Table 7.

Cross-Sectional Studies for Smoking and Smokeless Tobacco

Ref.	Goals	Product	Study Methods	Measures	Subjects
Smoking Studies
Bernert (91)	To examine biomarkers in smokers of either light or regular cigarettes	Commercial regular and light cigarettes	Subjects completed a brief questionnaire regarding smoking behavior; blood and untimed (spot) urine samples collected; inclusion criteria: current, active smokers	Serum cotinine, NNAL and NNAL-glucuronide, adducts of 4-aminobiphenyl hemoglobin, urinary creatinine	N=150; 109 males, 41 females; mean age=34.7 years; mean CPD=17.1; mean years smoked=18.7; 80 Blacks, 70 Whites
Blackford (92)	To examine salivary cotinine and addiction among smokers	Commercial cigarettes	Multi-country; Brazil: multistage random sampling; China: convenient sampling; Mexico: convenient sampling; Poland: random-route method; cotinine concentration was measured using a saliva sample from each participant; its relationship with numbers and types of cigarettes smoked was quantified by applying regression techniques; inclusion criteria: smoking 1–60 cigarettes in the previous 24 hours, regular smoker, did not smoke cigars, did not use any nicotine replacement therapy in the past 3 days, did not smoke hand-rolled cigarettes; exclusion criteria: ratio of cotinine concentration (ng/mL) to number of cigarettes smoked >35 ng/mL per cigarette	Salivary cotinine; height, weight, BMI; smoking behavior, FTND, American Thoracic Society's adult respiratory questionnaire	Brazil N=360, China N=490, Mexico: N=1006, Poland N=517
Borland (93)	To determine the relationship between levels of carbon monoxide in cigarettes and cardiovascular disease, lung disease and mortality	Commercial cigarettes	Each subject completed a questionnaire regarding smoking behavior; inclusion criteria: participants in the Whitehall study of men that examined 18,403 civil servants in 1967–9; exclusion criteria: carbon monoxide values of cigarettes that were unknown	Spirometry; smoking consumption and cardiovascular disease questions	N=4910; all males; 40–64 years old
Groman (97)	To examine differences in CO concentrations in the expired air of smokers who smoked light cigarette brands versus smokers who smoked regular brands	Commercial cigarettes	Smokers were divided into two groups: those who smoked a light cigarette brand and those who smoked a regular cigarette brand; recruitment through first visit clients at publicized information meetings held by the Nicotine Institute, Vienna during a three week period	Exhaled CO; FTND	N=178 (63 light cigarette brand smokers, 115 regular cigarette brand smokers); 83 males, 95 females; mean age=49.1 years
Harris (98)	To determine the association of smoking medium tar filter cigarettes versus low tar or very low tar filter cigarettes and mortality from lung cancer	Commercial very low tar filter, low tar filter, medium tar filter and high tar filter cigarettes	Data from participants in the cancer prevention study II (CPS-II) were analyzed regarding cigarette brand smoked between 1982–8 and the risk of lung cancer; inclusion criteria: ≥30 years old who had either never smoked, were former smokers, or were currently smoking a specific brand of cigarette when they were enrolled in the cancer prevention study, smokers of their current brand for at least 5 or 10 years; exclusion criteria: history of cancer other than non-melanoma skin cancer, of emphysema, reported any smoking related condition (emphysema, chronic bronchitis, heart disease, use of heart drugs, stroke, diabetes, claudication, currently sick); men who ever smoked pipes or cigars or chewed tobacco; and men and women whose current smoking status could not be ascertained	Race, educational level, marital status, blue collar employment, occupational exposure to asbestos, intake of vegetables, citrus fruits, and vitamins; analyses of current and former smokers, for age when they started to smoke and number of cigarettes smoked per day; death from cancer of the trachea, bronchus, or lung as the underlying cause, coded from the death certificate	N=940,774; 364,239; males 576,535 females
Hecht (94)	To evaluate levels of two urinary biomarkers of lung carcinogen uptake in smokers of different tar yield cigarettes	Commercial regular, light and ultra light cigarettes	Subjects completed a tobacco use questionnaire stating their current brand of cigarettes as regular, light or ultra light; urine samples were collected; recruitment in Study 1 through advertisements; Study 2 through invitation letters and advertisements; subjects were participants in two studies examining the effects of smoking reduction on levels of carcinogen biomarkers; inclusion criteria: (Study 1) cigarette smokers 18 to 70 years old and interested in reducing cigarette use but not quitting within the next 30 days, smoking 15 to 45 CPD for the past year, good physical health, no contraindications for nicotine replacement use, good mental health, not using other tobacco or nicotine products and not pregnant or nursing; (Study 2): 18 to 80 years old who also had heart disease and were interested in reducing cigarette use but not quitting within the next 30 days, smoking ≥ 15 CPD, having coronary artery disease, arrhythmia, congestive heart failure, peripheral vascular disease, or history of a cerebrovascular event; no unstable angina within the past 2 weeks; no unstable psychiatric or substance use diagnoses; and no contraindications to nicotine replacement therapy (including pregnancy or intention to become pregnant)	1-hydroxypyrene (1-HOP), total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol(NNAL plus its glucuronides), total cotinine (cotinine plus its glucuronides)	N=115 subjects in Study 1 and N=60 in Study 2; Pooled results: smoking regulars=26.9%, lights=45.7%, ultra lights=27.4%; mean age for smokers of regulars= 50.5 years, lights=49.1 years, ultra lights=51.4 years; mean CPD for smoking regulars=27.9, lights=24.1, ultra lights=26.1
Melikian (100)	To examine the relationships between delivered dosages of smoke constituents, (e.g., nicotine and select carcinogens) determined by using actual human smoking conditions with levels of corresponding urinary metabolites in smokers	Commercial cigarettes	Single visit; subjects collected butts 4 days before visit; administered comprehensive questionnaire about smoking history, gave urine sample after smoking 3–4 cigarettes during smoking topography measurements; recruitment through newspaper advertisement; inclusion criteria: 18 and 59 years old, smoked ≥ 10 CPD for 1 year, in good general health, no history of any tobacco-related disease, no unstable medical condition, no psychotropic medications and no psychiatric diagnosis at the time of study; exclusion criteria: using any tobacco or nicotine containing products other than cigarettes for at least 3 months before the study, pregnant and nursing women	Quantified nicotine, 4-(methylnitrosamino)-1 -(3-pyridyl)-1-butanone (NNK), and benzo(a)pyrene in the mainstream smoke condensate generated by machine smoking of each individual's cigarettes under conditions that reflect that individual's smoking pattern; urinary cotinine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), 1-hydroxypyrene (1-HOP); the brand of cigarettes smoked, type of pack (hard or soft), mentholated or nonmentholated cigarettes; occupational exposure, family medical history, diet and other lifestyle factors, FTND	N=257; 129 females, 128 males; mean age females=33.1, males=35.0; mean CPD females=15.9; males=16.8; mean FTND score females=4.1, males=4.6; mean BMI females =25.5, males=26.8
Russell (95)	To determine differences in biomarkers and smoking behavior for different tar yield cigarettes	Commercial cigarettes	Single visit; subjects smoked one of their usual cigarettes and a venous blood sample was taken 2 minutes later; recruitment through Maudsley Hospital smokers' clinic or from experimental studies on smoking at the addiction research unit; exclusion criteria: cigars or hand-rolled cigarettes	Carboxyhemoglobin, plasma nicotine	N=330; 124 males, 206 females; mean CPD males=36.2, females=32.6
Russell (99)	To estimate the tar intake of low tar smokers compared with smokers of other brands	Usual brand (middle, low to middle and low tar)	Subjects attended in afternoon, smoked one of their cigarettes, and a venous blood sample was taken two minutes later; the tar, nicotine and CO yields of the cigarettes were obtained from the Health Departments of the United Kingdom; exclusion criteria: use of cigars or hand-rolled, cigarettes in the 'middle to high' tar category (23–28 mg/cig)	Blood nicotine, cotinine, carboxyhemoglobin; CO, tar intake derived from the measured intake of a marker (e.g., blood nicotine) and the ratio of the tar to marker yields of the cigarette (e.g., Tar Intake=plasma nicotine x Tar/Nicotine yield ratio).	N=392; 255 females, 137 males; mean age females=38.4 years, males=40.4 years; mean CPD females=29.0, males=31.8
Woodward (96)	To determine differences in biomarkers and smoking behavior for different tar yield cigarettes	Commercial cigarettes	Single visit where subjects gave blood and CO samples and completed a smoking history questionnaire; recruitment through a baseline population survey of the Scottish Heart Health Study; inclusion criterion: current cigarette smokers; exclusion criteria: cigars and/or pipes and subjects who smoked cigarette brands that were not reported by the Government Chemist or rolled their own cigarettes	Serum thiocyanate, serum cotinine; exhaled CO	N=2754; 1133 males, 1621 females (13.7% males smoking plain cigarettes, 1.9% females smoking plain cigarettes, 25% males smoking low-nicotine cigarettes, 27.2% females smoking low-nicotine cigarettes)
Smokeless Tobacco Studies
Andersson (104)	To investigate the uptake and metabolism of nicotine by ST users and effects on oral mucosa	Loose snus, portion-bag snus and chewing tobacco	Subjects attended the dental clinic for a thorough oral examination; subjects used their usual brand ad libitum and kept track of amount used for 7 days; on Day 6, urine samples were collected for 24 hours; on the same day, the ST users saved all used portions of ST; on day 7, one saliva sample was collected 30 minutes after using a pinch of snus or a piece of chewing tobacco; after 30 minutes subjects rinsed their mouth with water and a whole mixed saliva sample was collected; recruitment from a previous study comprising 252 healthy men with a regular snus habit for at least the previous 3 months and with no other current tobacco use; the users of chewing tobacco were selected from another study of 20 healthy men with no other tobacco habit and who were living in the area; inclusion criteria: equal daily consumption and usage of the same tobacco brand	Urine nicotine and cotinine, glucuronic acid conjugates of nicotine and cotinine, trans-3'-hydroxycotinine and.nicotine-N'-(1)-oxide and cotinine-N-(1)-oxide; salivary cotinine; analysis of chemical constituents of smokeless tobacco products: nicotine and tobacco-specific nitrosomines (N'-nitrosonornicotine, N'-nitrosoanatabine, N'-nitrosoanabasine, and 4-(N'-methyl-N'-nitrosoamino)-1-(3-pyridyl)-1-butanone); clinical exam to record lesions in the oral mucosa; questions for ST use, general health, medication, previous tobacco habits and alcohol consumption	N=54 (22 loose snus users; 23 portioned snus users, 9 chewers); mean age range 38.8–50.4 years
Bolinder (111)	To examine whether long-term use of smokeless tobacco is associated with mortality from cardiovascular disease compared to nonusers and cigarette smokers	Smokeless tobacco and cigarettes	Construction industry workers received a health examination through the Swedish Construction Industry's Organization for Working Environment Safety and Health and the cause of their mortality during a 12 year period was determined; recruitment through invitation; exclusion criteria: women	Heart rate, blood pressure, weight, height; past and current health, medication use; cause of death; tobacco use	N=135,036; all males; age range=35–65 years; 6297 smokeless tobacco users, 14,983 smokers of fewer than 15 cigarettes per day, 13,518 smokers of 15 or more cigarettes per day, 17,437 ex-smokers, 50,255 “other” tobacco users and 32,546 nonusers
Eliasson (106)	To assess the relationship between cigarette smoking and snuff use and biomarkers	Usual brand cigarettes and snuff	Single visit; subjects (regular smokers, ex-smokers, snuff dippers and non-tobacco users) fasted overnight (12 hours) and underwent a 75 g oral glucose tolerance test; recruitment through choosing subjects at random from a cardiovascular disease study; inclusion criterion: 25–64 years old	Blood lipids, plasma glucose, serum insulin, plasma fibrinogen, tissue plasminogen activity and plasminogen activator inhibitor type 1 activity, glucose and insulin levels; plasma nicotine, cotinine; BMI, physiological measures	N=1266 (581 nontobacco users, 238 ex-smokers, 317 smokers, 92 snuff dippers analyzed, 38 snuff and cigarettes, but no other type of tobacco analyzed); 604 male, 662 female
Gyllen (118)	To determine if using smokeless tobacco or nicotine replacement effects serum lg levels	Oral moist snuff and NRT	Cross-sectional, parallel group study; subjects gave blood and urine samples and tobacco use history; healthy subjects with no exposure to nicotine served as a control group; recruitment through advertisements in 2 newspapers; inclusion criteria: 18–75 years old, former smokers in any group had quit smoking at least 6 months prior to study entry; exclusion criteria: diseases or medical treatments that influence serum Ig-levels, pregnancy; chronic liver or renal disease, diabetes, severe cardiac failure, severe chronic lung disease, any known immunodeficiency or rheumatologic disease, history of bronchial asthma, allergy or atopy; symptoms of infectious disease with pyrexia or any use of antibiotics, antihistamines or N-acetylcysteine during 4 weeks prior to the investigation; use of steroids including oestrogen hormone substitution or any other immunomodulating treatment or vaccination during 2 months prior to the investigation	Urinary cotinine, Immunoglobulin class and (Ig)G subclass data	N=77; 48 ST users, 29 NRT users; 35 males, 42 females; mean age=44 years; healthy controls: N=44; 20 males, 24 females; mean age=43 years
Hecht (109)	To determine biomarkers among ST users and smokers	Commercial cigarette users and smokeless tobacco	Baseline data from three studies involving smokers and three studies involving smokeless tobacco users who were seeking treatment for tobacco use reduction; recruitment through local advertising; inclusion criteria (Study 1): 18–70 years old, and interested in reducing cigarette use but not quitting within the next 30 days, smoking 15–45 CPD, in good physical health, no contraindications for nicotine replacement use, good mental health, not using other tobacco or nicotine products, and not pregnant or nursing; (Study 2): 18–80 years old who also had heart disease and were interested in reducing cigarette use but not quitting within the next 30 days, smoking ≥15 CPD, no unstable angina within the past 2 weeks, no unstable psychiatric or substance use diagnoses, and no contraindications to nicotine replacement therapy (including pregnancy or intention to become pregnant); (Study 3): smoking ≥15 CPD, an unsuccessful quit attempt in the past year, no specific plan to quit in the next 30 days and willing to attempt smoking reduction as a short-term goal, used other tobacco products three or fewer times in the past week, no current use of NRT, no use of Zyban in the past 2 weeks, not pregnant, and no treatment for alcohol or drug abuse in the past year; Studies 4–6: 18–70 years old, interested in reducing smokeless tobacco use but not quitting, using ST daily for the past 6 months, in good physical health and good mental health	Urine NNAL and cotinine	Smokers: pooled (studies 1–3): N=420; 62% male; mean age=49.5 years; mean CPD=25.8; 80% white; smokeless tobacco users: pooled (studies 4–6): N=182; all males; mean age=32.9 years; mean use of ST=4.2 tins per week; 99% white
Helander (110)	To determine levels of aldehyde dehydrogenase (ALDH) activity in Swedish moist snuff users	Swedish moist snuff and cigarettes	Blood samples collected between 9:00 and 12:00 am from cigarette smokers, moist snuff users and nontobacco controls was analyzed for biomarkers; recruitment through donors at a blood center	Aldehyde dehydrogenase activity (whole blood, erythrocytes and leukocytes), plasma nicotine, cotinine	N=66 (24 smokers, 17 moist snuff users, 25 nontobacco users); 46 males, 20 females
Huhtasaari (112)	To assess the risk of myocardial infarction (MI) among snuff users, cigarette smokers and nontobacco users	Snuff and cigarettes	Case-control study in Northern Sweden; male patients with a myocardial infarction were compared to those without a myocardial infarction from a population survey of cardiovascular risk factors (World Health Organization Multinational Monitoring of Trend and Determinants in Cardiovascular Disease Project; inclusion criteria: male, 35–64 years old	Serum samples for lipid concentrations and total cholesterol concentration; blood pressure; tobacco consumption (regular snuff dipping, regular cigarette smoking, non-tobacco use); questionnaire with items on tobacco habits, social background, medical history, and drugs taken	N=1174 (585 myocardial infarction, 589 no myocardial infarction); all males; 169 cigarette smokers (myocardial infarction), 114 cigarette smokers (no myocardial infarction), 59 snuff dippers (myocardial infarction), 87 snuff dippers (no myocardial infarction)
Huhtasaari (113)	To determine if snuff use affects the risk of myocardial infarction	Snuff and cigarettes	Population-based study associated with the Northern Sweden center of the World Health Organization Multinational Monitoring of Trend and Determinants in Cardiovascular Disease (WHO MONICA) Project; patients with a fatal or nonfatal myocardial infarction were compared to men without myocardial infarction from the MONICA project who were matched for age and place of living with regards to their tobacco habits; recruitment through population registers for referents and through hospital records, general practitioner reports and death certificates for cases; inclusion criteria: male, 25–64 years old	ECG and cardiac enzymes (in hospitalized patients); questionnaire about social conditions, risk factors, tobacco use	N=1374; (687 acute myocardial infarction, 687 no myocardial infarction) all males; 248 cigarette smokers (acute myocardial infarction), 99 cigarette smokers (no myocardial infarction), 59 snuff dippers (acute myocardial infarction), 90 snuff dippers (no myocardial infarction)
Johansson (114)	To examine the association between cigarette and snuff use and coronary heart disease	Snuff and cigarettes	A follow-up study; in 1988–9 men in a Swedish national survey were interviewed and were followed up with in 2000; inclusion criteria: male, healthy, 30–74 years old; exclusion criteria: poor self-rated health, a coronary heart disease hospitalization 2 years before the start of the study, participants who were interviewed with the aid of relatives, participants who lacked information about weight or height	BMI; the time to first hospitalization for fatal or non-fatal coronary heart disease event was classified according to the International Classification of Diseases, ICD 9 and ICD 10; socio-economic status, tobacco habits, leisure time activities, health questions	N=3120; all males; 1036 never-smokers, 854, former smokers, 793 daily smokers, 107 daily snuffers and never-smokers, 245 daily snuffers and former smokers, 85 daily snuffers and smokers; mean age=45.7 years
Kresty (105)	To establish the levels of urinary biomarkers in smokeless tobacco users and smokers	Oral snuff and oral chew	Subjects received an oral cavity examination; 24-hour urine samples were collected and biomarkers were determined; recruited through advertisements at the Ohio State University campus and surrounding area; inclusion criteria: male, nonsmokers, tobacco chewers and snuff dippers had been regular users of smokeless tobacco for ≥ 1 year	NNAL and NNAL-Gluc, cotinine, creatinine; gross appearance of the lips, oral mucosa, palate, tongue, mouth floor, oropharynx, and teeth; general oral hygiene and the presence of gingivitis and leukoplakia	N=47 (23 snuff dippers, 13 tobacco chewers, 3 users of both, and 8 nonusers); all males; mean age=27 years (snuff dippers), 25 years (tobacco chewers); 92% Caucasian
Luo (115)	To assess the risks associated with Swedish moist snuff for cancer of the oral cavity, lung and pancreas	Swedish moist snuff	Workers in the Swedish building industry were given a health exam during 1978–92 and were followed until end of 2004 by links with population and health registers; data from never smokers was also collected; inclusion criteria: snus user status (never, previous, or current), grams of snus per day (<10 g or ≥10 g), smoking status (never, previous, or current), grams of smoking tobacco per day (continuous), and body-mass index (BMI; <25, 25–29, or ≥30); exclusion criteria: records with incorrect National Registration Numbers, men with a death or emigration date before entry, men with cancer before entry, men with incomplete tobacco exposure data	Incident cancers of the oral cavity, lung and pancreas	N=279,897; all males; mean age=35 years; current or previous snuff users=31%
Persson (108)	To examine the relationship between cigarette smoking and use of oral moist snuff and impaired glucose tolerance and type 2 diabetes	Cigarettes and snuff	A population-based cross-sectional study conducted during 1992–94: 52% of subjects who had a family history of diabetes compared to a random sample of men without a family history of diabetes; information was also collected about tobacco use; recruitment through mailing a short questionnaire; exclusion criteria: men who had neither a strong family history of diabetes or men without diabetes in the family, men who were unable to provide complete answers on the presence of diabetes in relatives, men who were born outside Sweden, men who had diabetes known to themselves	Health examination included a standardized 75 g oral glucose tolerance test according to WHO 1985, weight, height and waist/hip ratios when wearing light indoor clothes without shoes, blood pressure; detailed questionnaire on tobacco use, dietary habits, physical activity and psychosocial conditions	N=3128; all males; age range=35–56 years
Rosenquist (116)	To determine the association between Swedish moist snuff and oropharyngeal squamous cell carcinoma (OOSCC)	Swedish moist snuff and cigarettes	Population-based, case-controlled study; during September 2000 and January 2004 subjects diagnosed with OOSCC and matched controls were interviewed and examined; inclusion criteria (cases): individuals with OOSCC, born in Sweden and without a previous cancer diagnosis, except for skin cancer; recruitment through the two university hospitals in the region where almost all oral cancer cases are treated; inclusion criteria (controls): persons born in Sweden with no previous cancer diagnosis with the exception of skin cancer and who were living in the Southern Healthcare Region of Sweden were selected from the Swedish Population Register through stratified random sampling matching for age, sex and county to cases..	Cell samples from the oral cavity were collected for human papillomavirus (HPV) DNA analysis; a thorough investigation of the individual's oral hygiene, dental status and oral mucosa was performed; a general assessment of the marginal bone level and the periapical status was made from panoramic radiographs; in current snuff users, mucosal changes at the site(s) where the snuff quid was regularly placed were recorded and classified according to the degree of clinical severity using a four-point scale; questions regarding medical history, medication, reactivated herpes labialis infection, oral sexual habits, use of tobacco and alcohol consumption	N=452; 132 cases; 320 controls; gender=91 males, 41 females (cases), 215 males, 105 females (controls)
Teo (117)	To evaluate the risks associated with tobacco use and second hand tobacco smoke	Cigarettes, beedies, pipes or cigars, chewing tobacco, paan, snuff, sheesha or water pipe, and other forms of smoked or non smoked tobacco	Standardized case-control study of acute myocardial infarction (AMI) among subjects in 52 countries; administered a standardized questionnaire and examination; inclusion criteria (cases): first AMI presenting within 24 h of symptom onset no cardiogenic shock or history of major chronic diseases; inclusion criteria (controls): age-matched (plus or minus 5 years) and sex-matched control without a history of heart disease or exertional chest pain	Concentrations of apolipoproteins B and A1 in serum; height, weight, waist and hip circumferences, blood pressure, heart rate; tobacco use, secondhand tobacco smoke exposure; information on dietary patterns, physical activity, alcohol consumption, education, income, psychosocial factors, personal and family history of cardiovascular disease, and risk factors (hypertension, diabetes mellitus)	N=27,098; 12,461 cases, 14,637 controls; 9456 males, 3005 females (cases), 10,851 males, 3786 females (controls); mean age=58.1 years (cases), 56.9 years (controls); current smokers=45.2% (cases), 26.8% (controls)
Wallenfeldt (107)	To evaluate the association of tobacco use and cardiovascular risk factors	Cigarettes and oral moist snuff	Population-based study; all measurements conducted during the morning; recruitment through being invited by mail to a screening examination; inclusion criteria were age 58 years, male, Swedish ancestry; exclusion criteria: cardiovascular or other clinically overt disease, treatment with cardiovascular drugs for ischaemic heart disease, heart failure, hypertension, diabetes mellitus and hyperlipidemia, unwillingness to participate	C-reactive protein; Intima-media thickness (IMT) in the carotid bulb, the common carotid artery and the common femoral artery and plaque occurrence were measured by ultrasound; cholesterol and triglyceride levels; blood glucose; plasma insulin; blood pressure, body weight, height, waist and hip circumference; BMI and waist-hip ratio; information on general health and tobacco habits	N=391; all males; all 58 years old