Tobacco and Nicotine

1. Prevalence of Tobacco Use in the US, 2013, According to NSDUH

Basic Data

"• In 2013, an estimated 66.9 million Americans aged 12 or older were current (past month) users of a tobacco product. This represents 25.5 percent of the population in that age range (Figure 4.1). Also, 55.8 million persons (21.3 percent of the population) were current cigarette smokers; 12.4 million (4.7 percent) smoked cigars; 8.8 million (3.4 percent) used smokeless tobacco; and 2.3 million (0.9 percent) smoked tobacco in pipes.
"• Between 2002 and 2013, past month use of any tobacco product among persons aged 12 or older decreased from 30.4 to 25.5 percent, and past month cigarette use declined from 26.0 to 21.3 percent (Figure 4.1). Past month cigar use decreased from 5.4 percent in 2002 to 4.7 percent in 2013. Rates of past month use of smokeless tobacco and pipe tobacco were similar in 2002 and 2013."

Substance Abuse and Mental Health Services Administration, Results from the 2013 National Survey on Drug Use and Health: Summary of National Findings, NSDUH Series H-48, HHS Publication No. (SMA) 14-4863. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2014, pp. 47-48.
http://www.samhsa.gov/data/NSD...
http://www.samhsa.gov/data/NSD...

2. Estimated Annual Number of Deaths Caused by Tobacco Use in the US - Mortality Data

"The 2014 Surgeon General's report estimates that cigarette smoking causes more than 480,000 deaths each year in the United States.1 This widely cited estimate of the mortality burden of smoking may be an underestimate, because it considers deaths only from the 21 diseases that have been formally established as caused by smoking (12 types of cancer, 6 categories of cardiovascular disease, diabetes, chronic obstructive pulmonary disease [COPD], and pneumonia including influenza). Associations between smoking and the 30 most common causes of death in the United Kingdom in the Million Women Study suggest that the excess mortality observed among current smokers cannot be fully explained by these 21 diseases.2

Brian D. Carter, M.P.H., Christian C. Abnet, Ph.D., et al., "Smoking and Mortality — Beyond Established Causes," New England Journal of Medicine, Feb 12, 2015;372:631-40. DOI: 10.1056/NEJMsa1407211.
http://www.nejm.org/doi/full/1...

3. Alternative Estimate of Total Number of Deaths In the US Caused By Tobacco Use

"Our results suggest that the Surgeon General's recent estimate of smoking-attributable mortality may have been an underestimate. The Surgeon General's estimate, which took into account only the 21 diseases formally established as caused by smoking, was that approximately 437,000 deaths among adults are caused each year by active smoking (not including secondhand smoke). However, the Surgeon General’s report presents an alternative estimate of 556,000 deaths among adults on the basis of the excess mortality from all causes. The difference between these two estimates is nearly 120,000 deaths.1 If, as suggested by the results in our cohort, at least half of this difference is due to associations of smoking with diseases that are causal but are not yet formally established as such, then at least 60,000 additional deaths each year among U.S. men and women may be caused by cigarette smoking."

Brian D. Carter, M.P.H., Christian C. Abnet, Ph.D., et al., "Smoking and Mortality - Beyond Established Causes," New England Journal of Medicine, Feb 12, 2015;372:631-40. DOI: 10.1056/NEJMsa1407211.
http://www.nejm.org/doi/full/1...

4. Composition of Cigarette Smoke

"Cigarette smoke is a complex mixture of chemical compounds that are bound to aerosol particles or are free in the gas phase. Chemical compounds in tobacco can be distilled into smoke or can react to form other constituents that are then distilled to smoke. Researchers have estimated that cigarette smoke has 7,357 chemical compounds from many different classes (Rodgman and Perfetti 2009). In assessing the nature of tobacco smoke, scientists must consider chemical composition, concentrations of components, particle size, and particle charge (Dube and Green 1982). These characteristics vary with the cigarette design and the chemical nature of the product."

US Department of Health and Human Services. "How Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease: A Report of the Surgeon General." Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2010, p. 29.
http://www.cdc.gov/tobacco/dat...

5. Estimated Prevalence of Daily and Heavy Tobacco Use in the US According to NSDUH, 2013

"• Among the 55.8 million current cigarette smokers aged 12 or older in 2013, 33.2 million (59.6 percent) used cigarettes daily. The percentage of daily cigarette smokers among past month cigarette users increased with age (19.4 percent of past month cigarette users aged 12 to 17, 43.1 percent of those aged 18 to 25, and 64.9 percent of those aged 26 or older).
"• The percentage of current smokers aged 12 or older who used cigarettes daily decreased from 63.4 percent in 2002 to 59.6 percent in 2013. During the same time period, daily cigarette use declined among current smokers aged 12 to 17 (from 31.8 to 19.4 percent), those aged 18 to 25 (from 51.8 to 43.1 percent), and those aged 26 or older (from 68.8 to 64.9 percent).
"• In 2013, 41.3 percent of daily smokers aged 12 or older reported smoking 16 or more cigarettes per day (i.e., approximately one pack or more). The percentage of daily smokers who smoked at least one pack of cigarettes per day increased with age, from 11.9 percent among daily smokers aged 12 to 17, to 22.2 percent of those aged 18 to 25, then to 44.6 percent of those aged 26 or older (Figure 4.6).
"• The percentage of daily smokers aged 26 or older who smoked one or more packs of cigarettes per day was lower in 2013 (44.6 percent) than in 2002 (56.9 percent). Declines also were seen among daily smokers from 2002 to 2013 for youths aged 12 to 17 (from 21.7 to 11.9 percent) and for young adults aged 18 to 25 (from 39.0 to 22.2 percent)."

Substance Abuse and Mental Health Services Administration, Results from the 2013 National Survey on Drug Use and Health: Summary of National Findings, NSDUH Series H-48, HHS Publication No. (SMA) 14-4863. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2014, p. 54.
http://www.samhsa.gov/data/NSD...
http://www.samhsa.gov/data/NSD...

6. Probability of Transition From First Use to Dependence For Various Substances

"In a large, nationally representative sample of US adults, the cumulative probability of transition to dependence was highest for nicotine users, followed by cocaine users, alcohol users and, lastly, cannabis users. The transition to cannabis or cocaine dependence occurred faster than the transition to nicotine or alcohol dependence. Furthermore, there were important variations in the probability of becoming dependent across the different racial-ethnic groups. Most predictors of transition were common across substances.
"Consistent with previous estimates from the National Comorbidity Survey (Wagner and Anthony, 2002a), the cumulative probability of transition from use to dependence a decade after use onset was 14.8% among cocaine users, 11.0% among alcohol users, and 5.9% among cannabis users. This probability was 15.6% among nicotine users. Furthermore, lifetime cumulative probability estimates indicated that 67.5% of nicotine users, 22.7% of alcohol users, 20.9% of cocaine users, and 8.9% of cannabis users would become dependent at some time in their life."

Catalina Lopez-Quintero, et al., "Probability and Predictors of Transition From First Use to Dependence on Nicotine, Alcohol, Cannabis, and Cocaione: Results of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC)," Drug and Alcohol Dependence, 2011 May 1; 115(1-2): 120-130. doi:10.1016/j.drugalcdep.2010.11.004
http://www.ncbi.nlm.nih.gov/pm...

7. Association of Tobacco Use with Alcohol and Illicit Drug Use

"• Use of illicit drugs and alcohol was more common among current cigarette smokers than among nonsmokers in 2012, as in previous years since 2002. Among persons aged 12 or older, 23.0 percent of past month cigarette smokers reported current use of an illicit drug compared with 5.2 percent of persons who were not current cigarette smokers. Among youths aged 12 to 17 who smoked cigarettes in the past month, 54.6 percent also used an illicit drug compared with 6.4 percent of youths who did not smoke cigarettes.
"• Past month alcohol use was reported by 65.4 percent of current cigarette smokers compared with 48.3 percent of those who did not use cigarettes in the past month. This association also was found for binge alcohol use (43.6 percent of current cigarette smokers vs. 17.1 percent of current nonsmokers) and heavy alcohol use (15.8 vs. 3.9 percent, respectively)."

Substance Abuse and Mental Health Services Administration, Results from the 2012 National Survey on Drug Use and Health: Summary of National Findings, NSDUH Series H-46, HHS Publication No. (SMA) 13-4795. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2013, p. 49.
http://www.samhsa.gov/data/NSD...
http://www.samhsa.gov/data/NSD...

8. Global Tobacco-Related Mortality

"Tobacco use continues to be the leading global cause of preventable death. It kills nearly 6 million people and causes hundreds of billions of dollars of economic damage worldwide each year. Most of these deaths occur in low- and middle-income countries, and this disparity is expected to widen further over the next several decades. If current trends continue, by 2030 tobacco will kill more than 8 million people worldwide each year, with 80% of these premature deaths among people living in low- and middle-income countries. Over the course of the 21st century, tobacco use could kill a billion people or more unless urgent action is taken."

World Health Organization, "WHO Report on the Global Tobacco Epidemic, 2011: Warning About the Dangers of Tobacco" (Geneva, Switzerland: WHO, 2011), p. 8.
http://whqlibdoc.who.int/publi...

9. Estimated Prevalence of Current Tobacco Use Among Pregnant Women in the US

"• The annual average rate of past month cigarette use in 2012 and 2013 among women aged 15 to 44 who were pregnant was 15.4 percent (Figure 4.5). The rate of current cigarette use among women aged 15 to 44 who were pregnant was lower than that among women who were not pregnant (24.0 percent). This pattern was also evident among women aged 18 to 25 (21.0 vs. 26.2 percent for pregnant and nonpregnant women, respectively) and among women aged 26 to 44 (11.8 vs. 25.4 percent, respectively). Rates of current cigarette use in 2012-2013 among pregnant women aged 15 to 44 were 19.9 percent in the first trimester, 13.4 percent in the second trimester, and 12.8 percent in the third trimester.
"• The annual average rates of current cigarette use among women aged 15 to 44 who were not pregnant decreased from 30.7 percent in 2002-2003 to 24.0 percent in 2012-2013 (Figure 4.5). However, the prevalence of cigarette use among pregnant women in this age range did not change significantly during the same time period (18.0 percent in 2002-2003 and 15.4 percent in 2012-2013)."

Substance Abuse and Mental Health Services Administration, Results from the 2013 National Survey on Drug Use and Health: Summary of National Findings, NSDUH Series H-48, HHS Publication No. (SMA) 14-4863. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2014, p. 37.
http://www.samhsa.gov/data/NSD...
http://www.samhsa.gov/data/NSD...

10. Tobacco Use and Young People

"Tobacco use is a global epidemic among young people. As with adults, it poses a serious health threat to youth and young adults in the United States and has significant implications for this nation’s public and economic health in the future (Perry et al. 1994; Kessler 1995). The impact of cigarette smoking and other tobacco use on chronic disease, which accounts for 75% of American spending on health care (Anderson 2010), is well-documented and undeniable. Although progress has been made since the first Surgeon General’s report on smoking and health in 1964 (U.S. Department of Health, Education, and Welfare [USDHEW] 1964), nearly one in four high school seniors is a current smoker. Most young smokers become adult smokers."

US Department of Health and Human Services. "Preventing Tobacco Use Among Youth and Young Adults: A Report of the Surgeon General." Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2012, p. 3.
http://www.surgeongeneral.gov/...

11. Initiation of Tobacco Use in the US, 2012

"• The number of persons aged 12 or older who smoked cigarettes for the first time within the past 12 months was approximately 2.3 million in 2012, which was similar to the estimates from 2004 through 2011 (ranging from 2.1 million to 2.5 million), but was higher than the estimates for 2002 and 2003 (1.9 million and 2.0 million, respectively) (Figure 5.7). The 2012 estimate averages to about 6,400 new cigarette smokers every day. About half of new cigarette smokers in 2012 (51.4 percent) initiated prior to age 18.
"• In 2002 and 2012, the numbers of cigarette initiates who were younger than age 18 when they first used were similar (1.3 million and 1.2 million, respectively). However, the number of cigarette initiates who began smoking at age 18 or older increased from 623,000 in 2002 to 1.1 million in 2012.
"• In 2012, among recent initiates aged 12 to 49, the average age of first cigarette use was 17.8 years, which was higher than the corresponding average age in 2011 (17.2 years).
"• Of those aged 12 or older who had not smoked cigarettes prior to the past year (i.e., those at risk for initiation), the past year initiation rate for cigarettes was 2.3 percent in 2012, which was similar to the rate in 2011 (2.4 percent).
"• Among youths aged 12 to 17 who had not smoked cigarettes prior to the past year (i.e., youths at risk for initiation), the incidence rate in 2012 was 4.8 percent, which was lower than the 2011 rate (5.5 percent). However, past year initiation rates in 2012 of 4.7 percent for males aged 12 to 17 and 4.8 percent for females in this age group who had never smoked prior to the past year were not significantly different from corresponding rates in 2011 (5.4 percent for males and 5.5 percent for females) (Figure 5.8). Past year initiation rates in 2012 among males and females aged 12 to 17 who were at risk for initiation of cigarette use were lower than the rates in 2002 to 2010."

Substance Abuse and Mental Health Services Administration, Results from the 2012 National Survey on Drug Use and Health: Summary of National Findings, NSDUH Series H-46, HHS Publication No. (SMA) 13-4795. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2013, pp. 60-61.
http://www.samhsa.gov/data/NSD...
http://www.samhsa.gov/data/NSD...

12. Efficacy of E-Cigarettes in Tobacco Cessation and Dual Use of ENDS and Cigarettes

"Among adults, reductions in cigarettes per day were observed in several of the clinical studies83,84,86 and in 1 population-based study4 among those who did not quit. Reduction in cigarettes smoked per day could have benefit if it promotes subsequent cessation, as has been found with NRT,90 but this pattern has not yet been seen with e-cigarettes. In the cigarette reduction analyses presented in some of the studies, many participants were still smoking about half a pack cigarettes per day at the end of the study.
"Both duration (years of cigarette use) and intensity (cigarettes per day) determine the negative health effects of smoking.91 People who stop smoking at younger ages have lower age-adjusted mortality compared with those who continued to smoke later into adulthood.92 Findings for decreased smoking intensity have been less consistent, with some studies showing lower mortality with reduced daily cigarette consumption93 and others not finding a significant overall survival benefit.94 The 2014 report of the US Surgeon General concluded that 'reducing the number of cigarettes smoked per day is much less effective than quitting entirely for avoiding the risks of premature death from all smoking-related causes of death.'95 Use of electronic cigarettes by cigarette smokers to cut down on the number of cigarettes smoked per day is likely to have much smaller beneficial effects on overall survival compared with quitting smoking completely."

Rachel Grana, Neal Benowitz and Stanton A. Glantz, "Contemporary Reviews in Cardiovascular Medicine: E-Cigarettes: A Scientific Review," Circulation (Dallas, TX: American Heart Association, May 13, 2014). 2014;129:1972-1986. doi: 10.1161/CIRCULATIONAHA.114.007667, p. 1981.
http://circ.ahajournals.org/co...
http://circ.ahajournals.org/co...

13. Tobacco and Nicotine Addiction

"In summary, nicotine is the most potent constituent associated with the reinforcing effects of tobacco. However, researchers have identified other constituents in tobacco and tobacco smoke that may be reinforcing or facilitate reinforcing effects of tobacco. Nicotine metabolites have also been identified as potential reinforcers or enhancers of the reinforcing effects of nicotine. Researchers have observed that in addition to nicotine and other constituents of tobacco and tobacco smoke, sensory aspects of nicotine and environmental stimuli also have a significant role in maintaining smoking behavior (Rose et al. 1993; Shahan et al. 1999; Caggiula et al. 2001, 2002b; Perkins et al. 2001d) (for details, see “Learning and Conditioning” later in this chapter)."

US Department of Health and Human Services. "How Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease: A Report of the Surgeon General." Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2010, p. 113.
http://www.cdc.gov/tobacco/dat...

14. Medicinal Nicotine Products and Addiction Potential

"Nonetheless, although the pharmacokinetics of some smokeless tobacco products may overlap with those of medicinal nicotine products, medicinal products tend to have a slower rate and a lower amount of nicotine absorption than do the most popular brands of conventional smokeless tobacco products (Kotlyar et al. 2007). Among the medicinal nicotine products, nicotine nasal spray has the fastest rate of nicotine absorption, followed by nicotine gum, the nicotine lozenge, and the nicotine patch.
"Together, these results demonstrate that the nicotine pharmacokinetics associated with cigarette smoking is likely to lead to high potential for addiction, whereas medicinal nicotine products have relatively minimal potential for addiction. For example, the extent of liking, and therefore the addiction potential for these products, are related to the speed of nicotine delivery (Henningfield and Keenan 1993). Nicotine delivered through cigarette smoking and intravenously shows the greatest dose-related liking for the drug, and nicotine delivered transdermally is associated with the least liking (Henningfield and Keenan 1993; Stratton et al. 2001)."

US Department of Health and Human Services. "How Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease: A Report of the Surgeon General." Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2010, p. 114.
http://www.cdc.gov/tobacco/dat...

15. Tobacco and Nicotine Addiction

"Tobacco products contain more than 4,000 chemicals, some of which could contribute to dependence. However, there is little debate that nicotine is a major tobacco component responsible for addiction (USDHHS 1988; Stolerman and Jarvis 1995; Royal College of Physicians of London 2000; Balfour 2004)."

US Department of Health and Human Services. "How Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease: A Report of the Surgeon General." Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2010, p. 111.
http://www.cdc.gov/tobacco/dat...

16. Tobacco and Nicotine Addiction

"Long-term exposure to nicotine produces biologic adaptations leading to reduced sensitivity to some of the effects of nicotine (tolerance) and symptoms of distress soon after cessation of drug use (withdrawal). Tolerance of nicotine in adolescent smokers may be related to onset of drug dependence, even though tolerance in adult smokers does not appear to be related to different indices of nicotine addiction. Withdrawal symptoms, especially self-reported cravings and negative affect, are related to some indices of addiction. A narrower focus on the individual withdrawal symptoms most strongly related to relapse, such as negative affect (e.g., depressed mood), may increase understanding of the underlying mechanisms associated with the maintenance of nicotine addiction and requires further study.
"Positive reinforcement from nicotine may play a more significant role in the initiation of smoking, and negative reinforcement, particularly relief from withdrawal, is an important contributor to the persistence of smoking and relapse. Measures of nicotine’s reinforcing effects, especially the most common measure—self-reported number of cigarettes smoked per day—are consistently related to other indices of addiction, including the risk of relapse. However, other objective measures of nicotine’s reinforcing effects, especially those reflecting persistence in smoking behavior, may provide even stronger markers of addiction for predicting clinical outcomes and for testing the efficacy of new treatments or tobacco products. Such measures may also be useful as endophenotypes of dependence for future research into the etiology of addiction, including the influence of a person’s genetic composition. Therefore, the development of these validated markers and measures for nicotine and smoking reinforcement is critical for future research examining the etiology and treatments for nicotine addiction and for tobacco product testing."

US Department of Health and Human Services. "How Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease: A Report of the Surgeon General." Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2010, p. 124.
http://www.cdc.gov/tobacco/dat...

17. Nicotine Dependence, Co-Occurring Substance Use Disorders, and Psychiatric Comorbidity

"It is estimated that nearly one-half of all cigarettes sold in the United States (44 percent) are consumed by people with mental illnesses or substance abuse disorders. In addition, the prevalence of tobacco use among those with either addictions and/or mental illness is between 38 to 98 percent, as opposed to 19.8 percent for the general population (Schroeder 2009). Breslau and colleagues (1991) have conducted several studies. One earlier population-based study in Michigan observed that young adults with a diagnosis of nicotine dependence reported higher prevalence of alcohol and drug dependence and major depression and anxiety disorders than did persons who had never experienced nicotine dependence (Breslau et al. 1991). The relationships between each disorder and nicotine dependence were observed even when adjustments were made for confounding comorbidities. These findings are similar to those observed for adolescent smokers described earlier (Dierker et al. 2001) (see 'Determinants of Nicotine Addiction' earlier in this chapter). However, the results were contrary to other findings among adolescents (Clark and Cornelius 2004; Rohde et al. 2004). Other population-based research and clinical studies have also pointed to the strong relationship between daily smokers or nicotine-dependent smokers (as opposed to lifetime nonsmokers or non-dependent smokers) and substance use disorders, anxiety disorders, and depression, with higher prevalence of comorbid psychiatric disorders among nicotine-dependent smokers and higher prevalence of nicotine-dependent smokers among persons with comorbid disorders. For example, in a U.S. population-based survey, Grant and colleagues (2004) observed that the prevalence of alcohol use disorders, current mood disorders, or current anxiety disorders among adult respondents with diagnoses of nicotine dependence during the past year ranged from 21 to 23 percent compared with 9 to 11 percent in the general population. Conversely, other studies have shown the percentage of persons with nicotine dependence among respondents with these comorbid disorders ranging from 25 to 35 percent and as high as 52 percent among respondents with drug use disorders compared with 12.8 percent in the general population (Glassman et al. 1990; Breslau et al. 1994, 2004b; Lasser et al. 2000; Degenhardt and Hall 2001; Kandel et al. 2001; Isensee et al. 2003; Schmitz et al. 2003; Grant et al. 2004; John et al. 2004)."

US Department of Health and Human Services. "How Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease: A Report of the Surgeon General." Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2010, pp. 167-168.
http://www.cdc.gov/tobacco/dat...

18. Nicotine Dependence and Psychiatric Disorders

"Comorbidity between ND and psychiatric disorders characterized these adolescent smokers. Nicotine dependent adolescents had higher rates of anxiety, mood, disruptive, and multiple disorders than non-dependent smokers. The study elucidates these associations. Foremost, comorbidity between ND and psychiatric disorders in adolescence results from the fact that psychiatric disorders increase the risk of ND, controlling for common underlying factors. ND increases the risk of psychiatric disorders to a much weaker extent. This partially is due to the fact that, on average, psychiatric disorders onset ND by at least two and a half years, as reported by others [32,50], and in most cases psychiatric disorders precede ND. With control for covariates, we demonstrated a bidirectional association between disruptive disorder and ND, a unidirectional association between anxiety and ND, and no association between mood disorder and ND. Comorbidity of ND with mood disorders is explained by a common etiology."

Pamela C. Griesler, Mei-Chen Hu, Christine Schaffran, and Denise B. Kandel, "Comorbid Psychiatric Disorders and Nicotine Dependence in Adolescence," Addiction, 2011 May; 106(5); 1010-1020. doi:10.1111/j.1360-0443.2011.03403.x
http://www.ncbi.nlm.nih.gov/pm...

19. Tobacco and Cancer

"Although cigarette smoke contains diverse carcinogens, PAH, N-nitrosamines, aromatic amines, 1,3-butadiene, benzene, aldehydes, and ethylene oxide are among the most important carcinogens because of their carcinogenic potency and levels in cigarette smoke. Moreover, the major pathways of metabolic activation and detoxification of some of the principal carcinogens in cigarette smoke are well established. Reactive intermediate agents critical in forming DNA adducts include diol epoxides of PAH, diazonium ions generated by ?-hydroxylation of nitrosamines, nitrenium ions formed from esters of N-hydroxylated aromatic amines, and epoxides such as ethylene oxide. Glutathione and glucuronide conjugation play major roles in detoxification of carcinogens in cigarette smoke.
"Familial predisposition and genetic polymorphisms may play a role in tobacco-related neoplasms. Researchers have established cigarette smoking as a major cause of lung cancer; more than 85 percent of lung cancers are attributable to smoking. However, not all smokers develop lung cancer, and lung cancer can arise in lifetime non-smokers. This variation in disease has stimulated interest in molecular epidemiology of genetic polymorphisms, including genes that regulate the cell cycle and genes for carcinogen-metabolizing enzymes that may lead to variations in susceptibility to the carcinogens in tobacco smoke. Studies to date suggest a role for these genetic polymorphisms in the risk of lung and bladder cancer in smokers, and they support the possibility of interactions between genes and smoking status."

US Department of Health and Human Services. "How Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease: A Report of the Surgeon General." Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2010, p. 302.
http://www.cdc.gov/tobacco/dat...

20. Tobacco Use, Cardiovascular Disease, and CVD Mortality

"Cigarette smoking is a major cause of CVD, and past reports of the Surgeon General extensively reviewed the relevant evidence (U.S. Department of Health, Education, and Welfare [USDHEW] 1971, 1979; USDHHS 1983, 2001, 2004). Cigarette smoking has been responsible for approximately 140,000 premature deaths annually from CVD (USDHHS 2004). More than 1 in 10 deaths worldwide from CVD in 2000 were attributed to smoking (Ezzati et al. 2005). In the United States, smoking accounted for 33 percent of all deaths from CVD and 20 percent of deaths from ischemic heart disease in persons older than 35 years of age (Centers for Disease Control and Prevention 2008). Cigarette smoking also influences other cardiovascular risk factors, such as glucose intolerance and low serum levels of high-density lipoprotein cholesterol (HDLc). However, studies have reported that smoking increases the risk of CVD beyond the effects of smoking on other risk factors. In other words, the risk attributable to smoking persisted even when adjustments were made for differences between persons who smoke and nonsmokers in levels of these other risk factors (Friedman et al. 1979; USDHHS 1983, 2001, 2004; Shaper et al. 1985; Criqui et al. 1987; Ragland and Brand 1988; Shaten et al. 1991; Neaton and Wentworth 1992; Freund et al. 1993; Cremer et al. 1997; Gartside et al. 1998; Wannamethee et al. 1998; Jacobs et al. 1999a). For example, in one study, the effect of cigarette smoking on the risk of coronary heart disease (CHD) was evident even among persons with low serum levels of cholesterol (Blanco-Cedres et al. 2002)."

US Department of Health and Human Services. "How Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease: A Report of the Surgeon General." Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2010, p. 355.
http://www.cdc.gov/tobacco/dat...

21. Electronic Nicotine Delivery Systems (ENDS), or E-Cigarettes, Explained

Electronic Nicotine Delivery Systems (ENDS) or E-Cigarettes

"PRODUCT DESIGN AND CONTENTS
"3. ENDS, of which electronic cigarettes are the most common prototype, deliver an aerosol by heating a solution that users inhale. The main constituents of the solution by volume, in addition to nicotine when nicotine is present, are propylene glycol, with or without glycerol and flavouring agents.
"4. Although some ENDS are shaped to look like their conventional tobacco counterparts (e.g. cigarettes, cigars, cigarillos, pipes, or hookahs), they also take the form of everyday items such as pens, USB memory sticks, and larger cylindrical or rectangular devices.
"5. Battery voltage and unit circuitry differences can result in considerable variability in the products' ability to heat the solution to an aerosol and, consequently, may affect delivery of nicotine and other constituents, and may contribute to the formation of toxicants in the emissions.
"6. User behaviour may affect nicotine absorption – length of puffs, depth of inhalation and frequency of use may be factors. However, while a faster, deeper puff increases nicotine delivery from a conventional cigarette, it might diminish it from ENDS due to cooling of the heating element.
"7. In addition to manufacturer differences, some users modify products at home to alter delivery of nicotine and/or other drugs. Products vary widely in the ease with which they can be modified and the ease with which they can be filled with substances other than nicotine solutions."

Electronic Nicotine Delivery Systems, Report by World Health Organization to 6th Session of the Conference of the Parties to the WHO Framework Convention on Tobacco Control, July 21, 2014, p. 2.
http://apps.who.int/gb/fctc/PD...

22. E-Cigarettes (Electronic Nicotine Delivery Systems) Explained

"Electronic nicotine delivery devices such as electronic cigarettes (e-cigarettes) are battery-powered devices that deliver nicotine, flavorings (e.g., fruit, mint, and chocolate), and other chemicals via an inhaled aerosol. E-cigarettes that are marketed without a therapeutic claim by the product manufacturer are currently not regulated by the Food and Drug Administration (FDA) (1).*"

"* Currently, e-cigarettes and their components, such as the nicotine they contain, that are intended for therapeutic purposes (e.g., for smoking cessation) are drug/device combination products. When they are marketed for therapeutic purposes they are regulated by the FDA's Center for Drug Evaluation and Research. FDA’s Center for Tobacco Products currently regulates cigarettes, cigarette tobacco, roll-your-own tobacco, and smokeless tobacco. FDA has stated its intention to issue a proposed rule extending FDA's tobacco product authorities beyond these products to include other products like e-cigarettes not intended for therapeutic purposes."

Kevin Chatham-Stephens, MD, Royal Law, MPH, Ethel Taylor, DVM, Paul Melstrom, PhD, Rebecca Bunnell, ScD, Baoguang Wang, MD, Benjamin Apelberg, PhD, Joshua G. Schier, MD, "Calls to Poison Centers for Exposures to Electronic Cigarettes - United States, September 2010-February 2014, Morbidity and Mortality Weekly Report (MMWR) (Atlanta, GA: Centers for Disease Control, April 4, 2014, Vol. 63, No. 13, p. 292.
http://www.cdc.gov/mmwr/pdf/wk...
http://www.cdc.gov/mmwr/previe...

23. Estimated Global Market for E-Cigarettes (Electronic Nicotine Delivery Systems (ENDS))

"THE ENDS MARKET
"8. The use of ENDS is apparently booming. It is estimated that in 2014 there were 466 brands1 and that in 2013 US$ 3 billion was spent on ENDS globally. Sales are forecasted to increase by a factor of 17 by 2030.2 Despite this projection, transnational tobacco companies are divided about the prospects of the growth of ENDS sales and some companies have reported a slowdown in sales in some markets.3, 4, 5 There are no data on ENDS use at the global level and for many countries. However, data mainly from North America, the European Union (EU) and Republic of Korea indicate that ENDS use at least doubled among both adults and adolescents from 2008 to 2012.6 In 2012, 7% of EU citizens aged 15 years and over had tried electronic cigarettes. However, only 1% of the total population used them regularly.7 In 2013, 47% of smokers and ex-smokers in the United States of America had tried e-cigarettes, but prevalence of established use was 4% in this group.1 Users report that the main reasons for using ENDS are to reduce or stop smoking and because they can be used in smoke-free places.2
"9. According to the recent WHO survey, ENDS availability is widespread. Slightly over half of the world’s population live in 62 countries that report the availability of ENDS in their jurisdictions, 4% live in countries reporting that ENDS are not available, while the rest live in countries that did not respond concerning the availability of ENDS.
"10. Recently, the transnational tobacco companies have entered the ENDS market. Some of them are aggressively competing with the independent companies to gain market share. Given the economic power of the tobacco industry, recent moves to sue other companies alleging patent infringement may be an indicator of how difficult it will be for ENDS to remain a business niche dominated by independent companies."

Electronic Nicotine Delivery Systems, Report by World Health Organization to 6th Session of the Conference of the Parties to the WHO Framework Convention on Tobacco Control, July 21, 2014, pp. 2-3.
http://apps.who.int/gb/fctc/PD...

24. Health Effects of E-Cigarette Use (Electronic Nicotine Delivery System) Use

"Propylene glycol and glycerin are the main base ingredients of the e-liquid. Exposure to propylene glycol can cause eye and respiratory irritation, and prolonged or repeated inhalation in industrial settings may affect the central nervous system, behavior, and the spleen.66 In its product safety materials, Dow Chemical Company states that "inhalation exposure to [propylene glycol] mists should be avoided,"67 and the American Chemistry Council warns against its use in theater fogs because of the potential for eye and respiratory irritation.68 When heated and vaporized, propylene glycol can form propylene oxide, an International Agency for Research on Cancer class 2B carcinogen,69 and glycerol forms acrolein, which can cause upper respiratory tract irritation.70,71
"Major injuries and illness have resulted from e-cigarette use,72 including explosions and fires.73,74 Less serious adverse events include throat and mouth irritation, cough, nausea, and vomiting.72"

Rachel Grana, Neal Benowitz and Stanton A. Glantz, "Contemporary Reviews in Cardiovascular Medicine: E-Cigarettes: A Scientific Review," Circulation (Dallas, TX: American Heart Association, May 13, 2014). 2014;129:1972-1986. doi: 10.1161/CIRCULATIONAHA.114.007667, p. 1978.
http://circ.ahajournals.org/co...
http://circ.ahajournals.org/co...

25. Calls to US Poison Centers About Human Exposures to E-Cigarettes, 2010-2014

"During the study period, PCs reported 2,405 e-cigarette and 16,248 cigarette exposure calls from across the United States, the District of Columbia, and U.S. territories. E-cigarette exposure calls per month increased from one in September 2010 to 215 in February 2014 (Figure). Cigarette exposure calls ranged from 301 to 512 calls per month and were more frequent in summer months, a pattern also observed with total call volume to PCs involving all exposures (5).
"E-cigarettes accounted for an increasing proportion of combined monthly e-cigarette and cigarette exposure calls, increasing from 0.3% in September 2010 to 41.7% in February 2014. A greater proportion of e-cigarette exposure calls came from health-care facilities than cigarette exposure calls (12.8% versus 5.9%) (p<0.001). Cigarette exposures were primarily among persons aged 0–5 years (94.9%), whereas e-cigarette exposures were mostly among persons aged 0–5 years (51.1%) and >20 years (42.0%). E-cigarette exposures were more likely to be reported as inhalations (16.8% versus 2.0%), eye exposures (8.5% versus 0.1%), and skin exposures (5.9% versus 0.1%), and less likely to be reported as ingestions (68.9% versus 97.8%) compared with cigarette exposures (p<0.001)."

Kevin Chatham-Stephens, MD, Royal Law, MPH, Ethel Taylor, DVM, Paul Melstrom, PhD, Rebecca Bunnell, ScD, Baoguang Wang, MD, Benjamin Apelberg, PhD, Joshua G. Schier, MD, "Calls to Poison Centers for Exposures to Electronic Cigarettes - United States, September 2010-February 2014, Morbidity and Mortality Weekly Report (MMWR) (Atlanta, GA: Centers for Disease Control, April 4, 2014, Vol. 63, No. 13, p. 292.
http://www.cdc.gov/mmwr/pdf/wk...
http://www.cdc.gov/mmwr/previe...

26. Health Effects of E-Cigarette Use

"In summary, only a few studies have directly investigated the health effects of exposure to e-cigarette aerosol, but some demonstrate the ability of e-cigarette aerosol exposure to result in biological effects. Long-term biological effects are unknown at this time because e-cigarettes have not been in widespread use long enough for assessment."

Rachel Grana, Neal Benowitz and Stanton A. Glantz, "Contemporary Reviews in Cardiovascular Medicine: E-Cigarettes: A Scientific Review," Circulation (Dallas, TX: American Heart Association, May 13, 2014). 2014;129:1972-1986. doi: 10.1161/CIRCULATIONAHA.114.007667, p. 1978.
http://circ.ahajournals.org/co...
http://circ.ahajournals.org/co...

27. Efficacy of E-Cigarettes in Tobacco Cessation

"In contrast to the assumption that e-cigarettes would function as a better form of NRT [Nicotine Replacement Therapy], population-based studies that reflect real-world e-cigarette use found that e-cigarette use is not associated with successful quitting; all4,79,80,82 had point estimates of the odds of quitting of <1.0. The 1 clinical trial examining the effectiveness of e-cigarettes (both with and without nicotine) compared with the medicinal nicotine patch found that e-cigarettes are no better than the nicotine patch and that all treatments produced very modest quit rates without counseling.86 Taken together, these studies suggest that e-cigarettes are not associated with successful quitting in general population-based samples of smokers."

Rachel Grana, Neal Benowitz and Stanton A. Glantz, "Contemporary Reviews in Cardiovascular Medicine: E-Cigarettes: A Scientific Review," Circulation (Dallas, TX: American Heart Association, May 13, 2014). 2014;129:1972-1986. doi: 10.1161/CIRCULATIONAHA.114.007667, pp. 1980-1981.
http://circ.ahajournals.org/co...
http://circ.ahajournals.org/co...

28. Limitations of Some Research on Health Effects of E-Cigarettes

"National Vaper’s Club, a pro–e cigarette advocacy group, published a 'risk assessment' of e-cigarette and cigarette use that concluded that 'neither vapor from e-liquids or cigarette smoke analytes posed a condition of 'significant risk' of harm to human health via the inhalation route of exposure.'77 The authors failed to detect benzo(a)pyrene in conventional cigarette smoke despite the fact that it is an established carcinogen in cigarette smoke, and their assessment of conventional cigarettes concluded that they did not pose significant risk, both of which point to fatal errors in the data, data analysis, or both. Another report15 funded by the Consumer Advocates for Smoke-free Alternatives Association and published on the Internet used occupational threshold limit values to evaluate the potential risk posed by several toxins in e-cigarettes, concluding that 'there is no evidence that vaping produces inhalable exposures to contaminants of the aerosol that would warrant health concerns by the standards that are used to ensure safety of workplaces.' Threshold limit values are an approach to assessing health effects for occupational chemical exposures that are generally much higher (often orders of magnitude higher) than levels considered acceptable for ambient or population-level exposures. Occupational exposures also do not consider exposure to sensitive subgroups such as people with medical conditions, children, and infants who might be exposed to secondhand e-cigarette emissions, most notably nicotine."

Rachel Grana, Neal Benowitz and Stanton A. Glantz, "Contemporary Reviews in Cardiovascular Medicine: E-Cigarettes: A Scientific Review," Circulation (Dallas, TX: American Heart Association, May 13, 2014). 2014;129:1972-1986. doi: 10.1161/CIRCULATIONAHA.114.007667, p. 1978.
http://circ.ahajournals.org/co...
http://circ.ahajournals.org/co...

29. Second-Hand Exposure From E-Cigarette (Electronic Nicotine Delivery System) Use

"17. In summary, the existing evidence shows that ENDS aerosol is not merely 'water vapour' as is often claimed in the marketing for these products. ENDS use poses serious threats to adolescents and fetuses. In addition, it increases exposure of non-smokers and bystanders to nicotine and a number of toxicants. Nevertheless, the reduced exposure to toxicants of well-regulated ENDS used by established adult smokers as a complete substitution for cigarettes is likely to be less toxic for the smoker than conventional cigarettes or other combusted tobacco products. The amount of risk reduction, however, is presently unknown. The 2014 Surgeon General's Report concluded that non-combustible products such as ENDS are much more likely to provide public health benefits only in an environment where the appeal, accessibility, promotion, and use of cigarettes and other combusted tobacco products are being rapidly reduced.7

Electronic Nicotine Delivery Systems, Report by World Health Organization to 6th Session of the Conference of the Parties to the WHO Framework Convention on Tobacco Control, July 21, 2014, p. 5.
http://apps.who.int/gb/fctc/PD...

30. Cigarette Use Among US Youth, 2014

"• Prevalence of cigarettes is generally higher than for any of the illicit drugs, except for marijuana. About one third (34%) of 12th graders reported having tried cigarettes at some time, and one seventh (14%) smoked in the prior 30 days. Even among 8th graders, about one seventh (14%) reported having tried cigarettes and 4% reported smoking in the prior 30 days. Among 10th graders, 23% reported having tried cigarettes, and 7.2% reported smoking in the prior 30 days. The percentages reporting smoking cigarettes in the prior 30 days are actually lower in all three grades in 2014 than the percentages reporting using marijuana in the prior 30 days: 4.0% for cigarettes versus 6.5% for marijuana in 8th grade; 7.2% versus 16.6% in 10th grade; and 13.6% versus 21.2% in 12th grade. These numbers reflect mostly the considerable decline in cigarette use that has occurred in recent years, though the recent increase in marijuana use has contributed to their standing relative to each other as well. Among 8th, 10th and 12th graders, lifetime prevalence of marijuana use in 2014 was also higher than lifetime prevalence of cigarette use. (Annual prevalence of cigarettes is not assessed.) As noted below, however, daily use in the prior 30 days was higher for cigarettes than for marijuana or alcohol in 8th and 12th grades. For 10th graders marijuana daily use was higher than daily cigarette use (3.4% versus 3.2%)."

Miech, R. A., Johnston, L. D., O’Malley, P. M., Bachman, J. G., & Schulenberg, J. E. (June 2015). Monitoring the Future national survey results on drug use, 1975–2014: Volume I, Secondary school students. Ann Arbor: Institute for Social Research, The University of Michigan, p. 85.
http://monitoringthefuture.org...