Clearing the Smoke Assessing the Science Base for Tobacco Harm Reduction (2001) / Chapter Skim
Currently Skimming:
12 Cancer
12 Cancer
Pages 367-469
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 367... ...
Therefore, the most beneficial harm reduction strategy in smokers is to stop smoking. The assessment of cancer risk from potential reduced-exposure agents (PREPs)
|
From page 368... ...
. Every one of these steps can influence cancer risk (Hecht, 1999a; Perera, 1997; Van Delft et al., 1998)
|
From page 369... ...
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~.
|
From page 370... ...
. 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.
|
From page 371... ...
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.
|
From page 372... ...
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.
|
From page 373... ...
and polycyclic aromatic hydrocarbons (PAHs) are classes of compounds that most affect human cancer risk (Hecht, l999b)
|
From page 374... ...
al., 2000~. Therefore, in this report so-called tar yields do not imply actual tar exposure.
|
From page 375... ...
, although experimental animal studies of DNA adducts from benzo~aipyrene 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.
|
From page 376... ...
Some of the Nnitrosamines 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)
|
From page 377... ...
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~.
|
From page 378... ...
Aromatic amine biomarker studies have generally focused on hemoglobin rather than DNA adducts. Levels are higher in smokers than nonsmokers, and different types of tobacco can lead to higher adduct levels (Bryant et al., 1988; Carmella et al., 1990; Dallinga et al., 1998~.
|
From page 379... ...
Assays are available that can do this, as reviewed in Chapter 10. Separately, decreasing one or more tobacco constituents might not affect cancer risk if other compounds such as 1,3-butadiene, benzene, aldehydes, and acrolein are not affected, or the risks from additives or fibers might be comparatively more important.
|
From page 380... ...
Blocking can occur with the fingers, lips, or tape, and can be intentional or unintentional. To consider the value of a harm reduction strategy, one must consider the effects on cancer risk of the targeted reduction in exposure and then place these risks in the context of reducing exposures by any means.
|
From page 381... ...
What is the dose-response relationship between targeted carcinogens and cancer risk? Where is the risk to persons from environmental tobacco smoke within the shape of the dose-response curve?
|
From page 382... ...
For smokeless tobacco products, oral TABLE 12-2 Causality Assessmenta Criteria Comment Strength of association What is magnitude of risk? Consistency Are there repeated observations by multiple investigators in different populations?
|
From page 383... ...
These appear in Table 12-3, along with their strengths and limitations. Most of these methods, however, have limited use currently for harm reduction evaluations.
|
From page 384... ...
, but it is unclear whether this information validates the use of the MTD or suggests that even 50% dose levels still cause significant physiological perturbations. Thus, the extrapolation of animal studies to humans remains questionable for harm reduction evaluation under these experimental designs.
|
From page 385... ...
and Pino, 1998~. There are large quantitative differences in cancer risks among any organ in experimental animals.
|
From page 386... ...
The major reason for differences in extrapolation from experimental systems to humans is that in vitro cell cultures and experimental animals from different species handle chemical exposures, DNA damage, and stress differently. The inclusion of biomarkers in experimental animal studies with analogy to human exposures would be helpful (Guengerich, 2000~.
|
From page 387... ...
Different methods are available for assessing tobacco-related cancer risk in humans. External exposure markers attempt to predict exposure
|
From page 388... ...
. In humans, only a few studies have investigated a link between carcinogen-DNA adducts and cancer risk.
|
From page 389... ...
4. Does a tobacco constituent cause DNA damage through the formation of DNA adducts, free-radical damage, and/or gross chromosomal aberrations, (each of these mechanisms might affect the success of a harm reduction strategy and all might have to be considered)
|
From page 390... ...
These are reviewed in Chapter 11, along with data indicating which markers are useful for assessment in target organs. Biomarkers of potential harm can range from isolated early changes with or without effects on function to events that clearly lead to carcinogenesis and can be observed in cancer cells.
|
From page 391... ...
Several types of assays are available. The main limitation today is that no assays have convincingly been shown to be sufficiently predictive of cancer risk, so they can not be used singly to predict harm reduction.
|
From page 392... ...
In Connecticut from 1959 through 1991, associations between cigarette smoking and death from AD versus SCC increased nearly seventeenfold in women and nearly tenfold in men, while smoking-related lung cancer risk increased from 4.6 to 19 in men and 1.5 to 8.1 in women (Thun et al., 1997~. This is presumably due to the use of lower-nicotine cigarettes, increased exposures to TSNAs, and greater depths of inhalation.
|
From page 393... ...
Ras gene mutations are present in about 30% of adenocarcinomas but are relatively rare in other lung cancers (Gealy et al., 1999; Slebos and Rodenhuis, 1992~. It has been reported that ras mutations are present only in smoking-related cancers and that these mutations are associated with cigarette smoking (Reynolds et al., 1987; Slebos et al., 1991~.
|
From page 394... ...
Reactive oxygen species, produced by tobacco smoke constituents, as well as through inflammatory responses, can affect many different protein kineses and transcription factors (Minamoto et al., 1999~. How these effects influence carcinogenesis is currently unknown, but perturbations in the balance between oxidative stress and response clearly affect cell survival.
|
From page 395... ...
An earlier age at initiation is a separate lung cancer risk factor (Benhamou et al., 1994; Benhamou et al., 1985; Hegmann et al., 1993; Khuder et al., 1998~. Zang and Wynder had proposed to estimate cumulative tar exposure by determining all brands used for different periods of life and the quantity per day for a person, using milligram yields calculated by the FTC method (Zany and Wynder, 1992~.
|
From page 396... ...
However, the argument by Law and coworkers for including an internal exposure assessment are compelling (Law et al., 1997~. Therefore it is likely that the use of biomarkers would provide better estimates of dose-response relationships and harm reduction.
|
From page 397... ...
models for dose-response relationships mostly do not consider duration of smoking. It is possible that the daily consumption of cigarettes and lung cancer risk have different relationships based on the number of years smoked (Mizuno and Akiba, 1989; Rylander et al., 1996~.
|
From page 398... ...
The slope of the response was greater for the "total" 32p_ postlabeled DNA adducts than for the 4-ABP-hemoglobin adducts in relation to cigarettes per day, and a third-order polynomial curve best fit the data. A plateau began at about 10 cigarettes per day for the former and 20 cigarettes for the latter.
|
From page 399... ...
This represented a 27% reduction in risk compared to continued smoking. Lung Cancer Risk and Cigarette Type An important question is whether smoking low-tar and nicotine cigarettes is associated with lower lung cancer risk and whether switching to such cigarettes has shown a benefit.
|
From page 400... ...
Several large studies have suggested that higher-tar cigarettes are associated with increased lung cancer risk or that the risk is less for smokers of low-tar cigarettes compared to high-tar or mixed exposures (Benhamou et al., 1985; Kaufman et al., 1989; Lubin et al., 1984b; Stellman and Garfinkel, 1989; Vutuc and Kunze, 1983~. Other studies have not shown a reduced risk due to low-tar cigarettes (Kuller et al., 1991; Lee and Garfinkel, 1981; Sidney et al., 1993; Wilcox et al., 1988~.
|
From page 401... ...
Lee and Garfinkel provided a summary of lung cancer risk and type of cigarette smoked (Lee and Garfinkel, 1981) and were unable to demonstrate a significant decrease in risk based on tar content.
|
From page 402... ...
Lee and Garfinkel provided a summary of lung cancer risk and type of cigarette smoked (Lee and Garfinkel, 1981) and concluded that there was about a 25% reduction in lung cancer mortality for filtered cigarettes.
|
From page 403... ...
Hand rolled cigarettes had an increased risk for SCC and not AD (Engeland et al., 1996~. This association is thought to be due to greater depths of inhalation when the filter is in place to compensate for lower nicotine amounts, as well as increased delivery of TSNAs.
|
From page 404... ...
Separately, these studies do not account for cohort effects where the public's overall lung cancer risk may have changed due to diet and lifestyle or for the possibility that persons who smoke low-tar cigarettes otherwise differ from those who smoke high-tar cigarettes. Additionally, it is important to note that these studies do not provide an assessment of what happens to persons who switch cigarette type, which is directly relevant to assessing PREPs.
|
From page 405... ...
An increased risk in women is also evidenced by data showing that there is a higher risk for lung cancer in women at similar ages of initiation and the risks are the same for women who start smoking over age 25 as for men over age 20 (Hegmann et al., 1993~. In a study of lung cancer risk among persons who switched from filtered to nonfiltered cigarettes, both women and men had a lower lung cancer risk if they smoked similar amounts of cigarettes per day before and after switching (Augustine et al., 1989~.
|
From page 406... ...
However, the effects of these factors on lung cancer rates are small compared to the overall increased risk for use of cigarettes. There are some data to suggest that lung cancer risk is higher in African Americans than Caucasians for a given level of smoking (Harris et al., 1993; Schwartz and Swanson, 1997~.
|
From page 407... ...
Whether this represents a method of harm reduction remains unknown since that was not specifically studied, and the lower risk might have been observed for many reasons. Caution must be used in attempting to implicate any particular factor for differences in lung cancer rates in different geographical
|
From page 408... ...
This report does not consider these coexposures in detail, but it should be recognized that they might affect the efficacy of PREPs. Prior lung disease history might increase lung cancer risk in smokers and persons exposed to tobacco smoke (Mayne et al., l999b)
|
From page 409... ...
In addition to carcinogen metabolism and DNA repair, genetic traits for other aspects of carcinogenesis and smoking behavior will undoubtedly be identified. Former Smokers and Lung Cancer Central to the issue of decreasing the harm from tobacco use in the general population is the evidence for lung cancer risk reduction among former smokers.
|
From page 410... ...
In that study, the OR reduction for lung cancer among former smokers ranged from 50 to 65%, depending on the age at smoking cessation and the age at admission, with stronger benefits accruing to men who quit at younger ages and who were diagnosed at younger ages. This study also is noteworthy because it documented a hazard reduction even among men in their seventies who had stopped smoking for just a few years: the decrease in cancer risk among male ax-smokers of this age group is significant due to the higher incidence of lung cancer among men this age than in the general population.
|
From page 411... ...
The amount of harm reduction depends not only on the length of time since quitting but also on the person's current age. Nonetheless, while the curves for each cohort of former smokers show downward trends for fatal lung cancer, the risk ratios never reach the low level experienced by persons who have never smoked cigarettes.
|
From page 413... ...
No data are available to suggest differences in risk by cigarette type among former smokers. Some data do not indicate a greater benefit for quitting in women 15 ~ .m to 1 0 ~ 10.2 <5 5-9 10-14 215 Years Since Quitting FIGURE 12-6 Relative risk of lung cancer death among former male smokers, relative to never smokers.
|
From page 414... ...
An overall challenge in assessing this cancer risk reduction is the question: Are quitters systematically different from current smokers and never smokers in ways that would explain the differences in cancer risks among these groups? A large, cross-sectional survey of nearly 9,000 adults in Britain (Thornton et al., 1994)
|
From page 415... ...
In summary, stopping smoking decreases the risk of lung cancer, and the earlier that an individual stops, the greater is the reduction in risk. Data are not sufficient to determine whether certain levels of prior smoking result in proportionately greater or lesser risk reduction, although clearly, a greater smoking history carries a greater lung cancer risk (Graham and Levin, 1971~.
|
From page 416... ...
Cigarette type and oropharyngeal cancer risk have not been extensively studied. Three reports have not shown a difference between filter and nonfilter cigarettes (Blot et al., 1988; Hayes et al., 1999~.
|
From page 417... ...
Deregulation of the cell cycle is related to the degree of tobacco exposure (Davidson et al., 1996; Gallo et al., 1995~. Oropharyngeal tissues clearly have the capacity to metabolically activate tobacco smoke carcinogens and cause DNA damage (Badawi et al., 1996; Degawa et al., 1994; Kabat et al., 1991; Liu et al., 1993; Matthias et al., 1998~.
|
From page 418... ...
The above information suggests that assessments for oropharyngeal and lung cancer risk related to the use of potential inhaled (i.e., tobacco smoke) PREPs are similar.
|
From page 419... ...
Another important bladder cancer risk factor is occupational exposure to aromatic amines (Ross et al., 1996~. Several studies report an interactive effect for increasing risk in such workers who smoke (D'Avanzo et al., 1990; Vineis et al., 1984; Vineis and Martone, 1996~.
|
From page 420... ...
Benefits from giving up cigarette smoking were quantified in a large cohort study of Kaiser Permanente Medical Care Program members in the United States (Habel et al., 1998~. Among current smokers, former smokers, and never smokers the standardized bladder cancer incidence ratios were 0.56, 0.68, and 1.04, respectively.
|
From page 421... ...
Only one study relates adduct levels to bladder cancer risk (Peluso et al., 1998) , but because this was a case-control study, conclusions are limited.
|
From page 422... ...
No studies have reported data for the effects by cigarette type. ENVIRONMENTAL TOBACCO SMOKE Environmental tobacco smoke (ETS)
|
From page 423... ...
because the impact of statistical confounding can obscure the true level of risk in such situations. Although Lee concluded that it was impossible to determine that ETS exposure is linked to increased lung cancer risk because of potential biases, his own estimates examining the available literature in many different ways still lead to the conclusion of an association.
|
From page 424... ...
For studies lacking this biomarker, a major issue in estimating the cancer risks associated with ETS is the potential misclassification of former smokers as nonsmokers, which would tend to inflate the true risk ratios. A study of two large cohorts in Sweden, one involving twins and the other of randomly surveyed adults in the population, estimated that about 5% of former smokers were misclassified as never smokers, with roughly equal proportions in men and women.
|
From page 425... ...
Accordingly, the Surgeon General warned that cigars should not be viewed by the public as a safe and lower-cost alternative to cigarette smoking and called for warning labels, increased public awareness, and youth education efforts about the risks of cigars. One of the limitations in studying the effects of cigar smoking on lung cancer risk is the relative rarity of cigar smokers compared to cigarette smokers in the population, and the fact that some smokers tend to mix tobacco products presents further challenges to disentangling potential cigar-related effects from cigarette-related effects.
|
From page 426... ...
SMOKELESS TOBACCO PRODUCTS Smokeless tobacco is consumed in a variety of different ways in various cultures around the world. Examples of smokeless tobacco products include chewing tobacco, dry snuff (used in the nasal cavity)
|
From page 427... ...
Idris et al., compared oral cancer risks in the Sudan, where there is an extremely high consumption of smokeless tobacco and found that users of toombak had an extremely high RR for such tumors (Idris et al., 1998~. Research from other parts of the world is far less complete, so it is not known at this point whether ethnic or cultural differences in susceptibility explain any of the
|
From page 428... ...
Some authors have concluded that there is no association between smokeless tobacco and bladder cancer risk, but few studies have examined this association and the results are inconsistent (Burch et al., 1989~. One of the few studies to report an increased risk of bladder cancer among snuff users was a very small study of 76 female cases and 254 controls, among whom 3 cases and 1 control reported snuff use (Kabat et al., 1986~.
|
From page 429... ...
Hemoglobin adduct levels have been found to be higher in snuff users than in nonusers (Carmella et al., l990~. However, such markers have been used only rarely in epidemiological studies to date and have not been used frequently in studies of human cancer risk.
|
From page 430... ...
Clearly, quitting smoking is the most effective method of reducing cancer risk, and the cancer risk to former smokers is the lowest-level risk that might occur from the use of any PREP. Importantly, it must be recognized that the use of any PREP will likely increase the risk of cancer at some level as long as there is exposure to tobacco carcinogens, in contrast to quitting, which stops exposure to all tobacco constituents.
|
From page 431... ...
In laboratory animals, the shape of the dose-response curves differs for different tobacco constituents, so that understanding the relationship to tobacco smoke as a complex mixture is difficult. In humans, there are sufficient data for different cancer types and tobacco products, although more data exist for tobacco smoking and lung cancer risk.
|
From page 432... ...
This chapter has not reviewed potential cancer risks due to fibers released from cigarette filters or tobacco additives, because it is thought that the risk from these exposures is substantially less than the risk from tobacco smoke constituents. However, there are no existing data to prove this assumption.
|
From page 433... ...
Thus, such studies can be used to assess harm reduction. Through the use of biomarkers and surrogate indicators of cancer risk these studies can evaluate the manipulation of carcinogens and nicotine to reduce exposures and how these changes might affect smoking behavior, metabolic activation, enzymatic induction, conjugation, excretion, biologically effective doses (or their validated surrogates)
|
From page 434... ...
Smokeless tobacco products are associated with oral cavity cancers, and a dose-response relationship exists. However, the overall risk is lower than for cigarette smoking, and some products such as Swedish snus may have no increased risk.
|
From page 435... ...
Thus, there are some biomarkers that can be used in smaller studies for assessing PREPs, such as the measurement of carcinogen-DNA adducts, where there are some data to support a relationship to cancer risk. There is less enthusiasm for markers where less specificity exists (i.e., chromosomal aberrations and sister chromatid exchanges)
|
From page 436... ...
Currently, the use of these technologies in cancer risk studies is embryonic, but such studies should begin for PREPs at the present time, notwithstanding the significant bioinformatic and data interpretation issues. If, for example, it is shown that enzyme induction in human lymphocytes is not substantially different between product types for key genetic pathways, then there would be less enthusiasm for the PREP.
|
From page 437... ...
Biomarkers of internal exposure, biologically effective dose, and harm should be used. In the context of harm reduction, developing fluorescent bronchoscopic techniques, coupled with molecular analysis, has the potential to identify smokers who have already sustained molecular damage and, depending on the type of damage, to indicate who might benefit most from harm reduction strategies.
|
From page 438... ...
The comparison group for short- and long-term epidemiological studies would have to be usual cigarettes, because it is not feasible to ask persons to smoke reference cigarettes, which are not designed for appeal. Thus, these studies must carefully characterize smoking behavior, and a range of cigarette types and smoking behaviors must be included.
|
From page 439... ...
2000. Alcohol consumption and cigarette smoking increase the frequency of p53 mutations in non-small cell lung cancer.
|
From page 440... ...
-1-butanone-hemoglobin adducts as biomarkers of exposure to tobacco smoke: validation of a method to be used in multicenter studies. Cancer Epidemiol Biomarkers Prev 7~9~:817-821.
|
From page 441... ...
1989. Changes in patterns of cigarette smoking and lung cancer risk: results of a case-control study.
|
From page 442... ...
1996. Combined analysis of inherited polymorphisms in arylamine N-acetyltransferase 2, glutathione S-transferases M1 and T1, microsomal epoxide hydrolase, and cytochrome P450 enzymes as modulators of bladder cancer risk.
|
From page 443... ...
Cancer Epidemiol Biomarkers Prev 7~6~:465468.
|
From page 444... ...
1996. Re: Differences in lung cancer risk between men and women: examination of the evidence.
|
From page 445... ...
J Natl Cancer Inst 85~6~:465473. Degawa M, Stern,SJ, Martin MV, Guengerich FP, Fu PP, Ilett KF, Kaderlik RK, Kadlubar FF.
|
From page 446... ...
Cancer Epidemiol Biomarkers Prev 1~1~:3543. Franks AL, Kendrick JS, Tyler CW Jr.
|
From page 447... ...
1998. Barbiturates, smoking, and bladder cancer risk.
|
From page 448... ...
1993. Race and sex differences in lung cancer risk associated with cigarette smoking.
|
From page 449... ...
1993. The effect of age at smoking initiation on lung cancer risk.
|
From page 450... ...
1998. Larynx cancer risk in relation to glutathione S-transferase M1 and T1 genotypes and tobacco smoking.
|
From page 451... ...
J Natl Cancer Inst 87~12~:902-907. Katoh T
|
From page 452... ...
1998. Polycyclic aromatic hydrocarbon-DNA adducts in humans: relevance as biomarkers for exposure and cancer risk.
|
From page 453... ...
1992. Ethnic differences in the lung cancer risk associated with smoking.
|
From page 454... ...
1996. Cancer risk and oxidative DNA damage in man.
|
From page 455... ...
1999a. Familial cancer history and lung cancer risk in United States nonsmoking men and women.
|
From page 456... ...
1992. Cancer risk assessment with intermittent exposure.
|
From page 457... ...
1997. Misclassification of smoking status and lung cancer risk from environmental tobacco smoke in never-smokers.
|
From page 458... ...
1986. Determinants of lung cancer risk in cigarette smokers in New Mexico.
|
From page 459... ...
1992. DNA adduct measurements and tumor incidence during chronic carcinogen exposure in animal models: implications for DNA adduct-based human cancer risk assessment.
|
From page 460... ...
1994. Lung cancer risk for female smokers.
|
From page 461... ...
1997. Genotypes of glutathione transferase M1 and P1 and their significance for lung DNA adduct levels and cancer risk.
|
From page 462... ...
2000. Cancer risk and low-penetrance susceptibility genes in geneenvironment interactions.
|
From page 463... ...
J Natl Cancer Inst Monogr (13~:23-29. Smith LE, Denissenko MF, Bennett WP, et al.
|
From page 464... ...
1992. Environmental tobacco smoke and lung cancer risk in nonsmoking women.
|
From page 465... ...
Cancer Epidemiol Biomarkers Prev 4~4~:341-346. Tang JL, Morris JK, Wald NJ, Hole D, Shipley M, Tunstall-Pedoe H
|
From page 466... ...
1990. Polycyclic aromatic hydrocarbon-DNA adducts in lung tissue from lung cancer patients.
|
From page 467... ...
2000. Vegetable and fruit consumption and lung cancer risk in the Netherlands Cohort Study on diet and cancer.
|
From page 468... ...
1979. Impact of long-term filter cigarette usage on lung and larynx cancer risk: a case-control study.
|
From page 469... ...
A new index for estimating lung cancer risk among cigarette smokers. Cancer 70~1~:69-76.
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.