacco constituent to cause a DNA lesion that confers a selective clonal advantage on a cell that ultimately becomes cancerous, the constituent must be absorbed and metabolically activated; it has to damage DNA, which evades repair; it has to occur in a critical part of a critical gene; and finally, the cell must evade cell death. Moreover, this has to occur in the target organ. Internal exposure can be affected by smoking behavior or storage depots in the body (e.g., adipose tissue). These pathways are important to consider for harm reduction strategies because altering the levels of different tobacco constituents or complex mixtures might affect these pathways differently, so that the net effect on carcinogenicity may not be predictable a priori, either for an individual or for the population. CARCINOGENESIS Carcinogenesis is a multistage process involving many different genes (Devereux et al., 1999). DNA damage is necessary, but not sufficient, to cause tumors as evidenced in experimental models (Pledger et al., 1977). One conceptual approach to understanding carcinogenesis is to consider that cancer is driven by defects in either caretaker, gatekeeper, or landscaper genes (Kinzler and Vogelstein, 1997, 1998). Caretaker genes are those responsible for maintaining genomic integrity, such as DNA repair and metabolism. Mutations or inherited variants in these genes increase the risk of mutations in other genes. Gatekeeper genes are those involved in controlling cell cycle, and replication of the genome, triggering
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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction apoptosis, and assisting caretaker genes in maintaining genomic integrity. Mutations in gatekeeper genes increase the risk for a cell to replicate uncontrollably and increase the likelihood of permanently establishing mutations. Landscaper genes are those that affect the external environment around the cells and thus control adjacent cells. Current data do not exist to indicate that tobacco-related harm preferentially affects any classes of genes, but an effect of tobacco carcinogens on all classes of genes is plausible and suggested by the observed complex genetic alterations in lung and other cancers. Another way to classify cancer genes is to consider them as oncogenes or tumor suppressor genes. This classification is based on studies showing that overexpression or mutation of the former increases proliferative potential, while loss of the latter stimulates proliferative potential. For oncogenes, only one allele has to be activated, whereas for tumor suppressor genes, both alleles are usually inactivated. Thus, the former is a dominant trait, while the latter is recessive. Oncogenes occur when proto-oncogenes, responsible for normal cellular processes, are mutated. Multiple oncogenes are involved in the pathogenesis of solid tumors including lung cancer (Fong et al., 1999; Kohno and Yokota, 1999; Rom et al., 2000). Only a few oncogenes, such as K-ras and c-MYC have been identified as playing crucial roles in the pathogenesis of several tobacco-related tumors (Reynolds et al., 1991; Rodenhuis et al., 1987; Slebos et al., 1991, 1992). However, most oncogenes remain to be discovered. The ras gene family consists of three members (K, N, and H). They are membrane-bound proteins that bind to guanosine 5′-triphosphate (GTP) when activated, and to guanosine 5-diphosphate (GDP) when inactivated. Activation sends a signal to the nucleus, via a cascade of kinases, that eventually results in the activation of transcription factors. Activating ras mutations occur at codons 12, 13, and 61 and result in loss of intrinsic guanosine triphosphates (GTPase) activity, locking in the activated form (Bos, 1988); experimental studies support the role of tobacco carcinogens that affect ras in lung cancers (Ronai et al., 1993). It has been reported that ras mutations are present usually only in smoke-related lung cancers (Gealy et al., 1999; Slebos et al., 1991). Such mutations also can be observed in smokers without lung cancer, suggesting that they can be early markers of smoking-related damage (Lehman et al., 1996; Slebos et al., 1991; Scott et al., 1997; Yakubovskaya et al., 1995). Tumor suppressor genes in tobacco-related cancers include p53 (also known as TP53), p16INK4A (p16), retinoblastoma (RB), and fragile histidine triad (FHIT) genes. A frequent method of inactivation of one allele of recessive oncogenes is by allelic deletion (i.e., loss of DNA material on one of the alleles). Often, this deletion is extensive and involves not only the gene of interest, but adjacent genes as well. The p53 gene is a tumor
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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction suppressor gene, and mutations of this gene may represent the most common genetic abnormality discovered to date in tumors, being present in about 50% of human carcinomas (Hollstein et al., 1996). It plays a central role in the balance between gene transcription, cell proliferation, and apoptosis. DNA damage results in the induction of genes upstream of p53 (Oren, 1999), which then stimulates p53 induction and stability through posttranslational modifications. This in turn affects p21, MDM2, GADD45, BAX, and other genes responsible for DNA repair, and delay of the cell cycle to allow additional time for DNA repair, or triggers cell death when DNA repair is not possible. The (p16) gene is located on chromosome 9p, and its protein plays a crucial role (along with the retinoblastoma gene product and the cyclins) in regulating the cell cycle. It is inactivated in many smoking-related cancers including non-small-cell lung, head and neck, and pancreatic cancer and squamous carcinomas of the esophagus (Geradts et al., 1999; Liu et al., 1995; Lydiatt et al., 1995), and occasionally bladder tumors (Orlow et al., 1999). Inactivation occurs by many mechanisms including hemizygous or homozygous deletions, point mutations, or aberrant methylation of the promoter region. The latter is an example of tobacco smoke constituents affecting genetic function without causing a mutation (i.e., an epigenetic change; Belinsky et al., 1998). The FHIT gene is a putative tumor suppressor gene located on chromosome 3p14 (Sozzi et al., 1998a, b). Inactivation of the gene product has been described in many tumors including lung, head and neck, and esophagus. It might be possible to consider mutations in different genes as “molecular fingerprints” of causation by tobacco smoke for an individual. This could be helpful in considering the effects of different types of tobacco products and changes in tobacco constituents over time. It might also be possible to identify which tumors in an individual were caused by tobacco versus some other agent. However, no such “fingerprints” have been identified for tobacco smoking, although some types of lesions occur more frequently (Kondo et al., 1996). This may be due to the numerous carcinogens in tobacco, which cause many types of DNA damage. New microarray technologies will provide sequence data for many genes, RNA expression profiles or protein expression profiles that—with sufficient bioinformatic support—a characteristic profile could enable tobacco effects to be discerned. Tobacco smoke exposes the entire respiratory and upper gastrointestinal mucosa to carcinogens, whereas smokeless tobacco exposes only the oral cavity and the gastrointestinal mucosa. Thus, these entire “fields” are at risk for the development of preneoplastic and neoplastic lesions (Slaughter et al., 1953; Strong et al., 1984). A field effect for cancer has been demonstrated on a molecular basis, where different molecular
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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction lesions were found in persons with multiple synchronous lesions (Sozzi et al., 1995). TOBACCO MUTAGENS AND CARCINOGENS The use of tobacco products, as they are intended to be used, results in exposure to more than 100 mutagens and carcinogens (Hoffman and Hoffman,1997; Zaridze et al., 1991) that have different potencies and effects. Mainstream smoke consists of particulate and vapor phases. Although carcinogens have been identified in both the vapor and the particulate phase, the latter shows more overall carcinogenic activity. The particulate phase contains more than 3,500 compounds, of which at least 55 have been identified as possible human carcinogens (Hoffman and Hoffman, 1997). The vapor phase contains more than 500 compounds (Hoffman and Hoffman, 1997). A list of some of these constituents is provided in Table 12–1, which is not all inclusive. Tobacco mutagens and carcinogens have different potencies and target organ specificities. A recent critical review summarizing data for tobacco constituents proposed that tobacco-specific nitrosamines (TSNAs) and polycyclic aromatic hydrocarbons (PAHs) are classes of compounds that most affect human cancer risk (Hecht, 1999b). Although this may be true, it is currently difficult to prove in human cancer, especially because these exposures are mixed with others. Other compounds also are likely to be important. The existing data are not sufficient to determine whether some compounds are clearly more carcinogenic in humans than others when delivered through the use of tobacco products, and whether there is a synergistic effect of coexposure. Therefore, the assessment of a harm reduction strategy for cancer must consider these constituents individually and as part of a complex mixture since the former can provide mechanistic information but only the latter can be used to fully understand the effect of PREPs on carcinogenesis. Tobacco and tobacco products have changed over time, with resultant differences in predicted exposure using the Federal Trade Commission (FTC) method for the measurement of “tar” and “nicotine” (Hoffman and Hoffman, 1997). It is known that the FTC method for estimating tar exposure underestimates actual human exposure because it does not sufficiently mimic human smoking behavior (Hoffman and Hoffman, 1997). Specifically, using a protocol that mimics actual human smoking behavior shows that the FTC method substantially underestimates the exposure to TSNAs and benzo[a]pyrene [BaP] (Djordjevic et al., 2000). While smokers of low-nicotine cigarettes have somewhat lower delivered levels of BaP and TSNAs, the daily amount of tar delivered is similar (Djordjevic et
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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction TABLE 12–1 List of Selected Tobacco Mutagens and Carcinogensa Constituent Class Phase IARC Evaluation Examples N-Nitrosamines Particulate Sufficient in animals Tobacco-specific nitrosamines (NNK, NNN), dimethylnitrosamine, diethylnitrosamine Polycyclic aromatic hydrocarbons Particulate Probable in humans Benzo[a]pyrene, benzo[a]anthracene, benzo[b]fluoranthene, 5-methylchrysene Arylamines Particulate Sufficient in humans 4-Aminobiphenyl, 2-toluidine, 2-naphthylamine Heterocyclic amines Particulate Probable in humans 2-Amino-3-methylimidazo[4,5-[b]quinolone (IQ) Organic solvents Vapor Sufficient in humans Benzene, methanol, toluene, styrene Aldehydes Vapor Limited in humans Acetaldehyde, formaldehyde Volatile organic compounds Vapor Probable 1,3-Butadiene, isoprene Inorganic compounds Particulate Sufficient in humans Arsenic, nickel, chromium, polonium-210 aThis list is intended to provide a conceptual overview of the complexity of tobacco product exposures. It is not all inclusive, but is included to allow the reader to understand the number of considerations that must be made in assessing PREPs. bInternational Agency for Research on Cancer: The classifications here refer to evaluations of the compound from any exposure, not just tobacco. Not all chemicals within the class are considered carcinogenic in humans. There is no consideration in this table of delivered dose or route of exposure. NOTE: NNK=nitrosonornicotine ketone; NNN=N-nitrosonornicotine. al., 2000). Therefore, in this report so-called tar yields do not imply actual tar exposure. Although it is important to understand the differences in risks by chemical class, in order to assess PREPs, it must be realized that affecting the exposure to one compound or class might not account for similar proportional decreases of other compounds, and we do not know if removing one compound or even a whole class will reduce unless other classes of compounds are also decreased. Further, the study of mixtures
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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction (i.e., the real-life scenario of simultaneous exposure to many chemicals and classes) has received insufficient attention, and exposure to tobacco constituents as complex mixtures would provide the most compelling evidence for prediction of a successful PREP. Cigarette smoke condensate is mutagenic in bacterial and human cell lines (Matsukura et al., 1991) and can cause a malignant transformation in human bronchial epithelial cells (Klein-Szanto et al., 1992). Whole smoke, which is also mutagenic, can be used as well (Bombick et al., 1997). Both the vapor phase of environmental tobacco smoke (ETS) and unfiltered ETS exposure causes lung cancer in laboratory animals (Witschi et al., 1997a). There is some evidence to suggest that the mutational spectra of a complex mixture reflects mostly that of the dominant chemicals in the mixture (DeMarini, 1998), although experimental animal studies of DNA adducts from benzo[a]pyrene and coal tars indicate that total adduct levels are not related to BaP content alone (Goldstein et al., 1998), suggesting that studying single chemicals is not sufficient to represent the effects of complex mixtures. Further, various polycyclic aromatic hydrocarbons cause different hotspots in p53 (Smith et al., 2000), and different dose levels of complex mixtures might have additive or synergistic effects (Hecht et al., 1999; Poirier and Beland, 1992). Thus, more studies are needed to determine the best approaches to assess the mutagenicity and carcinogenicity of complex mixtures (Guengerich, 2000). Several constituents of tobacco are considered likely agents of human carcinogenesis. Some of these are reviewed here to highlight the considerations needed in considering harm reduction strategies. People are commonly exposed to PAHs through tobacco products, diet, occupation, and consumption of fossil fuels (i.e., burning coal or wood). These compounds are formed from the incomplete combustion of tobacco leaves, and many types of PAHs are present in tobacco smoke as a complex mixture. Parent PAHs can be detected in human lung tissue (Lodovici et al., 1998; Seto et al., 1993). It is estimated that smokers are exposed to 2–5µg of PAHs per day per pack of cigarettes, and our diet provides PAHs of 3µg per day (Hoffman and Hoffman, 1997; Lioy and Greenberg, 1990; Waldman et al., 1991). As a class, they are mutagenic and carcinogenic in organs of laboratory animals (including the lung) and humans (Hoffman and Hoffman, 1997; IARC, 1986; Van Delft et al., 1998). PAHs have different potencies, which are thought to be related to metabolic activation of a compound that leads to either a bay region diolepoxide (potent), or a fjord region diol-epoxide (nonpotent) compound. PAHs are metabolically activated in humans through CYP1A1, CYP1B1, and CYP3A4 (Kim et al., 1998; Shimada et al., 1996a). They are conjugated for excretion by glutathione S-transferases, sulfuronyl transferases, and glucuronyl transferases (Robertson et al., 1988), and the lack of such
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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction activity increases mutagenic potential (Romert et al., 1989). In laboratory animals treated with benzo[a]pyrene, the half-life of DNA adducts following a single dose is 15 days in the liver, 17 days in peripheral blood lymphocytes, and 22 days in lung (Ross et al., 1990). In humans, there is more than a hundredfold variation in the resultant capacity for DNA-adduct formation (Harris et al., 1974) due to variation in induction and activity for these activating and detoxifying enzymes. PAH-related DNA adducts have been demonstrated in human lung (Kato et al., 1995), while the presence of hemoglobin and albumin adducts also shows that these compounds circulate in human blood (Day et al., 1990; Kriek et al., 1998). In vitro studies indicate that PAHs can cause the same types of p53 mutations observed in human tumors (Denissenko et al., 1996; Smith et al., 2000). DNA damage from PAHs is repaired by both excision and recombination pathways, and while there is clearly interindividual variation in the DNA repair capacity of these pathways, such variation have received little attention for PAHs (Xu et al., 1998). Tobacco products and smoke contain N-nitrosamines (Brunneman et al., 1996; Fischer et al., 1989b, 1990; Tricker et al., 1991), which are among the most potent rodent carcinogens (Lewis et al., 1997). Some of the N-nitrosamines in tobacco smoke are specific for tobacco, whereas others are the same types formed from dietary exposures. N-nitrosamines cause cancer in more than 40 animal species, and there is target organ specificity, including for TSNAs and lung tumors (Lewis et al., 1997; Rivenson et al., 1989), where there is a biphasic response in experimental animals indicating both a high affinity response at lower exposure levels and a saturation effect at higher levels (Belinsky et al., 1990; Pledger et al., 1977). Experimental animal studies also show that higher doses of exposure cause tumors in less time, suggesting that intensity and duration are equally important (La and Swenberg, 1996; Lewis et al., 1997). Mutations in K-ras have been found in lung tumors of experimentally exposed animals (Chen et al., 1993). TSNAs can transform human bronchial epithelial cells (Klein-Szanto et al., 1992). The same type of adducts that occur from TSNAs in experimental animals also have been detected in humans, including in lung tissue (Hecht et al., 1994). Different types of tobacco have different TSNA yields (Brunnemann et al., 1996). In humans, metabolites of TSNAs are found in urine (Carmella et al., 1993, 1995; Hecht et al., 1994), and adducts are detected in blood, so TSNAs circulate through the body, including in persons who are passively exposed (Atawodi et al., 1998; Hecht et al., 1993; Parsons et al., 1998). The elimination half-life of several TSNAs through the urine is estimated to be 40–45 days (Hecht et al., 1999). There is no mutational specificity for N-nitrosamines in several genes studied to date, although there is a propensity for G→A (guanine to adenine) transitions in experimental models (Chen et al., 1993; Ronai et al., 1993;
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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction Tiano et al., 1994). N-nitrosamines undergo metabolic activation by human cytochrome P-450s located in the lung, buccal mucosa, and other tissues (e.g., CYP2E1 and CYP2A6; Hecht, 1998; Patten et al., 1997; Smith et al., 1995, 1992). Ethanol induces CYP2E1 which may have implications for oropharyngeal and esophageal cancer (Garro et al., 1981; Ma et al. 1991). Cigarette smoking and exposure to other tobacco products increase endogenous nitrosation, so that there are additional exposures to nitroso compounds (Nair et al., 1996). The metabolic activation of TSNAs and other tobacco N-nitrosamines leads to the formation of DNA adducts in target tissues or is associated with specific cancers (Chang et al., 1990; La and Swenberg, 1996; Liu et al., 1993; Nesnow et al., 1994; Tiano et al., 1993; Yang et al., 1990; Zhang et al., 1991). TSNAs form three different classes of DNA adducts (Hecht, 1999a). The first involves methylation of different nucleotides, which also are formed by other N-nitrosamines, and some of these adducts are more promutagenic than others (O6-methylguanine more readily causes mutations than N7-methylguanine), and there are different repair enzymes for each. The O6-methylguanine is repaired by O6-alkyl-alkyltransferase. The activity of this enzyme varies among people and can be reduced in smokers, because once methylated it becomes inactive (Liu et al., 1997). Other classes of adducts formed by TSNAs, which are bulky (Atawodi et al., 1998; Hecht, 1999a), are probably repaired by nucleotide excision and recombination repair, similar to PAHs. The activity of these repair pathways also varies widely among individuals. Different tobacco products contain widely differing amounts of TSNAs (Fischer et al., 1989b). Snuff use can lead to higher levels of TSNAs than smoking (Hecht et al., 1994), and changing smoking patterns can result in higher delivery of TSNAs (Fischer et al. 1989a). For example, Swedish snuff products contain substantially fewer TSNAs than snuff sold in the United States. Lower-tar and nicotine cigarettes result in greater exposure to TSNAs than high-tar and nicotine cigarettes (Brunnemann et al., 1996; Hoffman and Hoffman, 1997). The third type of DNA adducts formed from TSNAs is related to oxidative damage (Hecht, 1999a). Aromatic amines are another class of compounds present in tobacco smoke; these consist of aryl amines and heterocyclic amines. The latter are not reviewed here. There are substantial data to implicate aryl amines and their metabolism in human carcinogenesis (Vineis and Pirastu, 1997), especially bladder cancer in occupationally exposed cohorts (e.g., dye workers; Cartwright et al., 1982). In experimental animals, 4-aminobiphenyl (4-ABP) adduct levels increase in both liver and bladder tissues, but the rise in the bladder as a target organ is substantial and correlated with tumor incidence (Poirier and Beland, 1992). Saturation pathways might occur in female mice at lower doses than male mice, and saturation effects at higher levels of smoking have been reported in
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Representative terms from entire chapter: