Affiliation of authors: Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.
Correspondence to: Andrew W. Bergen, Ph.D., National Institutes of Health, Executive Plaza South, Rm. 7110, Bethesda, MD 20892 (e-mail: Bergena{at}epndce.nci.nih.gov).
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ABSTRACT |
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INTRODUCTION |
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Smoking prevalence in men worldwide is higher than it is in the United States, while smoking prevalence among women worldwide is usually less than the prevalence in men, although it has equaled or exceeded that in men in some northern European countries (19,20). While annual per capita cigarette consumption has dropped in developed countries from a high of more than 3000 in the 1970s to about 2600 in 1990, it is increasing in developing countries (260% increase in China between 1970 and 1990), so that worldwide annual per capita cigarette consumption has not changed substantially over the last 25 years (20). Because of the delayed health effects of smoking, morbidity and mortality in developing countries attributable to smoking have not yet surpassed those in developed countries but are likely to do so in the next century (20,21).
The study of biomarkers in smoking-attributable cancer has concentrated on measures of exposure (i.e., cotinine, NNAL-Gluc1), dose (i.e., carcinogen-macromolecular adducts, such as 4-amino biphenyl hemoglobin adducts), micronutrients (i.e., ß-carotene), and genetic factors that may modify these factors or their effects (22). The investigation of such biomarkers is predicated on the assumption that an enhanced understanding of metabolic mechanisms will help to identify susceptible groups or individuals and direct future research or prevention efforts. Another group of risk factors for lung cancer and other smoking-related cancers are those that are associated with smoking, its initiation, and its persistence. We will review factors associated with current and persistent smoking that have been studied by use of pharmacologic, epidemiologic, behavior genetic, psychologic, and psychiatric perspectives. The identification of those factors consistently and statistically significantly associated with smoking will provide biologic and social variables with which to investigate mechanisms that contribute to the persistence of this behavioral phenotype. Improved understanding of these mechanisms may enable improved cancer prevention and control efforts.
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METHODS |
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SMOKING AND NICOTINE |
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Smokers of cigarettes increase smoking intensity, smoking rate, or inhalation to maintain
levels of nicotine, as measured by plasma levels of nicotine in both ad libitum and
laboratory smoking settings (43-46). Measured nicotine levels in the
arterial and venous circulation indicate that individual smokers can obtain plasma nicotine levels
of 20-50 ng/mL (46-48). This concentration range (100-300 nM) is one order of magnitude less than the equilibrium binding and activation concentration of
l-nicotine to the
4ß2 receptor, the predominant nAChR in the brain, but is
nearly equal to the effective concentration for inactivation and accumulation of the
4ß2
receptor (49,183). Nicotine absorption per cigarette has been measured
both by graphical methods from nicotine concentration curves obtained from plasma blood
measurements (46) and by parametric calculation by use of stable isotope
studies of nicotine to cotinine conversion and nicotine and cotinine clearance values obtained in
inpatient-infusion studies (47). These studies suggest that smokers are
extracting approximately 1-2 mg of nicotine per cigarette. The total amount of nicotine per
cigarette measured by smoking machines by use of human smoking parameters of puff volume,
duration, and frequency is about 2-3 mg per cigarette (50,51), suggesting
that smokers absorb more than half of the inhaled nicotine. However, none of these methods
measures the peak brain concentration of nicotine, which is presumed to be the major
pharmacologic factor that mediates reward, dependence, and the development of tolerance.
Studies of dosing kinetics in animal models demonstrate the development of higher levels of
tolerance with higher peak concentrations (31,52).
One behavioral mechanism responsible for differences in nicotine consumption may be
related to variation in nicotine and cotinine metabolism (53-55). Nicotine
from tobacco smoke is absorbed quickly (in seconds) throughout the body on initial dosing (46,48) and then is eliminated with a half-life of 2-3 hours (56). Nicotine is metabolized principally (80%) to cotinine by cytochrome
P450 2A6 (47,57,58), which is also responsible for much of the
metabolism of cotinine (59) and for much of the activation of the potent
tobacco smoke carcinogen NNK (60). The typical smoker experiences a
nicotine concentration nadir in the morning after overnight abstinence and then smokes to
increase nicotine levels over the first few hours of the day and to maintain a plateau throughout
the remainder of the day (46). Clearance of nicotine in humans is
primarily diurnal, peaking at midday, with spikes of increased clearance after meals, which is
concordant with increased human smoking rates early in the day, lowest smoking rates in the
evening, and increased smoking after meals (61).
P450 2A6 activity varies approximately 50-fold in humans as measured by analysis of protein levels and in kinetic experiments with liver samples (58,62,63). The basis for constitutive differences in activity has been associated with variant CYP2A6 alleles encoding inactive enzyme (62,64-67). A statistically significantly reduced frequency of two CYP2A6 null alleles in nicotine (and alcohol)-dependent smoking-clinic patients versus never nicotine-dependent individuals and a statistically significant negative association with the numbers of cigarettes smoked per week have been reported (68). This study needs to be replicated in additional samples to confirm the possible role of inherited variation at the CYP2A6 locus in smoking behavior. Misspecification of the CYP2A6 genotype because of incompletely specific CYP2A6 genotyping assays (64,67) may affect the statistical significance of findings relating CYP2A6 alleles to smoking behavior.
Plasma and urinary nicotine and cotinine concentrations have repeatedly been found to be associated with the number of cigarettes smoked per day (69-71). Since cotinine has a half-life an order of magnitude greater than that of nicotine, it is useful as a biomarker in smoking surveys, smoking cessation trials, and the assessment of exposure to environmental cigarette smoke (72,73). Interindividual variation in the conversion of nicotine to cotinine and in the clearance of cotinine may have effects on nicotine consumption and dependence (53). For example, cotinine levels were found to be higher in African-Americans than in Caucasian-Americans or Mexican-Americans, after adjustment was made for reported cigarette smoking (74). While nicotine metabolism was not found to be statistically significantly different in African-Americans and Caucasian-Americans, mean nonrenal and total metabolism (clearance) of cotinine was shown to be significantly lower in African-Americans than in Caucasian-Americans (74,75). Calculation of nicotine intake per cigarette on the basis of the inpatient infusion studies also indicates that African-Americans absorb statistically significantly more nicotine per cigarette smoked than do Caucasian-Americans (75). This suggests that differences in the numbers of cigarettes smoked among African-American and Caucasian-American smokers (76,77) may be influenced by metabolic differences between the groups.
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GENETIC FACTORS ASSOCIATED WITH CIGARETTE SMOKING |
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As in some previous studies of the D2 dopamine receptor in case-control studies of substance abuse (90), the less frequent allele (A1) at a genetic marker flanking the dopamine receptor D2 coding sequence (DRD2) was found to be at a higher frequency in the collections of smokers versus nonsmokers (82,83). In a sample of smokers undergoing a limited smoking cessation intervention, a protective association with a particular allele (allele 9) at the dopamine transporter (SLC6A3) was observed with smoking status, age at smoking initiation, and history of quitting, and the protective association with smoking status was stronger in those individuals with DRD2 A2 genotypes (88). Since the DRD2 A1 allele has been found previously to be associated with lower D2 receptor densities (91) and the SLC6A3 allele 9 has been associated with excess dopamine after cocaine abuse (92), this suggests that the protective association with smoking status observed may be due to normal densities of DRD2 receptors and increased synaptic dopamine that may provide some resistance to nicotine dependence (88). At the D4 dopamine receptor locus, allele DRD4.7, found previously to be associated with novelty seeking and substance abuse in some case-control studies (93), was found in African-Americans, but not in Caucasian-Americans, to be associated with smoking status, intensity, persistence, and initiation. In Caucasian-Americans, a statistically significant association of allele 4 of the DRD4 receptor (not associated with novelty seeking) with smoking for the regulation of mood in depressed smokers was observed (87), suggesting that the DRD4 locus may affect smoking behavior in depressed individuals as well as increase vulnerability to nicotine dependence in some populations (86). These preliminary candidate gene studies need to be repeated in larger samples, in samples with similar and different ethnic origins, and in family-based samples to confirm the effect of these alleles on vulnerability to nicotine dependence, to explore the effect in samples that differ in allele frequency and smoking prevalence, and to control for potential confounding in case-control samples. Future studies involving neurobiologic candidate loci that potentially affect smoking behavior should also emphasize the analysis of functional genetic polymorphisms or of linkage disequilibrium structure to identify haplotypes potentially carrying functional polymorphisms (94).
Genetic epidemiologic studies using the twin-study design (95), where multiple genetic and environmental risk factors and a threshold disease model are modeled by use of concordance data in monozygotic and dizygotic twins, have estimated the effects of genetic and environmental factors on current smoking, smoking initiation, and smoking persistence (96). A reanalysis of seven twin studies from Scandinavia, the United States, and Australia estimated that a mean of 60% of the variance in risk of being a current smoker in men and women is accounted for by additive genetic effects, with most studies demonstrating statistically nonsignificant shared environment effects (96). From the same studies, the mean additive genetic effect on the liability to smoking initiation (i.e., becoming a smoker) was estimated to be 57%, with an estimated mean shared environmental effect of 17%. From three of the studies where data were available to assess the relative contributions to smoking persistence, the mean additive genetic effect was estimated to be 69%, with statistically nonsignificant estimated shared environmental effects. A recent analysis of smoking initiation and persistence among twin pairs in the Vietnam Era Twin Registry found that the best-fitting model included statistically significant additive genetic factors (explaining 50% of variance in risk) and both shared (family, 30% of variance) and specific (to one twin) environmental factors (20% of variance) for smoking initiation. For smoking persistence, however, only genetic and specific environmental factors were found to be statistically significant, explaining approximately 70% and 30% of the variation, respectively (97). Thus, twin studies estimate that the majority of the liability to become and to remain a smoker is explained by additive genetic factors. A variable remaining portion of the risk is estimated to be related to specific environmental effects, but there is no consistent, statistically significant evidence for a shared or common environment effect.
To assess whether the decline in smoking initiation in men and the increase in smoking
initiation in women have led to a change in the interaction of genetic and environmental effects
with birth cohort, three large twin studies were reanalyzed that covered birth cohorts from the
early 1900s to the mid-1960s (98). Researchers tested heterogeneity of
twin tetrachoric correlations across samples and across sex and found increased genetic effects in
men in two of the samples compared with the third sample; however, there was no genetic
heterogeneity by age cohort (98). The modeling of age-related changes in
the effects of genetic and environmental factors in smoking initiation in adolescent twin pairs
showed that genetic effects increased with age; however, shared environmental effects, which
explain the majority of variation in risk at early ages (12-16 years), were not statistically
significant in early adulthood (99). Family studies of the relatives of
substance-dependent individuals ascertained in treatment settings, with control subjects located
via a random-digit-dialing protocol, suggest that there are both general factors increasing
vulnerability to substance abuse and specific factors increasing vulnerability to specific drugs,
including habitual smoking (100). Family studies of the siblings of
alcoholic and nonalcoholic probands ascertained in treatment and nontreatment settings
identified the sibling's own sex, birth cohort, and comorbid substance dependence as
statistically significant predictors of habitual smoking (defined as a smoking history of 20
cigarettes per day for
6 months) (101). Only habitual smoking in
the proband, but not other substance abuse, was a statistically significant predictor of habitual
smoking in siblings, suggesting a specific risk factor for nicotine dependence.
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SMOKING MOTIVES, PERSONALITY FACTORS, AND NICOTINE DEPENDENCE |
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Smokers experience self-reported increases in arousal and decreases in stress after smoking cigarettes, with absolute levels of arousal and stress peaking in midday and in the morning, respectively (107). Smokers experience stimulation and sedation simultaneously from each cigarette; however, they also experience lower equilibrium levels of arousal and higher equilibrium levels of stress than nonsmokers. After smoking cessation, mean arousal and stress levels are increased and reduced, respectively, suggesting that smoking cigarettes may contribute to the increased stress observed in smokers (108).
Personality and temperament constructs that use questionnaires to measure heritable personality dimensions quantitatively, e.g., Cloninger's Tridimensional Personality Questionnaire (79,109), have been used to investigate personality traits. Novelty seeking, extraversion, impulsivity, and neuroticism have been identified as the personality factors found at higher levels among smokers than among nonsmokers (110-113). That both dependent and nondependent smokers exhibit similarly increased sensation-seeking scores relative to nonsmokers suggests that, while increased sensation-seeking may increase liability to smoking initiation, it may not be related to differences in nicotine dependence among smokers.
Fagerstrom and colleagues proposed an eight-question "Tolerance Questionnaire" (FTQ) in 1978 (114) and a revised questionnaire (115), the Fagerstrom Test for Nicotine Dependence (FTND), in an attempt to provide quantitative information on nicotine dependence to assist in cessation therapy. FTQ and FTND scores have been found to show statistically significant associations with biochemical measures related to the quantity of cigarettes smoked (plasma nicotine, plasma or urinary cotinine, and expired CO) and are also associated with cessation outcome in trials without nicotine replacement therapy (115,116). FTQ and FTND scores have not been consistently correlated with percent abstinent at the end of the placebo-controlled trials with nicotine-replacement therapy; when they are predictive, they explain only 1% of the variation (116,117). FTND scores from population-based samples of smokers are statistically significantly lower than scores from smokers seeking cessation help (118).
A small fraction of active cigarette smokers are known as chippers or nondependent smokers, defined as smoking five or fewer cigarettes per day (119). Compared with regular smokers, chippers were found to extract similar amounts of nicotine per cigarette and to exhibit similar elimination half-lives of nicotine but to be statistically significantly less nicotine dependent and to have begun their smoking careers significantly more slowly (119-121). Regular smokers scored higher on pharmacologic smoking motive factors, and chippers scored higher on nonpharmacologic smoking motive factors (122). Chippers and regular smokers both appear to smoke for affect management; however, unlike regular smokers, chippers do not crave cigarettes and exhibit lower levels of smoking for stimulation and smoking to relieve negative affect.
The establishment of nicotine dependence in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM), third edition, represented the nosologic and diagnostic recognition of this drug dependency (123). The DSM-III/DSM-IV diagnosis of nicotine dependence (305.10) requires a minimum of three of seven diagnostic symptoms: tolerance, withdrawal, greater use than intended, persistent desire to quit, great amounts of time spent smoking, activities given up or reduced due to smoking, and continued smoking despite knowledge of having a persistent physical or psychologic problem with the substance (123,124). The DSM-IV diagnosis of nicotine withdrawal (292.0) requires four or more symptoms of eight to appear after abrupt cessation of tobacco use (124). A diagnosis of nicotine abuse is not recognized in either the DSM-III-R or the DSM-IV, primarily because nicotine does not meet two of the major criteria for a diagnosis of substance abuse. Specifically, nicotine is not considered to produce intoxication, and a diagnosis other than nicotine dependence would not be appropriate for maladaptive use of the substance (125). Nicotine dependence is a model for drug dependence, where tobacco smoking fulfills the physiologic, behavioral, and social characteristics of a dependence syndrome, but it also acts as a gateway drug for other drugs of abuse (126). However, the morbidity and mortality due to the direct effects of tobacco smoking exceed the direct or indirect effects of other drugs of abuse or, indeed, of any other single behavior on a population level (2,127). In contrast to the FTQ/FTND, there are no explicit quantitative measures assessed in the DSM substance dependence criteria, which are derived from the alcohol-dependence syndrome, a gradient of the severity of dependence comprising additional behavioral elements rather than increased consumption per se (128-130). Analysis of the factor structure of DSM-III-R nicotine dependence identified two factors named "general dependence" and "failed cessation," suggesting that DSM-III-R nicotine dependence is composed of multiple psychopharmacologic mechanisms that may differ in strength among smokers (131).
Among 15- to 54-year-old civilian, noninstitutionalized Americans (n = 4414) surveyed for tobacco use in the National Comorbidity Survey in 1991, lifetime DSM-III-R nicotine dependence was found at a population prevalence of 26% in men and 23% in women and at a higher prevalence among at least one-time tobacco users, i.e., 33% among males and 31% among females (132). With the use of data from the 1991-1992 National Household Survey on Drug Abuse (NHSDA) data (n = 61 426), of those who used cigarettes on a daily basis (n = 10 383), 91% experienced one or more symptoms of nicotine dependence; when grouped by cigarettes smoked per day, the frequency of those reporting symptoms of dependence was dose related (133,134). Among middle-aged, male daily smokers (n = 1006) from the Minneapolis-St. Paul area surveyed in 1982, 90% were found to qualify for DSM-III nicotine dependence (135). Among ever users of tobacco, defined as those who had used tobacco at least six times (n = 645), in a survey from the DSM-IV field trials using clinical populations in 1992 (136), 87% qualified for provisional DSM-IV nicotine dependence. DSM-III-R nicotine dependence occurs in 56% of daily smokers in an 18-year-old New Zealand sample (n = 321) and in 51% of daily smokers in a young-adult Michigan sample (n = 381) (137,138); however, very large samples of adolescent smokers have not been studied. While consumption and dependence are statistically significantly associated for all drugs of abuse, tobacco is similar to cocaine and the opiates in terms of its addiction liability; i.e., most users are dependent, in contrast to users of alcohol, amphetamines, and cannabis (136,184). For example, among last year users of alcohol (n = 54 998), nicotine (n = 28 392), cannabis (n = 11 237), and cocaine (n = 3410) in a nationally representative U.S. population sample (1991-1993 NHSDA), nicotine users were statistically significantly more likely to be nicotine dependent (28%) than alcohol (5.2%), cannabis (8.2%), or cocaine (11.6%) users (184). Also, only about 6%-12% of current smokers are intermittent (never daily) smokers (139); thus, the vast majority of cigarette smokers are daily smokers and, of these, the majority are nicotine-dependent smokers by DSM-III-R or DSM-IV criteria.
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SMOKING, PSYCHIATRIC COMORBIDITY, AND SUBSTANCE USE |
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An unresolved problem in the established association between depression and smoking is the issue of causality, since the potential for self-medication or precipitation of depression on cessation is inherent in the modulating effects of nicotine on neurotransmitter systems (24). For example, tobacco smoke, but not nicotine administration, statistically significantly reduces levels of monoamine oxidases A and B, which are essential metabolic enzymes for many neurotransmitters (148,149), suggesting that other components of tobacco smoke may have a substantial effect on synaptic dopamine concentrations (150). Multiple methods were used in a sample of female twins to assess possible causal relationships between the statistically significant and reciprocally associated diagnoses of nicotine dependence and major depression in co-twins and in their families (151). With the use of the co-twin control method that compares observed and expected rate differences between monozygotic and dizygotic twins, observed concordances rejected a causal model for one DSM-III-R diagnosis causing the other; in contrast, either a noncausal family environment or a noncausal genetic model fits the observed data. Modeling of genetic and environmental factors indicated a statistically significant genetic correlation between the liabilities to smoking and major depression, with specific environmental factors affecting the liabilities independently and a common environmental factor influencing the liability to smoking only (151). These data suggest that common genetic factors may contribute to both daily smoking and major depression.
The relationship between tobacco and alcohol use and abuse has been the subject of comprehensive reviews (126,152,153). Smoking and alcoholism are statistically significantly associated in population samples; e.g., 38% of ever smokers met the definition of DSM-III-R alcohol abuse and/or dependence versus only 16% of never smokers in a young Michigan sample (154), while 20% of ever smokers met the definition of DSM-III-R alcohol abuse and/or dependence versus only 8% of never smokers in a North Carolina NIMH-ECA sample (145). DSM-III-R-defined nicotine dependence and alcohol dependence were statistically significantly associated with each other, with the association at the same level as that with major depression and anxiety, i.e., odds ratios of 2-4 (146,154-156). A statistically significant association between the severity of DSM-III-R alcohol dependence (as defined by numbers of positive criteria) and nicotine dependence (as defined by FTQ score) was observed in a clinical (alcohol treatment) population where 88% of the alcohol-dependent individuals are current smokers and 92% of these smokers are defined as nicotine dependent by FTQ score (157).
Modeling of the statistically significant associations between alcohol use disorders and nicotine dependence in a university-based sample followed prospectively for 7 years, with individual diagnostic data and family history interview data, supports both reciprocal influence and common vulnerability models (158). Modeling of joint alcohol and tobacco use in a twin sample consisting of two age groups found that shared environmental factors are most important in early use (ages 12-16 years) and that genetic factors are more important in later use (ages 17-25 years) (99). More important, the shared correlation for the effect of genetic factors, which explain approximately 50% of the alcohol use and 50% of the tobacco use in older adolescents and young adults, is nearly unity, suggesting that substantially the same genetic factors are operating in this sample to influence both alcohol and tobacco use (99). With the use of the NAS-NRC World War II Twin Registry to investigate the genetic effects on multiple substance use, a twin model with a common genetic pathway to tobacco, alcohol, and coffee use, with no environmental effects and separate pathways with both genetic and shared environmental effects for each substance, provided the best fit to the data (159). Most of the genetic effect on tobacco consumption was found in the common genetic pathway, and most of the genetic effects on alcohol and coffee consumption were found in substance-specific pathways. Regression analysis of heavy consumers of the three substances in the NAS-NRC Twin Registry found two independent latent factors, one underlying heavy smoking and heavy alcohol use and one underlying heavy smoking and heavy coffee drinking (160). Separate factors contributing to the comorbidity of alcohol and nicotine dependence and to the comorbidity of nicotine dependence and coffee drinking may reflect independent regulation of the multiple pharmacologic effects of nicotine and the paired substance (161).
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DEMOGRAPHIC AND SOCIAL ENVIRONMENT FACTORS AND CIGARETTE SMOKING |
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In the United States, over the period from 1965 through 1994, current smoking prevalence among adults less than 65 years of age has decreased in every demographic category except those with less than 12 years of education (9). In those adults greater than or equal to 65 years of age, stable to increased rates of current smoking are observed in those with less than 12 years of education, in women, and in African-Americans (9). The quit ratio, defined as (former smokers)/(ever smokers), has increased in all groups; however, the rate of increase of the quit ratio has been slower in adults 65 years old or older. Combined with the postwar demographic bulge, the absolute number of older current smokers continues to increase despite a long-term decrease in smoking prevalence over the 30 years from 1965 through 1994.
The relationship between SES and smoking is complex, involving a number of related factors. The statistically significantly increased risk of smoking prevalence in those below the poverty threshold (14) is concordant with a statistically significantly increased risk for the opportunity of exposure to tobacco products over the age period 6-13 years because of neighborhood disadvantage, at least in Baltimore (MD) (165). In this same city, reduced levels of parental monitoring [statistically significantly associated with male sex of the child, reduced educational achievement, and a history of psychiatric disorder in mothers (166)] are statistically significantly associated with increased risk of smoking initiation (167). Cigarette acceptability and accessibility were the only school and neighborhood measures statistically significantly associated with cigarette smoking rates in a study of Midwestern elementary schools (168). However, neighborhood disadvantage is not always associated with increased rates of cigarette smoking; adjusted for attitude toward substance use and availability (including cigarettes), neighborhoods with lower population density, suggesting economic advantage, had higher rates of lifetime cigarette use in this Midwestern sample (168).
Intensive marketing of tobacco products has likely played an important role in establishing the prevalence of smoking observed today. Targeted promotion may be responsible for a menthol cigarette brand being the most prevalent brand among African-American smokers and for brand recognition among adolescents (2,169-171). Publication of a cigar-oriented magazine, endorsement of cigar use by celebrities, and marketing to high SES consumers may have reversed a 20-year decline in cigar consumption, the beginning of which coincided with advertising bans enacted in 1969 and 1973 (172).
There is evidence, however, that a number of social environmental factors, especially at the regulatory level, have been working to decrease the prevalence of smoking. Increasing societal disapproval of smoking since the 1964 Surgeon General's Report (173) has resulted in workplace regulation of smoking, among other antismoking sanctions (174). However, a national survey of 1992-1993 indoor workplace smoking policies reported by workers themselves observed statistically significantly different levels of workplace smoking restrictions by sex, age, smoking status, and occupation of the worker (175). These differences found between these sociodemographic factors and workplace smoking restrictions parallel differences in smoking prevalence by sex, age, and educational attainment. Recent U.S. Food and Drug Administration regulations and measures included in the first states' attorneys' general tobacco settlement were designed to modify the marketing behavior of the tobacco companies to susceptible youth populations and to contribute to smoking cessation programs (176,177). Analysis of media campaigns designed to reduce smoking initiation and to increase smoking cessation has demonstrated statistically significant associations between targeted media and reduced rates of smoking in adolescent females (178). A combination of a large state tax increase and tobacco control measures that included prevention, cessation, and environmental tobacco smoke programs was associated with an increased average quarterly decline in cigarette sales, during a period in which average levels of educational attainment and income were decreasing (179).
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SUMMARY |
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Nicotine dependence, major depression, and alcohol dependence are the three most prevalent specific psychiatric diagnoses in population samples in the United States, while substance abuse, anxiety disorders, and affective disorders are the three most prevalent diagnostic categories (132,180). Nicotine dependence is significantly associated with each of these three categories, an example of the striking concentration of psychiatric comorbidity in approximately one sixth of the U.S. population (180). The increased severity of nicotine dependence within the U.S. smoking population (118) and among those with psychiatric comorbidity (181) suggests that smoking cessation programs may be negatively affected (182), as has been observed (141,144). While it is the contamination of the nicotine delivery device with carcinogens, carbon monoxide, and cytotoxic compounds that is the probable source of the attributable risk from smoking in cancer and cardiovascular and respiratory diseases, an improved understanding of the neurobiologic mechanisms that maintain nicotine dependence may provide the basis for reducing morbidity and mortality, through improved smoking cessation therapies. Methods to incorporate covariates known to be significantly associated with smoking prevalence and behavior, including age, sex, SES, psychiatric history, and previously identified genetic loci, should be used in future candidate gene studies. Research sample design and future analyses of the smoking phenotype must address the consistent, statistically significant risks due to demographic, psychiatric, and genetic factors to improve our understanding of the socioeconomic, psychosocial, and neurobiologic bases of this behavior.
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NOTES |
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2 The contemporary Centers for Disease Control and Prevention categories
of cigarette smokers are current smokers (defined as those who currently smoke every day or on
some days), former smokers (ever smokers who do not currently smoke every day or on some
days), and never smokers (who have smoked fewer than 100 cigarettes in their lifetime) (11).
Supported by a postdoctoral fellowship from the Cancer Genetics and Epidemiology Training Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services (A. W. Bergen).
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Manuscript received January 8, 1999; revised June 3, 1999; accepted June 28, 1999.
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