THE ADVERSE HEALTH EFFECTS OF TOBACCO AND TOBACCO-RELATED PRODUCTS

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TOBACCO USE AND CESSATION

THE ADVERSE HEALTH EFFECTS OF TOBACCO AND TOBACCORELATED PRODUCTS Brenda E. Mitchell, MD, Howard L. Sobel, MD, and Miriam H. Alexander, MD, MPH

“Tobacco is a filthy weed, that from the devil does proceed; It drains your purse, it burns your clothes, And makes a chimney of your nose” BENJAMIN WATERHOUSE (1754-1846)

When Columbus arrived in the Americas, he found the natives using tobacco in much the same manner as it is used today. Tobacco use became popular among European settlers in the 16th century and soon became the chief commodity exchanged by the colonists for European-manufactured articles. Almost 500 years later, tobacco remains a large part of our culture because it directly affects the quality and quantity of life. Cigarette smoking is considered the single most significant cause of preventable morbidity and mortality.98,186 It is estimated that approximately 450,000 Americans die each year from diseases directly attributable to smoking. Twenty percent of all ischemic heart disease deaths are blamed on cigarette smoking. Furthermore, 38% percent of all cancer deaths in men and 23%of all cancer deaths in women are related to cigarettes. (This does not include cigars, pipes, smokeless tobacco use, or the estimated 3000-6000 cancer deaths to passive smoking in nonsmokers.)

From the General Preventive Medicine Residency (BEM, HLS) and the Department of Population and Family Health Sciences (MHA), Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland

PRIMARY CARE

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VOLUME 26 * NUMBER 3 SEPTEMBER 1999

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It is not enough that tobacco use takes a huge toll on human life. The economic costs of smoking on society are exorbitant. The direct health care cost associated with smoking in 1993was approximately $50 billion.62 This is only half of the annual economic toll of smoking, because the costs associated with lost productivity and earnings as a result of illness, disability, and death from smoking were estimated to be another $47 bil1i0n.132 The Centers for Disease Control and Prevention of the US Department of Health and Human Services chronicled the relative risks attributed to smoking and smoking-attributable mortality for the major causes of mortality (Table 1). This article uses this chronicle to systematically address the major, adverse health effects of tobacco. CARDIOVASCULAR DISEASE

In 1990, more than 40% of all deaths in the United States were caused by cardiovascular disease, with ischemic heart disease accounting for 489,000 deaths.197Smokers have higher death rates from coronary heart disease (CHD) at all ages. Smoking was estimated to cause 46% and 37% of the heart disease deaths in men and women under 65 years of age re~pectively.~~,'~~ The British Physicians study showed heavy smokers to have double the risk of death from coronary artery disease (CAD).82 The US Veterans Study reported that cardiovascular and CAD deaths increase with daily consumption of cigarettes.229The Nurses Health Study demonstrated an overall relative risk of over 4 of fatal myocardial infarction (MI) in women smokers when compared with nonsmokers and an increased risk of death with increasing daily consumption of cigarettes and with early age of initiation of smoking.I63Numerous studies have demonstrated the cardiovascular synergism of smoking with risk factors such as diabetes, hypertension, and hypercholester~lemia.~~~~~~~ Several intertwined mechanisms contribute to ischemic heart disease among smokers including atherosclerosis, thrombosis, coronary artery spasm, cardiac arrhythmia, unfavorable lipid profiles, reduced oxygencarrying capacity of the blood, and increased myocardial work. Smoking cigarettes has been demonstrated to contribute to each of these mechanisms (Table 2). Cigarette smoking accelerates atherosclerosis, leading to CAD, strokes, aortic aneurysms, and peripheral vascular disease. Nicotine directly administered to rabbits fed high fat and high cholesterol diets or rats receiv.~~~~~~~ ing calcium and vitamin D accelerated a t h e r o ~ c l e r o s i sFurthermore, nicotine caused endothelial damage in rats.178Smokers have an increased number of circulating endothelial cell carcasses after smoking a cigarette.75 Thus, tobacco and nicotine may play a role in the development of atherosclerosis through endothelial injury. Thrombosis contributes to atherosclerosisby release of growth factors that promote macrophage migration into vascular walls and smooth muscle proliferati~n.~~ Although smoking is directly linked to atherosclerosis, it also is an independent risk factor for thrombosis. Cigarette smokers with

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m

QI

Adult diseuses (persons aged 235 yrs) Neoplasms Lip, oral cavity, pharynx, (140-149) Esophagus (150) Pancreas (157) Larynx (181) Trachea, lung, bronchus (162) Cervix uteri (180) Urinary bladder (188) Kidney, other urinary (189) Cardiovascular diseases Hypertension (401-404) Ischemic heart disease (410-414) Persons aged 35-54 yrs Persons aged 265 yrs Other heart diseases (390-398,416-417, 420-429) Cerebrovascular diseases (430-438) Persons aged 35-64 yrs Persons aged 265 yrs Atherosclerosis (440) Aortic aneurysm (441) Other arterial diseases (442-448) Respiratory diseases Pneumonia and influenza (480-487) Bronchitis, emphysema (491-492) Chronic airway obstruction (496) Other respiratory diseases (010-012,493)

Disease Category (ICD-9 code)t

1.4 7.0 7.0 1.4

2.2 10.5 10.5 2.2 11,292 9,324 30,386 787

1.5 8.6 8.8 1.5 2.0 9.7 9.7 2.0

7,881 5,541 18,597 568

4,114 4,189 2,675 1,382 1,115 1.3 1.3 1.3

1.o

1.4

4.8 1.5 3.0 3.0 3.0 4,567 10,421 3,737 5,913 2,032 1.4 1.3 2.3 2.3 2.3

3.7 1.9 4.1 4.1 4.1

7,701 25,871 12.019

1.4 1.3 1.2 3.0 1.6 1.7 26,431 38,918 23,206

1.8 1.3 1.3

2.8 1.6 1.9

2,161

1.2

1.3

1.9

1.7

8.8 5.8 1.1 5.2 9.4 NA 1.9 2.0 3,299

SAM

1,442 1,616 3,447 611 35,741 1,294 980 353

Former Smokers

2.9 3.2 1.8 11.9 4.7 1.9 1.9 1.2

Current Smokers

Female

5.6 10.3 2.3 17.8 11.9 2.1 2.6 1.4

SAM

RR

5,033 5,658 2,667 2,379 81,179 NA 3,046 2,868

Former Smokers

Male

27.5 7.6 2.1 10.5 22.4 NAG 2.9 3.0

Current Smokers

RR

(confinued)

19,173 14,665 48,982 1,455

8,671 14,610 6,412 7,295 3,147

34,132 84,789 35,314

5,450

6,475 7,294 6,114 2,980 116,920 1,294 4,026 3,219

Total SAM

Table 1. RELATIVE RISKS* (RR) FOR DEATH AlTRlBUTED TO SMOKING AND SMOKING-ATTRIBUTABLEMORTALITY (SAM) IN DEATHS PER YEAR, FOR CURRENT AND FORMER SMOKERS, BY DISEASE CATEGORY AND SEX-UNITED STATES, 1990

1.5

1.8 1.8 4.8

RR

276,153

1,055

285 219 214 288

SAM

1.8 1.8 1.8 1.5

RR

Female

142,537

1,945

222 141 160 182

SAM

419,690

3,000

507 360 374 470

Total SAM

*Relative to never smokers. tlnternational Classification of Diseases, Ninth Revision. §Not applicable. ¶Source: National Fire Protection Association, 1993 (6). **Deaths among nonsmokers from lung cancer attributable to environmental tobacco smoke (Environmental Protection Agency, 1992 [71). From Centers for Disease Control and Prevention. Cigarette smoking attributable mortality and years of potential life lost-United States, 1990. MMWR 42645-649, 1993

Total

Pediatric diseases (persons aged < 2 yr) Short gestation, low birth weight (766) Respiratory distress syndrome (769) Other respiratory conditions of newborn (770) Sudden infant death syndroms (798) Burn deaths? Environmental tobacco smoke deaths''

Disease Category (ICD-9 code)t

Male

Table 1 RELATIVE RISKS* (RR) FOR DEATH ATTRIBUTED TO SMOKING AND SMOKING-ATTRIBUTABLEMORTALITY (SAM) IN DEATHS PER YEAR, FOR CURRENT AND FORMER SMOKERS, BY DISEASE CATEGORY AND SEX-UNITED STATES, 1990 (Continued).

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Table 2. FACTORS CONTRIBUTING TO ISCHEMIC HEART DISEASE AMONG TOBACCO USERS Condition

Atherosclerosis Thrombosis

Coronary vasospasm

Arrythmias

Adverse lipid profiles

Proposed Mechanism

Nicotine accelerates atherosclerosis; nicotine or cigarette smoke directly damages endothelium. ”Hypercoagulable state” from higher levels of fibrinogen and hematocrits among smokers, likely related more to combustion products and gases than to nicotine. Nicotine also enhances platelet aggregation. Possibly due to high arterial blood levels of nicotine achieved during smoking (as opposed to venous levels achieved through nicotine replacement therapy). Some studies suggest, however, that nicotine is not the agent responsible for vasospasm (see text). Nicotine stimulates catecholamine release, possibly lowering arrythmia thresholds. Catecholamines and relative polycythemia may increase myocardial oxygen demand, and in setting of stenotic coronary arteries and elevated carboxyhemoglobin levels, this may result in ischemia leading to arrythmias. Nicotine enhances lipolysis, releasing free fatty acids which results in higher LDL and lower HDL levels. Smokers may also have unhealthy diets with higher fat and lower fiber and micronutrient intakes.

MIS have less severe underlying CAD than non-smokers, which may imply that thrombi can form on less severely stenotic vessels than in nonsmokers.m Cigarette smoking also was found to be the only predictive factor for restenosis after obtaining normal coronary blood flow following percutaneous transluminal coronary angiop1a~ty.l~~ The increased thrombus formation and the restenosis of vessels may be secondary to the hypercoagulable state and the higher fibrinogen levels and hematocrits seen in smokers compared with Although the agent in cigarette smoke that causes thrombosis is not yet clear, evidence points to oxidant gases or other combustion products rather than n i ~ o t i n e , 2 ~although *~~,’~~ nicotine does induce platelet aggregation.’OO Coronary vasospasm has been demonstrated angiographically during but the role of nicotine in vasospasm is not entirely clear. In one study, pipe smokers were found to have higher serum cotinine levels (a metabolite of nicotine) than cigarette smokers; however, pipe smokers generally have lower CHD and overall mortality rates,J4r117,160,281 suggesting that nicotine may not be causing coronary vasospasm. Smoking also has been shown to cause more CAD than snuff or the nicotine patch, the latter having mortality rates similar to p l a ~ e b o . ~In~con,~~~,~~~ trast, patients with severe CAD had decreased overall myocardial contractility with chewing nicotine gum,16 suggesting spasm or coronary vasoconstriction may occur with nicotine dosing. The higher arterial concentrations of nicotine achieved during smoking (relative to venous concentrations from other forms of nicotine delivery)lS0may explain inconsistancies in studies of vasospasm that have relied on venous concentrations.

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Cigarette smoking is associated with increased arrythymias and myocardial work. Nicotine stimulates adrenal and neuronal catecholamine release, which increases heart rate, stroke volume and myocardial contractility, constricts blood vessels of the skin and systemic vasculature, and increases blood flow to m u ~ c ~ l a t t l Heart re~~ rates ~ ~ of~ smokers ~~~ are noted to be elevated even during sleep, when no cigarettes were s m ~ k e d .The ~ ~ catecholamine ,~~ release in response to smoking theoretically would account for the lower threshold of ventricular fibrillation seen in smoker^.^,^^ In one study of 52 smokers, ventricular ectopy did not increase in response to smoking compared with ba~e1ine.l~~ Arrhythmias may arise in individuals with diseased coronary arteries through ischemia, resulting from sympathetic stimulation and leading to increased myocardial work. Another possibility is that smoking causes thrombosis leading to ischemia and arrythmias.= Two case reports are of interest regarding the possible role of nicotine in atrial arrhythmias. In the first case report, atrial fibrillation developed in a man who chewed 30 pieces of nicotine gum per day. The second report concerned a man with known paroxysmal atrial fibrillation, who developed this arrhythmia 5 minutes after chewing the first piece of nicotine gum.z2z~256 An analysis of 54 published studies reveals serum lipid profiles of smokers to have significantly higher levels of total cholesterol, oxidized low density lipoproteins (LDL), triglycerides, and very low density lipoproteins and lower high density lipoproteins (HDL) compared with nonsmokers.120Although nicotine increases lipolysis and releases free fatty acids that are metabolized by the liver to cause higher LDL and lower HDL,lZ9patients on nicotine therapy show no adverse effects on lipid profiles, strongly suggesting that dyslipidemia results from a component of the cigarettes unrelated to nicotine.218,z68 In addition to its direct affect on lipids, cigarette smoking is associated with unhealthy eating patterns, including increased intakes of energy, total fat, saturated fat, cholesterol, alcohol, lower polyunsaturated fats, vitamins C and E, and beta-carotene.74,130 Cigarette smokers have a significantly higher carbon monoxide (CO) exposure than nonsmokers. CO binds hemoglobin to form carboxyhemoglobin (CO-Hb), with consequently reduced oxygen-carrying capacity. This relative lack of oxygen causes an increase in hematopoiesis and a relative polycythemia. Clinically, this results in increased resting cardiac output and myocardial work at all levels. Indeed, perfusion defect size correlates with CO-Hb levels, but not nicotine levels.25 Generally, smokers have slightly lower blood pressure than non~ m o k e r Smoking ~ . among ~ ~ hypertensive ~ ~ patients, ~ ~ how~ ~ ever, increases complication rates, including progression of atherosclerosis, renal disease, and malignant h y p e r t e n ~ i o n . ~Furthermore, ~,~~~~’~~ smokers have increased blood pressure by 5 to 10 mm Hg for 15 to 30 minutes after smoking; a similar effect is seen for smokeless Smoking cigarettes is associated with substantially increased risk of sudden death and acute myocardial infarction. Smoking even only 1 to 5

~

~

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cigarettes per day presents a significant risk for myocardial infarction.The risk increases less steeply with increased consumption.288 Between the 1960s and 1980s, the age-adjusted mortality among smokers and non-smokers declined by approximately 50%. There are many possible explanations for this decline. Therapy for acute myocardial infarctions has improved drastically, and includes use of aspirin, angiotensin converting enzyme inhibitors and beta blockers, coronary care units, thrombolytic therapy, angioplasty, and coronary artery bypass graft. Consequently, there has been an equally impressive decrease in case-faFurthermore, greater number of patients retality rates.48,155,215,243,265,266,267 ceive therapy for hypertension, hyperlipidemia, and estrogen replacement therapy (among men).^^,^^,^^^,^^^,^^^,^^ The nicotine content in cigarettes has halved during that same period of time, and the composition of the cigarette has changed considerably. Any of these components may have contributed to the declining mortality. Finally, the decline in CHD mortality over the same period of time parallels that of non-smokers. Parish et a1 found that the relative risk of MI in smokers and nonsmokers ranges from 2 in those 60 to 79 years of age to 5 in those 30 to 49 years of age. They found a 10% (P = 0.06) increase in mortality among those smoking medium rather than low tar cigarettes.208 A double-blind, placebo-controlled study revealed that nicotine replacement therapy does not adversely affect angina frequency, overall cardiac status, arrhythmias, or episodes of ST segment depression.295 Most importantly, smoking cessation dramatically reduces the risk of cardiovascular disease to baseline by approximately 5 years.60,133,172,280

PERIPHERAL VASCULAR DISEASE

There is a strong association between smoking and peripheral vascular disease that is probably mediated by the role smoking plays in the pathogenesis of atherosclerosis.6°~98 One study found that in smokers consuming less than one pack of cigarettes per day, the relative risk of developing peripheral vascular disease was ll .5 compared with nonsmokers, and the relative risk in those who smoked more than one pack per To date, there day was 15.6 compared with the rate in nonsmokers:1°1,285 have not been studies to demonstrate a link between cigar and pipe smokers and peripheral vascular disease. In a major prospective 9-year study by Suarez, with 2620 older white adults (60-79 years), current cigarette smoking had a large and significant interaction with diabetes. An estimated 65% of the cardiovascular disease deaths among diabetics was caused by the interaction of diabetes and cigarette smoking.262 The pathogenesis of peripheral vascular disease in smokers is not as clear as with the linkage between smoking and other health effects. Smoking cessation does, however, reduce the risk of peripheral vascular disease and its sequelae. Indeed, former smokers’ rates of atherogenesis are

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greater than never smokers' rates but are half that of smokers' rates. Complications from peripheral vascular disease in individuals who quit smoking are reduced, and performance and overall survival are increased.60 CEREBROVASCULAR DISEASE

Cerebrovascular disease accounts for 144,000 or 7% of all deaths in the United States.Ig7Smokers have an increased relative risk of approximately 2 for ischemic stroke as demonstrated through cohort studies and meta-analysis. In addition, smoking increases the risk for subarachnoid h e m ~ r r h a g e .Cigarette ~~~,~~ smokers ~ have significantly decreased cerebral blood flow using xenon inhalation.228A dose response relationship between the number of cigarettes smoked and stroke is such that the relative risk of stroke among those who smoked more than 40 cigarettes per day is twice the risk of those who smoked fewer than 10 cigarettes. Furthermore, stroke risk decreased to baseline by 5 years after smoking cessation, with a major decrease soon after cessation.294 CANCER

Smoking has long been associated with an increased risk of a variety of cancers (Table 3), which are reviewed below. The role of cigarette smoke and the pathophysiology of cancer is complex. Evidence abounds that cigarette smoke has carcinogenic p0tentia1.I~~ Of some 4000 components of tobacco, more than 50 have been shown to be carcinogenic in vivo and in ~ i t r o . 'Metabolic ~ , ~ ~ ~ activation by oxidation in rat lungs creates unstable metabolites that react with DNA to form methylated bases. These methylated bases correspond to point mutations in the k-ras oncogene.21,125,126, 212,227 Clinically, 20% to 30%of adenocarcinoma in smokers have activated mutated k-ras oncogene^.^^,^^^ Furthermore, elevated levels of alkylated DNA have been found in lung and trachea cells of smokers.'94People with occupational exposure to tobacco have been found to have chromosomal aberrations in lymphocytes including deletion fragments, chromatid gaps, and abnormal metapha~es.'~~

Lung Cancer Early this century, many investigators began addressing the rising incidence of lung cancer and the role of In the 1940s, Ochsner and DeBakey205noted the predominance of lung cancer of all visceral cancers in hospitalized men and the correlation of increased lung cancers with sales of cigarettes. Wydner and Graham296interviewed 684 patients with proven bronchocarcinoma, specifically classifying into smoking categories ranging from non-smoker to chain smoker. They found that 95% of the lung cancers occurred in the moderately heavy to

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Table 3. CANCERS ASSOCIATED WITH TOBACCO USE

Lung cancers (171,500) Large cell Small cell Adenocarcinoma Squamous cell carcinoma Head and neck cancers (41,400) Oral cavity and pharynx (30,300) Laryngeal (11,100) Esophageal cancer (12,300) Adenocarcinoma Squamous cell carcinoma Gastric adenocarcinoma (22,600) Colorectal adenocarcinoma (135,000) Bladder transitional cell carcinoma (54,400) Renal cell carcinoma (29,900) Cervical cancer (13,700) Prostate cancer (184,500) Breast cancer (180,300)

Adenocarcinoma is the most common lung cancer due to higher TSNA content relative to PAH c o n tent in cigarettes in recent decades Over 90% of head and neck cancers are squamous cell

Smoking most clearly related to squamous cell cancer

Results linking smoking to breast cancer have been inconsistent, but risk may be related to slow acetylation by N-acetyltransferase-2 enzyme among postmenopausal women

Number in parentheses reference to estimates in incidence for 1998. Data from Landis SH, Murray T, Bolden S, et al: Cancer Statistics, 1998. CA Cancer J Clin 48:6-30, 1998

chain smoking groups, with 50% in the excessive and chain smoking groups. In this latter group, smoking rates in the cancer group were 3 times higher than the noncancer Lung cancer is the leading cause of cancer deaths independent of S ~ X . Smoking ’ ~ , ~ was directly responsible for 83% of lung cancer deaths, or nearly one third of all cancer mortality in 1995.89,196,244 Lung cancer mortality rates and absolute death rates rose significantly from the early 1960s to the early 1 9 9 0 ~ . 5The ~ , ~rise ~ ~in lung cancer rates in men who smoke preceded that of women who smoke. In the early 1960s, mortality in men was approximately seven times that of women. By the late 1980s male mortality from smoking was only two and a half times that of fem a l e ~Currently, . ~ ~ ~ lung cancer rates for women approximate those for men of three decades Lung cancer potential from smoking has been largely attributed to polycyclic aromatic hydrocarbons (PAHs) and tobacco-specific nitrosamines (TSNAs), with a small contribution by polonium-210 and volatile aldehydes. Carcinogenicity is enhanced by cocarcinogenic catecholamines, nitrous oxides, and weakly acidic promoters. TSNA have been shown to cause adenocarcinoma in rats, mice, and hamsters. TSNAs are organ specific. For example, 4-(methylnitrosamine)-l-(3-pyridyl)-l-butone

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MITCHELL et a1

(NNK) and 4-(methylnitrosamino)-1-(3-pyridyl)-l-butanol (NNAL) have lung carcinoma p ~ t e n t i a l . ' ~Furthermore, ~,'~~ PAHs have been shown to cause squamous cell carcinoma both in vivo and in ~ i t r o . ' *Over ~ the past few decades, the blends of tobacco have tended toward tobacco with lower concentrations of PAHs and higher concentrations of T S N A S . ' ~ ~ , ' ~ ~ The nicotine content has progressively decreased to approximately one third of its 1950 level. In response to lower nicotine content, smokers inDeeper inhacrease the volume and frequency of lation exposes the relatively defenseless peripheral lung tissue to TSNA. Put together, higher TSNA relative to PAH, and lower nicotine content, have led to increasing adenocarcinoma rates relative to squamous cell carcinoma. The less dramatic changes in squamous cell carcinoma may be a result of the offset effect of increased exposure through more frequent puffs of smoke with less PAH. As stated, lung cancer in previous decades was mainly squamous cell carcinoma, whereas adenocarcinoma accounted for only 5% of all lung cancers. From 1969 to 1971 and 1985 to 1986, adenocarcinoma increased by 111%in white men, 151% in black men, and approximately 220% in both black and white women, whereas squamous cell carcinoma has increased approximately 25% to 50% in men and 150 to 200% in women.28,152,255 The relatively larger increases in adenocarcinoma compared with squamous cell carcinoma explain why adenocarcinoma is now the most prevalent lung cancer. The changing cigarette has significantly affected lung cancer histology. For instance, filter tip cigarettes have increased from 0.56% of all cigarettes sold in the 1950s to 97% in 1992.I4l Scientificallydesigned cigarettes, with perforated filter tips, highly porous cigarette paper, reconstituted and expanded tobacco incorporating ribs, and stems into the tobacco have led to diluted smoke and enhanced efficiency of combustion resulting in reduced volatile aldehydes, carbon monoxide, and nitrous o x i d e ~ . ' Cigarette ~ ~ , ~ ~ ~filters have helped; exclusive filter cigarette smokers have a 30% to 50% decreased risk of lung cancer.152 It should be noted that other lung cancers also are associated with smoking, including large and small cell carcinoma. The odds ratio of smoking two packs or more per day for patients with large cell carcinoma was 37 for men and 73 for ~ 0 m e n . l ~ ~ In addition to the significant increase in lung cancer and its attendant mortality among smokers in general, there is a clear dose-response relationship between the number of cigarettes smoked per day and the increasing risk of death from lung cancer.174,298 Lung cancer incidence increases by a power of 4 to 5 as the duration of smoking increases.s1 Importantly, the depth of inhalation also correlates positively with increasing mortality, even though smokers who report slight inhalation or no inhalation have up to an eight-fold relative risk of lung cancer.118Finally, there is a risk reduction of lung cancer with smoking cessation. The risk is correlated to the dose, duration, type of cigarette, and depth of inhalation and is gradual. After 10 years, the risk is about 30% to 50% the risk for ongoing smokers.60

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There is evidence that pipe and cigar smokers have an increased risk of lung cancer, but it is lower than that of cigarette s m ~ k e r ~ .The " ~ ~ ~ ~ ~ lower cancer rates among pipe and cigar smokers compared with cigarette smokers is related to dose-response; cigar and pipe smokers tend to smoke less tobacco and inhale less In cigar and pipe smokers who inhale more deeply, lung cancer rates approach those of cigarette ~ m o k e r s . ~ ~ ! ' ~ ~ Lung cancer has an overall-5-year survival rate of 13%,which is even worse for large-cell and small-cell carcinoma. The major reason for such dismal survival is that only 21% of patients with lung cancer present with localized disease. Furthermore, 50% present with inoperable disease. The 5-year survival rate among those with localized disease is 37%.For those with regional lymph node spread, the 5-year survival rate is 13%.71,94,245 The majority of patients with lung cancer have symptoms related to the primary tumor, intrathoracic extension of the tumor, or distant metastases. Twelve percent of patients are discovered by routine chest radiograph.71Cough is the most common symptom and relates to irritation of the bronchial mucosa or mechanical compression of the airway. Though cough in a smoker may be a relatively common symptom, and is usually ignored by patients, any change in cough warrants inve~tigation.~~ Head and Neck Cancer

There is extensive evidence linking smoking and other tobacco use Recent research has highlighted to carcinomas of the head and the synergistic effect of tobacco smoking and alcohol on the development and progression of these disfiguring diseases. In a 1998 population-based study in Sweden, attention focused on the impressive increased relative risk of head and neck cancer among smokers. In current smokers, relative risks ranged from a low of 4.9 for the oral cavity to 8.5 for cancer of the pharynx, with esophageal and laryngeal cancer in the middle.177 In longterm smokers who were older than 45 years, the relative risk of all head and neck cancers was almost 150% of the younger smokers who had smoked for shorter periods of time. Most tobacco-related head and neck cancers are squamous cell carcinomas. Oral Cancer

An important subset of head and neck cancer is oral cancer. An estimated 30,000 new cases of oral cancer are diagnosed in the United States annually, with a projection of 8000 deaths per annum caused by this disease.39The origin of oral cancer is multifactorial, but it can be traced to past and present use of alcohol and tobacco products (cigarettes, cigars, pipe, spit tobacco), exposure to the sun (lip cancer), and exposure to carcinogens in the w o r k p l a ~ e . ~ There ~ , ~are ~ ~specific , ~ ~ ~ data, however, highlighting the unique contribution of tobacco use in development of oral

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cancer.162 In comparison with nonsmokers, smokers have a twofold to 18fold increase in risk of developing oral cancer.1s9The disease crosses all racial categories and has remained relatively constant in the general population, although its incidence in black men seems to be increasing.196 Higher rates of tobacco and alcohol use are the major factors that account for the higher incidence of oral and pharyngeal cancer in blacks than whites.196 Oral cancer predominantly occurs in older people, with the majority being diagnosed at 65 years of age and older.’” In the United States, this disease is more common than leukemia; melanoma; Hodgkin’s disease; and cancer of the brain, liver, bone, thyroid gland, stomach, ovaries, or cervix.196Globally, the prevalence of oral cancer is striking, with figures . ~ ~number ~~~~~ in India ranging from 3.8 to 11 per 100,000 p o p ~ l a t i o nThe of new cases of oral cancer in men each year is more than twice as high as in women and is most frequent in men over age 40.7 Recent research into the gender differences in the risk of development of oral cancer demonstrated (with the use of a cumulative lifetime measure of exposure to cigarette tar), the adjusted odds ratio for men, according to increasing quartile of tar consumption and relative to never smokers, was 1.0 for the lowest category, 0.9 for the second category, 1.6 for the third category, and 2.1 for the highest category. Among women, the corresponding odds ratios were 1.8,2.8, 3.2 and 4.6 re~pective1y.l~~ Oral cancer and premalignant changes of the oral mucosa are much more common among users of smokeless tobacco compared with nonu s e r ~ . The ~ ~ oral ~ , ~ effects ~ ~ of smokeless tobacco are discussed in more detail below. There is clearly a synergistic effect of tobacco and alcohol consumption in increasing the risk of oral cancer and various other forms of .head and neck cancer.Io9The mechanism for alcohol-related carcinogenesis is beyond the scope of this article, but there may be a multiplicative effect of combining high exposure to both tobacco and alcohol, with a relative risk (RR) of 22.1 (95% CI = 12.9-37.8).177The exact mechanism is unknown, but a genetic component with a link to DNA repair may be the answer.’” On a molecular level, the frequency of p53 mutations among patients with squamous cell carcinoma of the head and neck is higher in smokers than in nonsmokers and even higher in smokers who also drink alcoh01.~’

Esophageal Cancer It is likely that the role of tobacco in esophageal cancer is stronger for squamous cell than adenocarcinoma and stronger in women than in men? In a nine-state area, from 1976 to 1987, an increase in the incidence of adenocarcinoma of the esophagus and gastric cardia has been identified.36 Over 9400 esophageal cancers were identified among whites and blacks, with squamous cell carcinomas most prominent among black men and adenocarcinoma most prevalent in white men. Generally, similar patterns

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were observed among women. These results, although not conclusively pointing to smoking as the cause, raise concern about the changing demography of cancer and indicate a need for more extensive investigation. Recent studies have examined the association between adenocarcinomas of the esophagus and gastric cardia, with treatment of gastroesophageal r e f l ~ x .Chow ~ ~ , ~et~aF4reported a declining risk of adenocarcinomas of the esophagus and gastric cardia with increasing use of prescription medications, which suggests that use of anticholinergics might actually be protective among high-risk patients. Cigarette smoking is clearly an extremely important risk factor for esophageal squamous cell carcinoma, however, there are important sex difference^.^ Zhang and Wynder have suggested that women are more susceptible in a biologic sense to the carcinogens in tobacco smoke than men because of a complex interaction between the higher level of activation of tobacco procarcinogens by certain cytochrome P-450 enzymes, slower metabolism of nicotine or the role of female sex hormones on tumor development. This requires further e x p l o r a t i ~ n . ~ ~ ~ ~ ~ ~ ~ The mode of tobacco use is important in exploring the association between tobacco and cancer. This relationship was examined in a large population-based case-control interview study of 174 white men with adenocarcinoma of the esophagus and 750 controls in three areas of the United States. Cigarette smokers had a considerably elevated risk of esophageal adenocarcinoma and there was a significant trend of increasing risk associated with increasing number of cigarettes smoked per day. In addition, there was no protective effect with smoking cessation. Nonfilter cigarettes appeared to result in a lower risk than filtered cigarettes, although in those who smoked nonfilter cigarettes only, the odds ratio increased significantly when two packs of cigarettes per day were inhaled. The absence of a cessation effect of smoking on morbidity associated with esophageal cancer may suggest that smoking acts at a relatively early stage in development of esophageal adenocarcinomas and that the effects of smoking in adolescence and early adulthood may cause permanent damage. Stomach Cancer

There has been an increase in incidence of adenocarcinoma of the esophagus and gastric cardia over the past 10 to 15 years in western countries.300A case-control study by Zhang and in 1996 showed that tobacco smoking was related to a modest risk of adenocarcinomas of the esophagus and gastric cardia. The risk of distal stomach cancer, however, was associated with stomach ulcers and pack-years of smoking. The doseresponse relationship between smoking and stomach cancer is particularly relevant in Madras India, where stomach cancer is the most frequent cancer among men and the third most common cancer among women.1o2 Significant dose response relationships were observed with age at initiation of smoking bidi (a type of tobacco) ( P < 0.001) and with lifetime exposure to bidi ( P < 0.001), cigarette (P < O.Ol), and chutta (a type of

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tobacco) (P < 0.05) smoking. The effect of duration of smoking behavior was recently emphasized in the results of a study in which smoking duration was associated with an increased risk (OR of 2.2) for smokers over 50 years of age, with a significant dose-response pattern, even after controlling for major confounding factors.77A younger age of smoking initiation was associated with an increased risk, whereas pack-years of cigarettes showed a significant dose-response. Research by Burns et a149 supports the role of smoking in stomach cancer, with significant increases observed among black men (OR = 2.0), white women (OR = 1.7)/ and black women (OR = 1.4) for ever smokers. The role of smoking in the cause of stomach cancer is controversial, because some studies have found no such relationship between smoking or alcoh01.’~’

Pancreatic Cancer Smoking increases the risk of pancreatic cancer in both men and women. The proportion of deaths attributable to smoking is estimated at about 30%, and there does appear to be a dose response relationship. There are approximately 24,000 people who develop cancer of the pancreas each year, with an estimated 22,000 deaths annually. Patients with this form of cancer have one of the poorest 5-year survival rates for any form of cancer.57

Colon Cancer In a cohort study of veterans, the risk of death for colon and rectal cancer was 16%and 22% higher, respectively, in tobacco users when compared with never users. The risk increase held for cigarette, pipe and cigar smoking, and smokeless tobacco. Furthermore, the risk increased with pack years for cigarette smokers.128 Cigarettes have been associated with an approximate twofold increase in risk of colon adenomas or polyps, which are in turn strongly In one study, smoking during the related to colon cancer.85,128,140,165,176,199,204 prior two decades had relative risk of small adenomas of nearly 3 and 1.45, respectively, for men and women with greater than 35 pack years of smoking. The risk for large adenomas in women was 1.3 and in men was not different from non-smokers. A relative risk of 2.4 and 1.3 for men and women of large adenomas in smokers becomes apparent only at greater than 20 years of smoking. Finally, in both groups a relative risk of 2 for colon cancer becomes apparent only after an a lag time of 35 year^.'^^,'^^

Bladder and Renal Cell Cancer Smoking is thought to be a contributory factor to excess risk of cancer of the bladder and renal cell carcin0ma.5~Over 50,000 Americans develop bladder and kidney cancer each year, with an associated 20,000 deathc

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The 5-year survival rates are 50% and 60% respectively. In fact, investigators estimate that between 30% and 40% of bladder cancer cases are smoking related, with slightly higher estimates for men than women.57 Bladder cancers are predominantly transitional cell in origin. In a case-control study in Alexandria, Egypt, there was a significant relationship between smoking and the development of invasive cancer of the bladder.20The risk was significantly related to duration of smoking (OR of 16.5 for >40 years), inversely related to the age at initiation (OR of 8.8 for starting <20 years), and inversely related to time since smoking cessation. Furthermore, the synergistic effect of alcohol use and cigarette smoking and bladder cancer (among other cancers) was Aromatic amines, or arylamines, are constituents of tobacco smoke and have been implicated in the carcinogenesis of bladder cancer. Activation and detoxification of arylamines in the body is partly regulated by metabolism with the enzymes N-acetyltransferase 1 and 2 (NAT1 and NAT2). In a study by Taylor, stratified and logistic regression analyses both demonstrated an increased risk for individuals carrying the NATl*lO allele among smokers. There was evidence of a statistically significant geneenvironment interaction, indicating that bladder cancer risk depends on both NATl genotype and smoking exposure.264 Breast Cancer

The association between cigarette smoking and breast cancer is not entirely clear. Most studies have not found a definite relationship between breast cancer and smoking*, however, some studies have found an increased risk for breast cancer among smokers,t whereas others have found a decreased r i ~ k . ~ These ~ ~varying , ~ ~results ~ , ~may ~ be ~ caused ~ by genetic susceptibility to components found in tobacco. Ambrosone et a16considered cigarette smoking, N-acetyltransferase 2 (NAT2) genetic polymorphism, and breast cancer risk. This enzyme is responsible for detoxifying carcinogenic aromatic amines found in tobacco. Among premenopausal women, there was no relationship between NAT2 polymorphisms and breast cancer risk. Among postmenopausal women, however, ever having smoked increased the risk of breast cancer fourfold if the woman was a slow-acetylator. This increase in risk was also dose-dependent. There was no increase in breast cancer risk among women who were fast acetylators. These results may explain previous inconsistent findings between tobacco use and breast cancer risk. Cervical Cancer

There appears to be a dose-response relationship for smoking and cervical cancer, because smokers consistently show an increased risk of *References3,6,15,83,92,97,136,180,231,236,237,279. tReferences 43,46,66,135,190,207,230,257.

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cervical n e ~ p l a s i a sIn . ~ 1978, ~ Wright and others published a case control study involving 65 women with cervical dysplasia or neoplasia out of 17,039 women followed in a longitudinal manner from 1968 to 1974 in the Oxford Family Planning Contraceptive Study. The findings included a graded relationship between smoking and cervical cancer independent of method of contraception, age at first marriage, age at first pregnancy, and social class. Lyon and others studied 217 cases of carcinoma in situ of the cervix and compared them with 243 controls in Utah. The relative risk was 3.0 for cigarette smoking after controlling for sexual and socioeconomic factors, indicating a strong association. The smoking association was much stronger in the age group 20 to 29 years (17-fold) than in older women. The authors reviewed a number of epidemiologic and biologic phenomena consistent with a causal relationship between smoking and cervical cancer, but their ultimate findings are interpreted cautiously. In a study by Brinton et al, a strong relationship between smoking and risk of invasive squamous cell tumors of the cervix was elucidated. This study verified the dose-response relationship aforementioned and is supportive of a direct effect of smoking on the squamous epithelium of the cervix.44 However, when controlling for human papilloma virus infection, which strongly correlates with cigarette smoking, the independent effect of smoking on cervical cancer risk is less striking.

OTHER DISEASES

Hormone-Related Disorders Because of the anti-estrogenic effect of tobacco use, a variety of hormone-dependent disorders are related to tobacco.280aThese are briefly mentioned here. Women who smoke experience menopause at an earlier age than women who do not smoke. In addition, among both men and women, osteoporosis, lowered bone mineral density, and osteoporotic fractures are more frequent among smokers. Cigarette smokers also have a higher incidence of hormone-related cancers such as breast, prostate, and cervical cancers. Endometrial cancer, which depends on estrogen for its pathogenesis, is reduced among women who smoke. Finally, a variety of benign disorders related to hormone levels are increased among smokers such as gall bladder disease and prostatic hyperp1asia.2*Oa

Chronic Obstructive Pulmonary Disease Cigarette smoking and age are the only factors consistently associated with an increased loss of forced expiratory f u n c t i ~ nAlthough . ~ ~ ~ ~ only ~~ 10% to 15%of cigarette smokers develop chronic obstructive pulmonary disease (COPD), cigarette smoking accounts for about 80% to 90% of the risk of developing COPD in the United States. Cigarette smokers have higher COPD mortality than nonsmokers, and have higher rates of other respiratory symptoms, bronchitis, and decline of FEW. These differences

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between smokers and nonsmokers increase with pack years of smoking. Pipe and cigar smokers have morbidity and mortality rates intermediate to cigarette smokers and n ~ n ~ m ~ k e r ~ . ~ ~ , ~ ~ ~ , ~ ~ ~ , ~ ~ Smoking cigarettes leads to acceleration of the normal aging process of lungs, with loss of elastic recoil resulting in expansion of distal airspaces. Physiologically, this results in hyperexpansion and decreased FEVl . Additionally, changes in inflammatory cellular infiltrates in the terminal airspaces, giving rise to bronchiolitis, leads to fibrosis and distortion of the small airways.201,250,293 The natural history of the development of COPD in smokers is relatively straightforward. Approximately one third of cigarette smokers develop chronic cough and phlegm production, but only one seventh of smokers develop accelerated rate of loss of lung function. Smokers with the lowest FEVl also have the greatest fall per year. The first limitations of activities occur at approximately an FEVl of 50%)and significant limitations of activities occur with declines to 30% to 40%. When the loss of lung function becomes disabling, mean survival is only 5 years. Smoking cessation decreases accelerated decline by first year to half that of smokers.50,99,151.214 In the absence of symptoms, only smoking cessation positively influences the course of COPD9,50-52,99,138,181 The Lung Health Study shows there to be an increase in lung function following quitting, with normal age related decline thereafter in those with mild COPD? Similar benefits are seen even in the elderly. Furthermore, those who intermittently quit and relapse show an attenuated decline in FEVl compared with those who smoked c~ntinuously.~ There was not a similar benefit from other therapeutic modalities including inhaled ipratroprium and aerosolized steroid~.~ Chronic obstructive pulmonary disease is an independent risk factor for pneumonia and mortality from pneumonia and i n f l ~ e n z a . ~ It ~is,also '~~ an independent risk factor for lung cancer, coronary heart deaths, and cardiovascular deaths.73,87,96,156,169,171,173,202,248,270 Gastrointestinal Disease

Cigarette smoking is associated with symptomatic gastroesophageal reflux disease. Furthermore, peptic ulcer disease is significantly associated with number of cigarettes smoked per day (RR = 1.12) but not significantly with either tar or nicotine yield.213Peptic ulcers are also associated with chronic bronchial hypersecretion.161Duodenal ulcers heal more slowly in smokers even when treated. Smoking cessation, however, is associated with fewer duodenal ulcers,5' compared with current smoking. Perinatal Effects of Tobacco

Tobacco abuse is associated with intrauterine growth retardation, small for gestational age, low birth weight, placental complications,

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premature rupture of membrane, perinatal mortality, spontaneous abortions, ectopic pregnancies, placenta abruption, and sudden infant death syndrome (SIDS).13,45,67,69,79,119,168,216,286,289,290 Low birth weight is the most important determinant of perinatal m ~ r t a l i t y . That ~ ~ , ~smokers ~~ have smaller babies than non-smokers is well established.276 The effect of smoking on pregnancy was investigated in a large study of 1500 women at delivery controlling for alcohol, caffeine, and various psychosocioeconomic indicators. Smoking was identified as the most important risk factor for low birth weight corresponding to a 5% decrease in birth weight. After controlling for smoking, alcohol, had an effect only in smokers. Caffeine and socioeconomic and stress factors were not significant when controlling for smoking.45 Maternal mortality rates are increased in smokers. Smoking habits were recorded of 96% of all women expected to deliver in northern Finland, who were then followed for 28 years. The mortality ratio for smokers and those who stopped smoking before the second month of pregnancy was 2.3 and 1.6 respectively, compared with Ectopic pregnancy is the leading cause of maternal death during the first trimester, and smoking may reduce tuba1 motility, delay ovum entry into the uterus, and increase the risk of pelvic inflammatory disease. The pooled odds ratio of ectopic pregnancy in smokers when compared with nonsmokers is 1.77, for a smoking-attributed portion of at least 13%.4,55,216 The increased rates of abruptio placenta in smokers may be because smoking causes vasoconstriction and may allow the placenta to separate from the uterine wall.55In addition, maternal blood pressures in smokers is lower, which leads to reduced placental blood perfusion. The pooled odds ratio in smokers for placental abruption is 1.62, with at least 11%of the risk attributable to smoking.55Placenta previa is also increased in smokers, with an odds ratio of 1.58 and a smoking-attributed portion of at least Biologically, this is probably through chronic hypoxia leading to placental enlargement. Smokers have an increased rate of premature rupture of the membranes, with an odds ratio of 1.70 for a smoking attributable portion of at least 12%.55The risk of spontaneous abortions also is increased in smokers. Smoking leads to a pooled odds ratio of 1.32 for a smoking attributable portion of 6% of clinically recognized spontaneous abortions.79Furthermore, smokers are more likely to abort chromosomally normal embryos than non-smokers. The mechanism by which smoking exerts all these adverse outcomes is not clear, though it is known that smoking affects maternal nutritional status, impairing protein metabolism, reducing levels of amino acids, ascorbic acid, and vitamin BIZ,and increasing maternal susceptibility to infections. Finally, SIDS has an odds ratio range from 2 to 4 for infants whose mothers smoke. These effects increase in a dose-response relationship. Though it is difficult to differentiate the prenatal effects of smoking from the effects of second-hand smoke in the first year of life, two of three studies of homes with paternal smokers and maternal nonsmokers found significant effects.8

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Smokeless Tobacco Because of the unique epidemiology and increased popularity of smokeless tobacco use, particularly among adolescents, it is important to consider this product's health effects in more detail. Although cigarettes are known to contain many carcinogens, the carcinogens contained in snuff are less well appreciated. These include polonium-210, N-nitrosamines (volatileand nonvolatile),volatile aldehydes, and polycyclic aromatic hydrocarbons (PAH).It has been shown that these substances and related substances cause oral cancer in laboratory rats.80,145,159 The carcinogenic N-nitrosamines are abundant in snuff. Even more significant, tobacco-specific nitrosamines (TSNA) derived from the Nicotiana alkaloids contribute 70% to 90% of the total N-nitr0~amines.I~~ Two of the most potent carcinogens, N-nitrosonornicotine (NNN) and NNK (4-[methylnitrosamine]-l-[3-pyridyl]-l-butone) are very abundant in snuff.125 Placing smokeless tobacco next to the gingiva and teeth damages the periodontiurn, inducing gingival recession, loss of periodontal attachment, and in some cases tooth l0ss.2~~ Although there is probably no increased rate of dental caries with smokeless tobacco smokeless tobacco stains and significantly abrades tooth s t r u c t u r e ~ . ~ ~ , ~ ~ ~ Oral soft tissue effects of smokeless tobacco use include leukoplakia (a white patch or plaque on the mucosa that does not wipe ~ f f ) ; ~ ~ J ~ ~ , erythroplasia, a red mucosal change with a very high degree of malignant transformation and carcinoma in situ or invasive squamous cell carcinoma.253There are three principal factors contributing to the mechanism of oral mucosal changes in snuff users: loss of cell cohesion, hyperkeratosis, and micronuclei f ~ r m a t i o n .Loss ~~~ ~ ~ cohesion ~ of, cell has been detected in several The most remarkable changes, anucleation or hyperkeratosis and loss of cell cohesion, have been shown to be reversible, indicating that they are of a reactive or reparative nature rather than neop1a~tic.I~~ This, however, is controversial. Other studies have shown dysplastic or malignant regions in these lesions in certain select ca~es.~O,'~~ The most significant change associated with snuff use is the increased incidence of micronuclei, the likely key to understanding the neoplastic changes that may occur with prolonged snuff use (40 years or more).2uIn addition to oral cancer, smokeless tobacco use is associated with prostate cancer, pancreatic cancer, and cervical cancer, and:291a Dental and periodontal effects Gingival recession Periodontal attachment loss Tooth staining Tooth abrasion Halitosis Oral soft tissue effects 'Leukoplakia Erythroplasia

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Carcinoma in situ Invasive squamous cell carcinoma Systemic nicotine effects Elevated LDL and lowered HDL Elevated triglycerides Accelerated atherosclerosis Thrombosis (platelet aggregation) Increased cardiovascular mortality Gastroesophageal reflux disease Peptic ulcer disease Perinatal morbidity and mortality Cancers Oral squamous cell carcinoma Prostate cancer Pancreatic cancer Cervical cancer Other diseases Crohn’s disease Ulcerative colitis Smokeless tobacco generally contains a higher concentration of nicotine relative to cigarettes. The typical single dose of nicotine in snuff is almost twice that of cigarettes, whereas the single dose of nicotine in chewing tobacco can be over 15 times greater.24Because of this, all the systemic effects of nicotine mentioned above can occur with smokeless tobacco use. Nicotine enhances the release of catecholamines, acutely increasing heart rate, contractility, and blood pressure. This substance also adversely affects the lipid profile by raising the total cholesterol and low density lipoprotein levels and lowering the high density lipoprotein levels through its effect on triglycerides. Nicotine also inhibits prostacycline synthesis, which promotes platelet aggregation. Taken together, these nicotine-mediated effects can accelerate atherosclerosisof the coronary and peripheral vasculature, predisposing the smokeless tobacco user to thrombosis, MI, hypertension, and stroke.24Indeed, a study from Sweden among 137,000 male construction workers found a 40% increase in cardiovascular death among smokeless tobacco users versus n o n - ~ s e r s . ~ ~ Smokeless tobacco use may also be linked to gastroesophageal reflux disease, peptic ulcer disease, perinatal morbidity (including low birth weight and p r e m a t ~ r i t yand ) ~ ~inflammatory bowel disease.291a

ADVERSE HEALTH EFFECTS OF ENVIRONMENTAL TOBACCO SMOKE EnvironmentalTobacco Smoke and Children

Environmental tobacco smoke is known to be hazardous to health, especially in children, and has been extensively documented.258In an ar-

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ticle by Barnes et al,14 it was noted that of 106 reviews, 37% concluded that passive smoking is not harmful to health; 74% (29 of 39) of these were written by authors with tobacco industry affiliations. Multiple logistic regression analyses controlling for article quality, peer review status, article topic, and year of publication, revealed that the only factor affiliated with concluding that passive smoking is not harmful was whether an author was affiliated with the tobacco industry.14A meta-analysis of 29 studies found the relation between bronchial hyper-responsiveness to be unclear. Although the odds ratio was 1.3 (95% CI 1.1 to 1.51,several of the studies found no effect and the authors argue that the effects were overestimated by publication bias.68The literature, however, is replete with other studies showing worsened asthma and other respiratory effects, including increased health care use, among children exposed to environmental toIn addition, environmental tobacco smoke bacco smoke.1~63~ss~104~150~170~260~263 increases the risk of lower respiratory tract infections, otitis media, pulmonary hypertension of the newborn (as measured by higher cotinine levels), and pulmonary complications after general anesthesia.Z,1s,249,259

Environmental Tobacco Smoke and Adults

Passive smoking is known to exert adverse effects and has been studied extensively in the workplace. A questionnaire and spirometry examination was conducted in a study of 275 men and women nonsmokers in Tehran aged 18 to 65. The results revealed that the adverse effects of passive smoking was greatest among men exposed at the workplace (reduction in percentage predicted FEVl 9.4%, FVC 7.6%, and FEF25-35). When male passive smokers were divided into subgroups according to source of exposure, there was a significant reduction in spirometric values only among those exposed at work. The group exposed to smoke at the workplace with or without exposure at home had a reduction of 9.4% in FEV1, 7.6% in FVC, and 15.3% in FEF 25-75 values. Men exposed to environmental tobacco smoke only at home had smaller (and non-significant) reductions in FEVl (4.2%, FVC 1.8%, and FEF25-75 (10.7%) than those exposed in the

MINORITIES AND GENDER DIFFERENCES Tobacco Use in American Indians and Alaskan Natives

Cancer is the leading cause of death for Alaskan Native women and the second leading cause of death among American Indian women. The preponderance of cancers affecting this population is related to tobacco use. Chronic cigarette smoking and spit tobacco use appear to be the two links to adverse health according to the US Surgeon General’s Report. Although the use of tobacco may vary regionally, combined survey data

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show, in 1994 and 1995, among the five major racial and ethnic groups, adult smoking prevalence was 39.2% for American Indians and Alaskan natives, compared with 26.5% for African Americans, 25.9% for whites, 18.9%for Hispanic, and 15.3%for Asian Americans and Pacific Islanders.61 Tobacco use is a risk factor for heart disease, cancer and stroke, all leading causes of death among American Indians and Alaska N a t i ~ e s .Al~~~,~~~ though the prevalence of cigarette smoking has declined for minorities and whites, this has not been proven for American Indian and Alaskan Native women. In 1994 and 1995, the rate of smoking among American Indian and Alaskan Native women of reproductive age was higher (44.3%) when compared with whites (29.4%), African Americans (23.4%), Hispanic (16.4%),and Asian American and Pacific Islander (5.7%)women of reproductive age? Aggregated high school senior data from 1990 to 1994 show that smoking prevalence was 41.1% among American Indians and Alaskan Native boys and 39.4% for American Indians and Alaskan Native girls. Smoking prevalence was 33.4% for white men and 33.1% for white women, 28.5% for Hispanic men and 19.2%for Hispanic women, 20.6% for Asian American and Pacific Islander men, and 13.8%for Asian American and 11.6%for African American men and 8.6% for African American men.^^,^^^

Smoking rates and consumption among American Indians and Alaskan Natives vary by region and state. Smoking rates are highest in Alaska (45.1%)and the North Plains (44.2%)and lowest in the Southwest (17.0%). The prevalence of heavy smoking (25 or more cigarettes per day) is also highest in the North Plains (13.5%).2

Tobacco Use in African Americans

Smoking rates among African American adults historically have been higher than among the general population in the United States; however, in recent years smoking rates have been similar. Smoking among African American teens has declined dramatically since 1976; however, recent increases in teen smoking among African Americans document the need for continued prevention efforts. African Americans continue to suffer disproportionately from chronic and preventable disease compared with white Americans. Of the three leading causes of death in African Americans-heart disease, cancer, and stroke-smoking and other tobacco uses are major contributors to these If current patterns continue an estimated 1.6 million African Americans who are now under the age of 18 will become regular smokers. About 500,000 of those smokers will die of a smoking-related disease. In 1994 and 1995, African American men (31.4%)smoked at a higher rate than white men (27.6%),although African American women (22.7%)and white women (24.4%)smoked at a similar rate.242

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Of current African American adult smokers, more than 70%indicated that they want to quit smoking completely.8African American smokers are more likely than white smokers to have quit for at least 1 day during the previous year (48.7% versus 40.3%) African Americans (7.9%),however, are much less likely than whites (14.0%)to remain abstinent for l month or more.275

Hispanics and Tobacco

By 2005, it is projected that Hispanics will surpass African Americans as the nation’s second largest racial/ ethnic group, behind only non-Hispanic ~ h i t e s . The 5 ~ majority of Hispanic Americans are of Mexican, Puerto Rican, Cuban, or South Central American ancestry. Aggregated 1994 and 1995 national survey data show that the overall smoking prevalence among Hispanic adults was 18.9%,compared with 15.3%for Asian Americans and Pacific Islanders, 25.9%for whites, 26.5% for African Americans and 39.2%for American Indians and Alaskan Natives.242 In 1994 and 1995 22.9% of Hispanic men smoked compared with 27.6% of white men. The smoking rate among Hispanic women was 15.1%compared with 24.4% among white w0men.2~~

SUMMARY

Tobacco use continues to occur in epidemic proportions and with it, significant morbidity and mortality. One third of smokers will die prematurely of a smoking-related disease. In fact, of the five major causes of death in the United States, tobacco use is implicated in four: MI, lung cancer, strokes, and chronic obstructive lung disease. Tobacco use also contributes to many other disorders including other cancers (e.g., oral, esophageal, and cervical),other respiratory conditions such as asthma and infections, and perinatal morbidity and mortality. Environmental tobacco smoke contributes to illness and even death (e.g., SIDS).The costs of these ailments, in both economic and human terms, is staggering. This article has reviewed the adverse health effects of tobacco use, therefore, clinicians should be aware of the benefits patients will reap when they stop using this lethal substance. In many cases, the risk of tobacco-related morbidity and mortality is reduced after cessation to levels approaching those of never-users of tobacco (Fig. 1).

ACKNOWLEDGMENT The authors would like to thank Joan S. Gould for her assistance in preparing this manuscript.

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Cervical Cancer risk reduced compared to "CS" a few years after quilting.

quilting Low Birthweight Baby risk reduced to that of "NS lor women who quit before pregnancy or durinc '

first trimester

Figure 1. Benefits of smoking cessation. CS = continuing smokers; NS = never smokers. (FromCenters for DiseaseControl and Prevention, Office on Smoking and Health:The health benefits of smoking cessation: A report of the surgeon general. 1990 at a glance. Rockville MD; 1990. Centers for Disease Control and Prevention. US Department of Health and Human Services publication CDC 90-8419.)

References 1. Abulhosn RS, Morray BH, Llwewllyn CE, et al: Passive smoke exposure impairs recovery after hospitalization for acute asthma. Arch Pediatr Adolesc Med 151:135, 1997 2. Adair-Bischoff CE, Sauve RS: Environmental tobacco smoke and middle ear disease in preschool-age children. Arch Pediatr Adolesc Med 152:127, 1998

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3. Adami HO, Lund E, Bergstrom R, Meirik 0 Cigarette smoking, alcohol consumption and risk of breast cancer in young women. Br J Cancer 58332-837, 1988 4. Adams ED, Melvin CL: Costs of maternal conditions attributable to smoking during pregnancy. Am J Prev Med 15212-219,1998 5. Ahsan H, Neugut AI, Gammon MD: Association of adenocarcinoma and squamous cell carcinoma of the esophagus with tobacco-related and other malignancies. Cancer Epidemiol Biomarkers Prev 6:779, 1997 6. Ambrosone CB, Freudenheim JL, Graham S, et a1 Cigarette smoking, N-acetyltransferase 2 genetic polymorphisms, and breast cancer risk. JAMA 276:1494-1501,1996 7. American Cancer Society: Oral Cavity and Pharynx Cancer. Cancer Facts and Figures, 1996 8. Anderson HR, Cook DG: Passive smoking and sudden infant death syndrome: Review of the epidemiological evidence. Thorax 52:1003, 1997 9. Anthonisen NR, Connett JE, Kiley JP, et al: Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEW. JAMA 272~1497-1505,1994 10. Arkin A, Wagner D H Primary carcinoma of the lung. JAMA 106:587-591,1936 11. Ashton H, Stepney R, Thompson W Self titration by cigarette smokers. BMJ 2:357,1979 12. Badgett RG, Tanaka DJ: Is screening for chronic obstructive pulmonary disease justified? Prev Med 26:466, 1997 13. Bakketelg LS, Jacobsen G, Hoffman HG, et al: Prepregnancy risk factors of small-forgestational age births among parous women in Scandinavia. Acta Obstet Gynecol Scand 72:273, 1993 14. Barnes D, Bero L A Why review articles on the health effect of passive smoking reach different conclusions. JAMA 279:1566,1998 15. Baron JA, Byers T, Greenberg ER, et a1 Cigarette smoking in women with cancers of the breast and reproductive organs. J Natl Cancer Inst 77:677-680,1986 16. Bayer F, Bohn I, Strauer DE: Das Kontraktionsverhalten des linen ventrikels unter nikotinexposition. Therapiewoche 35:1968, 1985 17. Beard MC, Annegers JF, Woolner LB, et al: Bronchiogeniccarcinoma in Olmsted County, 1935-1979. Cancer 55:2026,1985 18. Bearer C, Emerson RK, ORiordan MA, et al: Maternal tobacco smoke exposure and persistent pulmonary hypertension of the newborn. Environ Health Perspect 105:202, 1997 19. Beaty TH, Menkes HA, Cohen BH, et al: Risk factors associated with longitudinal change in pulmonary function. Am Rev Respir Dis 129:660-667,1984 20. Bedwani R, el-Khwsky F, Renganathan E, et al: Epidemiology of bladder cancer in Alexandria, Egypt: Tobacco smoking. Int J Cancer 73:64,1997 21. Belinsky SA, Deveroux TR, Maronpot RR, et al: Relation between formation of promutagenic adducts and the activation of the K-ras proto-oncogene in lung tumors in A/J mice treated with nitrosamines. Cancer Res 495305, 1989 22. Benowitz NL: Cotinine as a biomarker of environmental tobacco smoke exposure. Epidemiol Rev 18:188, 1996 23. Benowitz NL: Pharmacologic aspects of cigarette smoking and nicotine addiction. New Engl J Med 319:1318-1330,1988 24. Benowitz N L Pharmacology of smokeless tobacco use: Nicotine addiction and nicotinerelated health consequences. In Smokeless tobacco or health: an international perspective. Bethesda, MD: Department of Health and Human Services, Public Health Service, National Institutes of Health, 1993; NIH publication no. 93-3461:219-28 25. Benowitz NL: The role of nicotine in smoking-related cardiovascular disease. Prev Med 26:412-417,1997 26. Benowitz NL: The use of biologic fluid samples in assessing smoke consumption. In Grabowski J, Bell CS (eds): Measurement in the analysis and treatment of smoking behavior. Washington, 1983,6-26 27. Benowitz N, Jacob P 111: Daily intake of nicotine during cigarette smoking. Clin Pharmacol Ther 35:499-504,1984 28. Benowitz NL, Jacob P I11 Metabolism of nicotine to cotinine studied by a dual stable isotope method. Clin Pharmacol Ther 56:483-493, 1994

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