INTRODUCTION

The potential adverse health effects of “premium”¹ cigars need to be viewed in the context of harms of combusted tobacco smoking broadly. Cigarette smoking is the most common form of combusted tobacco use, and its health effects are well established. These include increased overall mortality, cardiovascular disease (CVD), chronic obstructive lung disease, cancer, susceptibility to respiratory infection, adverse reproductive outcomes, and other diseases (HHS, 2004, 2010, 2014). When tobacco is burned, the generated toxicants are generally similar across tobacco types. The extent of inhalation and the frequency and duration of use are major factors in determining whether tobacco smoking will cause disease. The health risks of little cigars and cigarillos, which are commonly inhaled and may be smoked more frequently, may be expected to be similar to those of cigarette smoking. Chapters 2 and 3 address inhalation and frequency of use for large cigars.

Mechanisms of tobacco smoke toxicity and biomarkers of toxicant exposure are applicable to understanding the potential harms of premium cigars. The toxicants generated by combustion of tobacco include oxidizing chemicals, carcinogens (such as nitrosamines and polycyclic hydrocarbons), carbonyls (such as acrolein, formaldehyde, and acetaldehyde), carbon monoxide (CO), metals, and particulates. When these substances are inhaled, oxidant stress, systemic inflammation, endothelial dysfunction, DNA damage, hypercoagulability, and changes in microbial populations occur, which lead to organ dysfunction and disease (HHS, 2010). While inhalation is necessary to deliver toxicants to the heart, lungs, and other body organs, taking tobacco smoke into the mouth without inhalation exposes the mouth, pharynx, and esophagus to various toxicants. Thus, upper respiratory tract and esophageal disease can occur even in tobacco users who do not inhale, which is typical of some premium cigar smokers.

While products of combustion are thought to be responsible for most of the disease caused by smoking, nicotine may also contribute. Nicotine comes from the tobacco itself, and its absorption does not require combustion or even inhalation. Nicotine is a weak base, and, in the presence of an alkaline pH, is readily absorbed across mucous membranes, such as the mouth. Users of smokeless tobacco products absorb, on average, similar amounts of nicotine each day as do cigarette users (Piano et al., 2010). While fewer data are available on cigar users who do not inhale, the potential for substantial nicotine exposure is clear (see Chapter 2). In contrast to cigarettes, where the wrapper is paper, cigar wrappers contain tobacco, so nicotine can be absorbed orally through direct contact with the tobacco leaf, as well as through the smoke.

The most important harmful effect of nicotine is sustained use of combusted tobacco by causing addiction (Benowitz, 2010); evidence of addiction in premium cigar users is discussed later in this chapter. Other effects of concern include contributions to CVD, increased risk of diabetes and pro-atherogenic lipid profiles, reproductive toxicity, including low birth weight and effects on fetal neurodevelopment, and possible adverse effects on adolescent brain maturation (Benowitz and Burbank, 2016; HHS, 2010). Nicotine also releases catecholamines, which cause constriction of blood vessels, which in turn may promote oral pathology or result in impaired wound healing after surgical procedures.

Other tobacco and substance use behaviors also need to be considered in assessing potential adverse effects of premium cigar use. Former or concurrent cigarette or small cigar users are more likely to inhale more intensively compared to users who have smoked exclusively large and premium cigars (see Chapter 2). All tobacco products, including premium cigars, are commonly used in conjunction with drinking alcoholic beverages (see Chapter 3). Alcohol and smoking act synergistically to increase the risk of head and neck and esophageal cancer.

To assess the health effects of premium cigars, including secondhand smoke, this chapter considers biological plausibility, including the chemical nature of the tobacco leaf and emissions from premium cigars compared to other combusted tobacco products, and the evidence for the extent of inhalation of premium cigar smoke, including use of biomarkers of exposure that might establish levels of systemic exposure (see Chapter 2). This chapter reviews harmful constituents of tobacco smoke, the epidemiology of overall mortality and particular diseases in relation to cigar use, and the issue of addiction to cigar smoking. Because the epidemiology on premium cigar use is quite limited, the committee examined cigar use in general, with particular focus on inhalation, frequency, and duration. These data were considered as a whole to assess specific disease risks. Because most studies did not specify the type of cigars, the committee was unable to compare risks among various types. (See Appendix A for the list of research questions that were reviewed for this chapter.)

HEALTH EFFECTS OF EXPOSURE TO HARMFUL AND POTENTIALLY HARMFUL CONSTITUENTS OF CIGAR SMOKE

The Food and Drug Administration (FDA) has established a list of harmful and potentially harmful constituents (HPHCs) in tobacco products and tobacco smoke (FDA, 2012). All of these compounds have been detected in cigarette smoke. While studies of cigar smoke specifically, and particularly of premium cigar smoke, have not reported analyses of all HPHCs, there is every reason to believe that each of these compounds would be detected in premium cigar smoke if the specific analyses were performed, because they are all either transferred from tobacco during smoking or formed during smoking by combustion processes. HPHC concentrations in premium cigar smoke may be different from those in the smoke of cigarettes and other cigars, but the spectrum of compounds will be similar if not identical. Thus, the health effects of HPHCs per gram of premium cigar tobacco smoked are expected to be very similar to those observed from nonpremium cigar smoking.

The carcinogenic and other health effects of tobacco smoking can be expected to follow a dose–response relationship: health risks will depend on the total toxicant and carcinogen exposure. A recent review concluded that mechanisms of interaction of tobacco smoke constituents with human genetic material after use of tobacco products other than cigarettes are similar to those associated with cigarette smoking (Szyfter et al., 2019). See Box 5-1 for a list of HPHCs organized by category and discussed below.

BOX 5-1

List of Established Harmful and Potentially Harmful Constituents (HPHCs).

A plethora of adverse health effects of compounds in each category are well established, and some are briefly summarized here. Nicotine is the major chemical component responsible for addiction to tobacco products, exerting its effects by stimulation of nicotine acetylcholine receptors. In its unprotonated state, it readily crosses cell membranes and enters the body. When inhaled, unprotonated nicotine is more volatile and acts on nicotinic cholinergic receptors in the mouth and throat, producing sensations of irritation and harshness (Benowitz et al., 2021; Leventhal et al., 2021). Since cigar smoke is often more alkaline than smoke from cigarettes or small cigars, more nicotine in the smoke is in the unprotonated state, so the smoke is more irritating and difficult to inhale (see Chapter 2). For this reason, the pH of cigar smoke is a critical factor influencing whether or how deeply a user inhales, and the expression of nicotine's effects. Other established properties of nicotine include acute toxicity at high doses and negative effects on maternal and fetal health (England et al., 2017). The negative effects of nicotine withdrawal on cognitive function have been established. It is also associated with dysphoric mood, including anxiety and depression. Relief of these symptoms is rewarding (termed “negative reinforcement”) and contributes to nicotine addiction. Nicotine exposure during adolescence causes long-term structural and functional changes to the brain in rodents and might also do so in human youth (HHS, 2014). Some evidence exists for abuse potential of the minor tobacco alkaloids nornicotine and anabasine, which could play a role in abuse potential of tobacco products, including premium cigars (Hoffman and Evans, 2013). Some evidence also suggests the endogenous nitrosation of nornicotine in the human body, leading to formation of the carcinogen NNN (Knezevich et al., 2013; Stepanov et al., 2009).

Considerable amounts of CO (e.g., 97 mg/cigar in the Macanudo premium cigar brand) are present in premium cigar smoke (NCI, 1998). CO binds rapidly with hemoglobin in the blood, diminishing its oxygen-carrying capacity and potentially leading to a number of negative health effects, particularly in people with underlying cardiovascular or pulmonary disease. Ammonia causes a burning sensation in the eyes, nose, throat, and respiratory tract, and hydrogen cyanide is a known poison.

Acetaldehyde has some addiction potential and binds to DNA (Balbo et al., 2012; FDA, 2012). As the major initial metabolite of ethanol, most of its potentially toxic, genotoxic, and carcinogenic effects are associated with alcohol consumption (IARC, 2012c). Acrolein (55–60 µg/g cigar tobacco smoked) is one of the most irritating and toxic compounds in tobacco smoke (Haussmann, 2012; NCI, 1998). It reacts with DNA to form well-characterized adducts (Paiano et al., 2020) and is considered probably carcinogenic to humans by the International Agency for Research on Cancer (IARC) (IARC Monographs Vol 128 group, 2021). Benzene is a known human carcinogen causing acute myeloid leukemia/acute nonlymphocytic leukemia (IARC, 2012e), and 1,3-butadiene is considered “carcinogenic to humans” by IARC, causing cancer of the hematolymphatic organs (IARC, 2012e). IARC also considers ethylene oxide and formaldehyde carcinogenic to humans. The former is based on evidence from studies in laboratory animals and compelling evidence from genotoxicity studies in humans (IARC, 2012c). Formaldehyde is an accepted cause of cancer of the nasopharynx and of leukemia (IARC, 2012d).

Tobacco-specific nitrosamines are among the most well-characterized carcinogens in unburned tobacco and tobacco smoke, with consistently problematic levels in both, as summarized in Chapter 2. NNK causes tumors of the lung in all species tested, including rats, hamsters, ferrets, and multiple strains of mice, independent of the route of administration (Hecht, 1998). The lowest total dose of NNK shown to induce lung tumors in rats was 1.8 mg/kg body weight. The carcinogenicity of NNN has also been established in multiple species, including various strains of rats and mice and in Syrian golden hamsters and mink (Hecht, 1998). In one study, chronic oral administration of (S)-NNN (the major form in tobacco) at a dose of 14 ppm in drinking water induced 89 benign and malignant oral cavity tumors and 122 esophageal tumors in a group of 20 rats (Balbo et al., 2013). IARC considers NNK and NNN, which always occur together in tobacco and tobacco smoke and are present in all tobacco products, carcinogenic to humans (IARC, 2012b).

Polycyclic aromatic hydrocarbons (PAH) represent a well-established class of carcinogens that are formed by incomplete combustion of organic matter, including tobacco. They are widespread environmental contaminants also found in air, water, soils, sediments, and broiled foods. Multiple PAH are present in tobacco and tobacco smoke. One study tentatively identified more than 500 different PAH in tobacco smoke condensate fractions (Snook et al., 1978). Benzo[a]pyrene (BaP) is the most extensively investigated, and many of its properties are illustrative of the class (IARC, 2012e). BaP induces tumors in laboratory animals by various routes of administration; is a complete carcinogen (affects tumor cells in all stages of development) and tumor initiator when applied to mouse skin; and induces tumors at the injection site and sometimes lungs in mice when administered by subcutaneous injection. Many other PAH have similar carcinogenic properties as those of BaP, which IARC considers carcinogenic to humans (IARC, 2012e).

Aromatic amines, such as 4-aminobiphenyl and 2-naphthylamine, are recognized human bladder carcinogens in tobacco smoke (IARC, 2012e). Heterocyclic aromatic amines are a broad class of well-established carcinogens formed during high-temperature combustion processes involved in food preparation as well as in cigarette and cigar smoking (Bellamri et al., 2021).

Phenols, such as catechol, occur in relatively high concentrations in cigarette smoke. Catechol is a co-carcinogen, enhancing the tumorigenic activity of PAH in mouse skin models, and can be involved in oxidative damage by tobacco smoke. Phenols, while generally not carcinogenic themselves, may enhance the activity of carcinogens in smoke (Hecht, 2011).

Metals are among the HPHCs in tobacco and tobacco smoke; some of these, including lead, cadmium, and nickel, have been identified in cigar smoke (NCI, 1998). Prolonged exposure to lead may have a variety of health effects, including high blood pressure, heart disease, and kidney disease (CDC, 2018). Cadmium and nickel are considered carcinogenic to humans by IARC, causing lung cancer as well as some other cancer types (IARC, 2012a).

HEALTH EFFECTS OF PREMIUM CIGARS²

CARDIOVASCULAR DISEASE

Cigarette smoking is a major cause of CVD, including coronary heart disease, stroke, and aortic aneurysm (Barua et al., 2018; HHS, 2010). The risk is nonlinear, meaning that it increases sharply with smoking a few cigarettes per day. Smoking 5 cigarettes per day has 50 percent or more of the risk compared to smoking 20 per day (Inoue-Choi et al., 2020). Most of the epidemiologic studies of cigar use and CVD were performed many years ago, and none provide data by the type of cigar smoked.⁴ Some studies report risk by the number of cigars smoked per day but not for nondaily smokers. Several studies provide data on primary versus secondary cigar smokers, and several provide data on self-reported depth of inhalation. Many from the British Regional Heart Study and other studies present data on a combined group of pipe and cigar smokers but not cigar smokers alone.

The committee's review located two studies of the acute cardiovascular effects of cigar smoking. Vlachopoulos et al. (2004) examined the effects of smoking one premium cigar (Cohiba) compared to sham smoking in 12 young healthy cigarette smokers who had abstained from tobacco use for 12 hours. The cigar was smoked over 1 hour, producing an increase in expired CO of 12 parts per million (ppm), an average increase in heart rate of 5 beats per minute (bpm), and increase in systolic blood pressure of 10 mmHg. Arterial stiffness measured using carotid-femoral pulse wave velocity (more stiffness produces higher velocity) was increased by cigar smoking. These effects are similar to those produced by cigarette smoking. The effect peaked at 60 minutes and declined toward baseline over the next 60 minutes. Arterial stiffness increased by 15 percent with cigar smoking, compared to prior studies showing an increase of 26 percent with active and 21 percent with passive cigarette smoking. These physiological effects are likely due to the sympathomimetic effects of nicotine and endothelial dysfunction known to be produced by smoke inhalation. Claus et al. (2018) studied 42 large cigar smokers who were instructed to smoke their cigar as desired for 60 minutes. Plasma nicotine levels increased to a level similar to that seen after cigarette smoking. Maximal increase in heart rate averaged 6.5 bpm (standard deviation [SD] 10.1), systolic blood pressure 12.3 mmHg (14.5), and diastolic blood pressure 8.2 mmHg (7.0). These studies support that idea that inhaling smoke from any combusted tobacco product can produce the same pathophysiological effect, depending on dose and duration of use.

The 1998 NCI monograph reviewed the association between cigar use and CVD through 1997, including unpublished data from CPS-I (NCI, 1998). There was generally a slight (and often nonsignificant) increased risk of coronary heart disease in primary and secondary cigar users, with variability across studies. There was a trend for increased risk based on the number of cigars smoked per day for primary cigar smokers (1–2 versus 3–4 versus 5+ per day) and for depth of inhalation (none versus slight versus moderate-deep); the risk in all cases was less than that of cigarette smoking.

Data from the CPS-I study found no increased risk of stroke death in either primary or secondary cigar smokers, regardless of the number of cigars smoked per day or the depth of inhalation. CPS-I found a significant increase in risk of aortic aneurysm deaths for both primary and secondary cigar smokers, with no clear dose–response or relationship to depth of inhalation.

Chang et al. (2015) reviewed coronary heart disease mortality. This analysis included published data from CPS-I and CPS-II. The authors overall found a slight and generally nonsignificant increased risk in cigar-only smokers, with the exception of CPS-II, in which those age 30–74 who inhaled moderately deeply or had smoked for 25 or more years had a significant HR of approximately 1.4.

Several studies not included in previous reviews, or that are particularly informative (e.g., large sample size) are summarized here. Wald and Watt (1997) used a prospective cohort study of British men 35–64 years old to examine the cause of death over the following 11–18 years and compared primary to secondary cigar smokers (those who had switched to cigars from cigarettes). The type of cigar was not reported. They also measured carboxyhemoglobin levels and found that secondary cigar smokers had higher levels than primary smokers (1.0 percent versus 0.9 percent), with both being much lower than that of cigarette smokers (4.6 percent). These data indicate that smoke inhalation on average was much lower in cigar than cigarette smokers. However, some cigar smokers reported moderate to deep inhalation and had carboxyhemoglobin levels similar to those in cigarette smokers. Ischemic heart disease mortality data were presented only for combined cigar and pipe smokers. Primary cigar/pipe users had no higher mortality than lifelong nonsmokers, while secondary cigar/pipe users had a slight but not significant increase in mortality risk (RR 1.29; 95 percent CI: 0.88–1.99). The relative mortality of current cigarette smokers compared to never-smokers was 2.27 (1.81–2.84).

Iribarren et al. (1999) conducted a prospective cohort study in the Kaiser Health system in California of 17,774 men 30–85, followed for 25 years. The group included 1,546 men who currently smoked cigars but never smoked cigarettes. No data were available on type of cigar, but it was estimated that 21 percent smoked large cigars.⁵ CVD, both nonfatal and fatal, was determined from hospital discharge diagnoses. In a multivariate analysis, cigar smoking was associated with a significantly increased risk of coronary heart disease compared to never-smokers (RR: 1.27; 1.12–1.45). Risk estimates for cigar smoking and ischemic stroke, hemorrhagic stroke, and peripheral arterial disease were nonsignificant, although the case numbers were relatively small. Compared to never-smokers, cigar smokers who used fewer than 5 per day had a lower RR for coronary heart disease (RR: 1.20; 1.03–1.40) compared to those who smoked more than 5 (RR: 1.56; 1.21–2.01). The study could not distinguish occasional versus daily cigar smokers.

CPS-II was another prospective cohort study of 121,278 male primary cigar smokers over age 30 who smoked at least one cigar per day (Jacobs et al., 1999). They were followed between 1982 and 1991, during which time 2,508 deaths occurred. In a multivariable analysis, the IRR for coronary heart disease mortality was 1.30 (1.05–1.62) for current cigar smokers aged 30–74 but was not significantly increased for those 75 or older. Analysis by amount smoked found a significant increase in mortality for those smoking two or more cigars daily, but no increase among those smoking one cigar per day. Analysis by duration found an increase in mortality for those who had smoked for 25 or more years but not for less than 25 years. The mortality risk was also higher among those who reported inhaling compared to those who did not.

Christensen et al. (2018) identified the causes of death based on ICD-10 codes, including circulatory, cardiovascular, and cerebrovascular causes. The age-adjusted risk of circulatory death was significantly increased in former (HR: 1.50; 1.23–1.82) and current (HR: 1.42; 1.12–1.81) cigar smokers compared to never-tobacco users, but these effects became nonsignificant in multivariable analysis controlling for sex, race and ethnicity, education, and survey year. The age-adjusted risk of cardiovascular death was significantly increased in former (HR: 1.56; 1.25–1.94) but not current (HR: 1.24; 0.94–1.62) cigar smokers, with no significant risk after multivariable analysis. No significant increased risk was found for cerebrovascular disease, but the number of deaths was small and considered to be too low to make a robust analysis of daily versus nondaily use (Christensen et al., 2018).

Rostron et al. (2019) studied morbidity associated with current primary cigar smokers age 35 or more using NHIS data between 2000 and 2015. Current use was defined as every day or some days. Health conditions were based on self-report or ever having a heart condition (angina, coronary heart disease, heart attack, other heart disease, or stroke). Current primary cigar smoking was not associated with an increased risk of heart attack or stroke. However, former primary cigar smoking was associated with an increased risk of heart conditions (adjusted prevalence ratio [aPR]: 1.33; 1.03–1.72) and stroke (aPR: 2.42; 1.57–3.75) compared to never-smokers. The authors speculate that former cigar use might be explained by smoking cessation in response to disease onset.

Inoue-Choi et al. (2019) used NHIS data from 1991 to 2010 to examine tobacco-related mortality. The analysis included 1,592 exclusive cigar users, but cigar type was not determined. The risk of coronary heart disease mortality was more strongly associated for daily (HR: 1.32; 0.69–2.50) than nondaily (HR: 1.21; 0.57–2.56) cigar smokers compared to never-smokers. For cerebrovascular disease death, neither daily nor nondaily cigar use was associated with increased risk compared to never-tobacco users. A limitation of this study was the relatively small number of deaths (Corrigendum, 2019; Inoue-Choi et al., 2019).

LUNG CANCER AND RESPIRATORY DISEASE

PERIODONTAL DISEASES AND CANCERS OF THE ORAL CAVITY, HEAD, AND NECK

While many premium cigar smokers may not inhale as much smoke as do smokers of cigarettes and other types of cigars, they do take smoke into their oral cavity and often hold it over long periods. Smoke constituents will therefore interact with tissues in the mouth and pharynx, and may, by swallowing, interact with esophageal tissues.

OTHER CANCERS

Cigar use is associated with the risk of other cancers. In particular, the 1998 NCI monograph reviewed the literature on the associations between cigar use and bladder and pancreatic cancer based on the evidence through 1997 (NCI, 1998). It concluded that although a few studies suggested an association between BC risk and cigar use, several other studies had not found evidence of such association. In contrast, the 1998 review concluded that cigar users have higher rates of pancreatic cancer with increasing risk with higher number of cigars per day, level of inhalation, and age. It also concluded that regular cigar use causes cancers of the lung, oral cavity, larynx, esophagus, and probably pancreas.

Recent studies evaluating the associations of cigar use with bladder, pancreatic, and other cancers since 1997 are discussed next (note that esophageal, bladder, and pancreatic cancer are also discussed in greater detail in the following sections).⁶ Andreotti et al. (2017) evaluated the associations between exclusive cigar, cigarillos, and smokeless tobacco ever use with the incidence of several cancers in the prospective Agricultural Health Study (n = 84,015). They found that ever exclusive cigar use at baseline was associated with all cancers (HR: 1.51; 95 percent CI: 1.20–1.90) and smoking-related cancers⁷ (HR: 1.87; 95 percent CI: 1.24–2.82), but no statistical association was found with gastrointestinal cancers (HR: 1.58; 95 percent CI: 0.84–2.98). The study also found a positive association with urinary cancer (i.e., bladder, kidney, and ureter cancers combined) (HR: 2.50; 95 percent CI: 1.27–4.93). Only 76 total cancers in exclusive ever cigar users were available for the study, precluding site-specific analyses. The study found that dual cigarette and cigarillo use is associated with higher risks of overall, smoking-related, and lung cancers than exclusive cigarette smoking but that dual cigar and cigarette smoking has similar risks as exclusive cigarette smoking.

Engeland et al. (1996) evaluated the associations of smoking habits, including cigar smoking, and the incidence of cancers other than lung among 26,000 Norwegian men and women recruited in 1965 and followed through 1993. The cancers studied were urinary, bladder, kidney, pancreas, upper digestive and respiratory tract (i.e., head and neck and esophageal cancer combined), uterine, cervix, stomach, colon, rectum, breast, corpus uteri, ovary, and prostate, and leukemia. No association was found between cigar use and any of the studied cancers.

Malhotra et al. (2017) evaluated the association between cigar and/or pipe smoking and cancer incidence risk in men and found that ever cigar and/or pipe users were at significantly increased risk for head and neck cancer, lung cancer, and liver cancer versus never-smokers of cigarettes, cigars, and pipes. The risk of smoking-related cancers combined and of all cancers combined was also found to be significantly higher in ever cigar and/or pipe smokers. Exclusive ever cigar smokers were found to be at higher risk of head and neck cancer (HR: 1.40; 95 percent CI: 0.98–2.00), lung cancer (HR: 2.73; 95 percent CI: 2.06–3.60), smoking-related cancers (HR: 1.47; 95 percent CI: 1.34–1.61), and all cancers combined (HR: 1.07; 95 percent CI: 1.02–1.16).

McCormack et al. (2010) evaluated the association of cigar and pipe smoking in the prospective EPIC cohort. The cancers evaluated included lung, UADT, bladder, liver, stomach, pancreas, kidney, colorectal; lung, UADT, and bladder combined; and all these tobacco-related cancers combined. Exclusive current cigar smokers were found to have higher risk compared to never-smokers of lung (HR: 3.9; p < 0.05); UADT (HR: 3.5; p < 0.05); lung, UADT, and bladder combined (HR: 2.6; p < 0.05); and all tobacco-related cancers combined (HR: 1.6; p < 0.05). Other cancers were not associated with exclusive current cigar use or had no cases among exclusive current cigar users to measure any association (pancreatic). Ever exclusive cigar use was found to be significantly associated with UADT risk (HR: 4.0; 95 percent CI: 1.7–9.4), lung, UADT, and bladder cancers combined (HR: 2.2; 95 percent CI: 1.3–3.8), and all tobacco-related cancers combined (HR: 1.3; 95 percent CI: 1.0–1.8). Other cancers were not associated with ever exclusive cigar use. Lung, UADT, and bladder cancer combined risk among exclusive cigar smokers increased by depth of inhalation, duration of use, and intensity (cigars per week). Risk among former cigar users increased by the age at smoking cessation (see study description in the lung cancer section for additional results).

As explained previously, Shapiro et al. (2000) conducted a prospective study of the relationship between cigar use (baseline) and cancer mortality in CPS-II. In addition to the previously noted increased risk of death from cancers of the lung and oral cavity/pharynx, the study found that current cigar smoking at baseline was associated with an increased risk of death from cancers of the larynx (IRR: 10.3; 95 percent CI: 2.6–41.0). However, no significant associations were found for overall current cigar smoking and esophagus, pancreas, and bladder mortality cancer risk. As with lung and oral cavity/pharynx, cancer mortality risks were considerably higher for cigar users reporting inhalation versus never-users: larynx (IRR: 39.0; 8.4–180.1), pancreas (IRR: 2.7; 95 percent CI: 1.5–4.8), and bladder (IRR: 3.6; 95 percent CI: 1.3–9.9). No association was found for cigar smokers reporting inhalation and esophagus cancer mortality.

As noted earlier, Christensen et al. (2018) evaluated the association of cigarette, cigar, and pipe use with cause-specific mortality, including tobacco-related cancers (e.g., bladder, esophagus, larynx, lung, oral cavity, and pancreas) in the NLMS (n = 357,420). Exclusive current cigar users had an increased risk of tobacco-related cancer mortality (HR: 1.61; 95 percent CI: 1.11–2.32). Exclusive daily cigar users were found to have higher risk of tobacco-related cancer mortality (HR: 1.80; 95 percent CI: 1.20–2.69), but not exclusive nondaily cigar smokers (HR: 1.08; 95 percent CI: 0.45–2.61).

Two studies evaluated the relationship between cigar use and non-Hodgkin's lymphoma (NHL). Bracci et al. (2005) addressed the associations between tobacco use, including past-year cigar use, and NHL in a case-control study of HIV-negative NHL patients and population controls from the San Francisco Bay area (N = 1,593 total patients, N = 2,515 total controls). Among men, the study found no associations between cigar use and overall NHL (OR: 1.3; 95 percent CI: 0.54–3.0) but an association with follicular NHL (OR: 2.8; 95 percent CI: 1.1–7.2). Neither female cases nor controls reported exclusive cigar use. Fernberg et al. (2006) considered the associations between tobacco use, including cigar smoking, and the risk of malignant lymphomas in a cohort of 386,000 Swedish construction workers recruited at clinics from 1971 and 1992 and followed through 2000. Smoking cigarettes, pipes, or cigars was not associated with NHL or Hodgkin's disease. In particular, the study found that smoking one or more than one cigar per day was not related to a higher risk of NHL (IRR: 0.86; 95 percent CI: 0.58–1.27).

Sorahan et al. (1997) evaluated the association between parental tobacco use, including current cigar use among fathers, and childhood cancers in children from the Oxford Survey of Childhood Cancers study (2,587 cancer cases and 2,587 controls). No associations were found between paternal cigar use and childhood cancer (RR: 0.98; 95 percent CI: 0.69–1.40).

OTHER HEALTH CONDITIONS

The committee identified several studies that investigated lesser-known and understudied potential health effects: skin health (contact dermatitis), diabetes, eye health (lens opacification), hepatitis C, fertility, and the health of cigar factory workers. Few studies examined primary cigar smoking. There appears to be some evidence that there are health effects for cigar factory workers.

HEALTH EFFECTS: SUMMARY AND CONCLUSIONS

Tobacco smoking is associated with increased risk of mortality, CVD, respiratory disease, cancer, and other adverse health outcomes. Health risk associated with tobacco use, including use of premium cigars, may be determined by smoking behaviors, including smoking frequency, intensity, duration of use, and depth of inhalation. At the time of the review, no epidemiologic studies have examined the association of premium cigars with health outcomes; however, several epidemiologic studies have examined the health effects of cigar use in general, which may include premium cigars. Additionally, premium cigar smoke contains many hazardous and potentially hazardous constituents that have been associated with increased risk of adverse health outcomes. Based on the findings from epidemiologic studies evaluating the health effects of cigar use in general, as well as biological plausibility, the absence of any important threats to validity, generalizability of study inferences, and the smoking behaviors of premium cigar users, the committee concludes:

Conclusion 5-3: There is strongly suggestive evidence that the health risks of premium cigar use (overall mortality; cardiovascular disease; lung, bladder, and head/neck cancer; chronic obstructive pulmonary disease; and periodontal disease) depend on frequency, intensity, duration of use, and depth of inhalation.

Conclusion 5-4: There is insufficient evidence to determine if occasional or nondaily exclusive cigar use in general is associated with increased health risks.

Conclusion 5-5: There is strongly suggestive evidence that health consequences of premium cigar smoking overall are likely to be less than those smoking other types of cigars because the majority of premium cigar smokers are nondaily or occasional users and because they are less likely to inhale the smoke.

Conclusion 5-6: There is strongly suggestive evidence that many of the health risks of daily exclusive cigar use in general (overall mortality; cardiovascular disease; lung, bladder, and head/neck cancer; chronic obstructive pulmonary disease; and periodontal disease) are significantly higher than those of never-smokers and lower than those of daily cigarette smokers.

Conclusion 5-7: There is moderately suggestive evidence that the health risks among primary cigar users in general (those who were never established cigarette users) are generally lower than among secondary cigar users (those who were former users of cigarettes) because secondary cigar users may be more likely to inhale the smoke. Likewise, concurrent users of premium cigars and other combustible tobacco products would experience greater health risks than those smoking only premium cigars.

Conclusion 5-8: There is insufficient evidence to draw conclusions on the health effects of premium cigars on

• Youth or young adults,
• Racialized and ethnic populations,
• Pregnancy,
• Those with underlying medical conditions,
• People with occupational exposures to premium cigars (e.g., cigar lounges, manufacturing), and
• Health effects compared to other cigar types.

DIFFERENCES BY SOCIODEMOGRAPHIC CHARACTERISTICS

Very few studies on the health effects of cigars examine different sociodemographic characteristics. Most studies did not examine differences by sex or were conducted only among male populations, given the relatively low rates of cigar use among women. Regarding overall mortality, two studies (Inoue-Choi et al., 2019; Lange et al., 1992) that included women considered differences by sex; in both studies, associations of cigar smoking with all-cause mortality were stronger among women. Among the studies that included nonwhite populations, most studies accounted for race and ethnicity as a confounder by either using it as a covariate in multivariable models or matching cases and controls based on race and ethnicity (see, for example, Hartge et al., 1985; Inoue-Choi et al., 2019; Malhotra et al., 2017; Morrison et al., 1984; Rodriguez et al., 2010). No studies were identified that examined potential differences by race and ethnicity in the association of cigar smoking and health risks.

POTENTIAL HEALTH IMPLICATIONS OF FLAVORINGS IN PREMIUM CIGARS

In the research questions provided by FDA and the National Institutes of Health, the committee was asked what the impact of adding flavors to premium cigars would be (see also Chapter 2). Commonly marketed flavors in tobacco products, including cigars, are fruits/candy (e.g., grape, mango, melon, strawberry, apple, peach, berry), crème/butter, cinnamon, cheesecake, coffee/tea/chocolate, alcoholic beverages, and nonidentifi-able varieties (e.g., “tropical,” “cosmopolitan”). Some of the chemicals in these flavorings have known respiratory toxicity (e.g., diacetyl, cinnamaldehyde). Many of these chemicals are included on FDA's list of additives shown to be “generally recognized as safe” under conditions of intended use (FDA, 2019); however, this designation applies to consumption and/or topical use, and the criteria do not include an examination of inhalation risks. In fact, the flavor chemical profile for flavored tobacco products is similar to that for candy (e.g., Swisher Sweet grape small cigars versus Kool-Aid grape mix), and flavored tobacco products may also have higher levels of some flavor ingredients per serving (Brown et al., 2014).

Different flavoring chemicals used in cigars may differentially influence toxicity in the production of oxidative stress, DNA damage, epithelial barrier dysfunction, and inflammatory responses with varying intensity and duration of exposure. Limited information is available on their adverse respiratory health effects even from manufacturer to manufacturer within the same class of flavorings. A significant concern exists regarding the ingredient purity and the general lack of oversight in manufacturing or marketing/communication (Kaur et al., 2018). Common flavorings have potential respiratory effects and have been shown to further enhance inhalation toxicity of tobacco smoke (Kaur et al., 2018; Paumgartten et al., 2017; Roemer et al., 2012).

Flavors in tobacco mask harsh taste, reduce throat irritation, and make smoke easier to inhale, which increases carcinogen exposure, nicotine intake, and addiction potential (Kostygina et al., 2016). Cigar flavors have been shown to increase the appeal of cigar smoking by masking the harshness and smell of tobacco (Delnevo et al., 2015). By doing so, flavorings may also make it easier for young and novice smokers to initiate tobacco use (King et al., 2013; Villanti et al., 2019, 2021). A study based in the Southeastern United States found that flavored cigarillos were mood-enhancing and flavors made cigar products more palatable (Sterling et al., 2015).

Flavors may also influence smokers' perceptions of potential health risks associated with smoking tobacco products. Promoting sweet flavorings that alter cigar's sensory effects may explain the misperceptions of cigars as less harmful relative to cigarettes (Malone et al., 2001; Nyman et al., 2002; Sterling et al., 2013, 2016; Villanti et al., 2021).

HEALTH EFFECTS OF SECONDHAND CIGAR SMOKE

Combusted tobacco product use produces smoke that is released into the environment, which presents a risk to health. Secondhand tobacco smoke (SHS) exposure is a well-established cause of disease in nonsmokers; associated diseases include lung cancer, coronary heart disease, stroke, asthma and other respiratory diseases, and reproductive problems, including low birth weight and increased risk of sudden infant death syndrome (HHS, 2006; Vanker et al., 2017). The vast majority of SHS health effects studies are based on nonsmokers living with cigarette smokers who smoke in the home. Children are particularly susceptible to SHS harms. While the committee did not identify studies of disease risk in nonsmokers who live with cigar users who smoke indoors, the risks are likely to be similar to that of secondhand cigarette smoke for similar levels of exposure.

SHS consists of a combination of emissions related to passive burning of the tobacco (sidestream smoke) and exhaled mainstream smoke. For cigar smokers, exhaled smoke may contribute a smaller percentage to overall SHS due to small puff volumes in premium cigar smokers who do not inhale. The constituents of SHS from cigars are qualitatively similar to secondhand cigarette smoke. Particulate matter in smoke is an important toxicant, which contributes to CVD and pulmonary disease and possibly other diseases. Inhaled particulates cause oxidative stress and inflammation and affect autonomic nervous system function, which can promote disease.

A few studies have examined indoor air SHS from different types of cigars by measuring airborne particulates, CO, and PAH concentrations. The air concentrations depend on emission rates of particular substances from the cigar, the number of smokers, duration of smoking, size of the room, and ventilation. Studies generated SHS using smoking machines, volunteer smokers, or sampled real-life cigar social events. Large and premium cigars are smoked for much longer than cigarettes, so the peak concentrations of particles and CO are higher after smoking. However, if multiple cigarettes are smoked during the day, the cumulative exposure could be higher.

Particulate emissions in one small study averaged 0.2–0.7 mg/min for cigars compared to 0.7–0.9 mg/min for cigarettes (Klepeis et al., 2003). One premium cigar was tested in this study with an emission rate of 0.35 mg/min. Mass-normalized emissions were lower for cigars than cigarettes: 3.3–5.2 versus 7.0–7.6 mg/gram smoked. The premium cigar studied yielded 3.7 mg/g smoked. The particle size distribution was similar for cigarettes and cigars, with most of the particles between 0.02 and 2 micrometers. In another study, volunteers smoked one cigar (Italian Toscanello)¹⁰ over 30 minutes or three cigarettes, one per hour, in a test room with measurement of particle concentrations over 200 minutes (Protano et al., 2017). The peak particle concentration was substantially higher for cigar compared to cigarette smoking, and the cumulative predicted lung particle deposition for children was also higher with cigar smoking.

Klepeis et al. (1999) measured air concentrations of CO, particulates (PM_2.5), and PAH from different cigars in three environments. In a vacant office on different occasions, five different cigars were machine-smoked (for 7 to 40 minutes, depending on the cigar) with measurement of CO levels over time. The emissions included both mainstream and sidestream smoke. One premium cigar was studied (Todo El Mundo¹¹ or Ashton); it was smoked for 28 minutes and generated a peak CO concentration of 15 ppm, with an average emission rate of 42 mg/min or 82 mg/gram smoked. Other smaller cigars generally generated similar peak CO concentrations, while having higher emission rates per gram tobacco smoked. In a residence, volunteer smokers smoked a large cigar (Santona, 13.2 g;¹² Paul Garmirian, 15.4 g¹³) or a Marlboro cigarette. The cigars were smoked for 1.3 and 1.5 hours and compared to one cigarette. One cigar generated a peak CO concentration of 3 ppm, with an average emission rate of 14 mg/min or 130 mg/gram smoked. The other cigar generated a peak respirable suspended particle concentration of 0.35 mg/m³, with an average emission rate of 0.98 mg/min or 8.2 mg/gram smoked. The cigarette generated a peak respirable suspended particle concentration of 0.16 mg/m³, with an average emission rate of 1.9 mg/min or 43 mg/gram smoked. Finally, the investigators sampled CO concentrations in two large cigar social events with a high degree of ventilation due to open doors and windows. Indoor CO concentrations were 5–11 ppm, averaging around 6 ppm. The contribution of cigar smoking was similar to that measured on the freeway driving to the events.

ADDICTION POTENTIAL

RESEARCH GAPS

As noted in the chapter opening, premium cigars' potential adverse health effects need to be viewed in the context of harms of combusted tobacco smoking broadly, and the mechanisms of tobacco smoke toxicity and biomarkers of toxicant exposure are applicable to understanding the potential harms of premium cigars. However, the committee identified key research gaps in the health effects literature for premium cigars specifically (see Box 5-2) and provides two recommendations to address these gaps (see Recommendations 4 and 8 in Chapter 6).

BOX 5-2

Key Research Gaps.

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Chapter 5 Annex. Health Effects Evidence Tables

These tables provide descriptive and methodological information on the studies cited in Chapter 5 that studied primary cigar smokers for all-cause mortality, cardiovascular disease, lung cancer and respiratory illness, oral health and head/neck cancer, and other cancers. The findings and results are discussed in the chapter proper (see Chapter 5 reference list for full citations).