Naeye and Peters (1984) investigated the mental development of smokers’ children by comparing siblings whose mothers smoked in one but not in subsequent pregnan- cies and found that hyperactivity. short attention span, and lower scores on spelling and reading tests were more frequent for the children whose mother had smoked during pregnancy, but the differences were relatively small, the test scores being only 2 to 4 percent lower. Dunn also studied neurological and electroencephalographic abnor- malities among 6-year-old children of smokers and found these conditions to be slight- ly more common in the children of mothers who had smoked during pregnancy, but again the differences were not statistically significant. Small sample sizes in many of these studies and the relative infrequency of the events of interest limit interpretation of the studies (Dunn et al. 1977). Peptic Ulcer The 1964 Surgeon General's Report noted an association between peptic ulcer and cigarette smoking. The 1979 Report stated that the relationship between cigarette smoking and peptic ulcer is significant enough to suggest a causal relationship. Peptic ulcer disease is more likely to occur, less likely to heal, and more likely to cause death in smokers than in nonsmokers. Cigarette smoking retards the healing of peptic ulcer (Sontag et al. 1984; Lane and Lee 1988: Korman etal. 1983). A large trial of cimetidine. a drug used in the treatment of peptic ulcer. was reported in 1984 by Sontag and associates. Ulcer recurrence was much more frequent among smokers compared with nonsmokers for both the placebo- and the cimetidine-treated groups. Nicotine decreases pyloric sphincter pressure and therefore permits increased reflux of duodenal contents into the stomach. Nicotine also decreases pancreatic bicarbonate secretion. This may impair neutralization of gastric acid in the duodenum, contributing to the formation and persistence of duodenal ulcers. Smoking cessation probably reduces the incidence of peptic ulcer and is an important component of peptic ulcer treatment even with the available effective drug therapy. Osteoporosis The 1964 Report did not discuss osteoporosis. The interest in osteoporosis is fairly recent because of the increasing number of older individuals. especially women, at risk of fracture: the better methods of measuring bone mineral mass: and the understanding of osteoporosis pathophysiology and risk factors. Osteoporosis leading to fractures, especially of the hip, wrist, and spine, is an impor- tant cause of disability and death, predominantly among postmenopausal women. About 15 to 20 million persons in the United States have osteoporosis. Each year about 1.3 million fractures are attributed to this disease (Journal of the American Medical As- sociation 1984). Smoking may be a risk factor for osteoporosis (Willett et al. 1983). Women smokers have an earlier age of menopause, an important risk factor for osteoporosis (Willett et al. 1983). Smokers may have a lower intake of calcium during adolescence and young 76 adult life when maximum bone mineral mass is reached (Sandler et al. 1985). Smokers also weigh less than nonsmokers (US DHHS 1988). Obesity substantially reduces the risk of hip fracture (Kiel et al. 1987). Overweight women have higher endogenous estrogen levels and greater bone mass (Cauley et al. 1986). Exogenous estrogen intake among postmenopausal women results in a decreased risk of fracture (Ernster et al. 1988). Women who smoke and are on estrogen therapy may have reduced levels of estrogens in their blood compared with levels for nonsmoking women. Among women who smoked and were given high doses of estradiol, blood levels of estrone and estradiol were only one-half of those among nonsmokers (Jensen, C hristiansen, Rodbro 1985). Increased hepatic metabolism of exogenous oral estrogen may result in lower estrogen levels among postmenopausal cigarette smokers. Several case-control studies have evaluated the relationship between osteoporosis and cigarette smoking. Most find an increased risk of fractures among smokers. However, problems with study design, especially the potential effects of confounders such as obesity and age, have limited the interpretation of these studies, as have con- tradictory findings. For example, a large study of hip fractures among postmenopausal women in four Connecticut hospitals did not find any differences in risk between smokers and nonsmokers (Kreiger et al. 1982). A study in lowa by Sowers (Sowers, Wallace, Lemke 1985) of 86 women aged 20 to 35 years did not find any relationship between forearm bone mineral mass and smoking during maximal bone mineralization. A study in Denmark (Jensen 1986) compared bone mineral content among 77 long- term smokers and 103 nonsmokers. Bone mineral content correlated with fat mass. For the same degrees of obesity, smokers did not have any lower level of bone mineral con- tent than nonsmokers. The results of these studies suggest that the effect of smoking as a risk factor for osteoporosis and fracture among postmenopausal women may be primarily determined by the inverse relationship between smoking and obesity. It is possible that the early age of menopause among smokers may also contribute to the risk of osteoporosis. Involuntary Smoking The issue of involuntary smoking was not raised in the 1964 Surgeon General’s Report. The first report of the Surgeon General to address the possible health effects of involuntary smoking was published in 1972 (US DHEW 1972). Over the ensuing 15 years, evidence on the adverse consequences of involuntary smoking began to amass, with several hundred papers being published. In 1986, the Surgeon General’s Report (US DHHS 1986a) focused exclusively on this subject. Nonsmoking adults exposed to ETS have a higher frequency of symptomology, such as eye irritation and upper respiratory symptoms (US DHHS 1986a). The relationship between lung cancer among nonsmokers and ETS has been documented in both case— control and longitudinal studies. Most of these studies have measured the increased risk of lung cancer among nonsmoking women, usually wives exposed to their husbands’ tobacco smoke. A 1.3-fold increased risk of lung cancer has been estimated from these studies and is consistent with the amount of exposure to carcinogens from 77 ETS (US DHHS 1986a), the duration of exposure, and the differences in the distribu- tion of potential carcinogens between sidestream and mainstream smoke. The 1986 Surgeon General’s Report on involuntary smoking concluded (US DHHS 1986a): 1. Involuntary smoking is a cause of disease, including lung cancer, in healthy non- smokers, 2. The children of parents who smoke compared with the children of nonsmoking parents have an increased frequency of respiratory infections, increased respiratory symptoms, and slightly smaller rates of increase in lung function as the lung matures. 3. The simple separation of smokers and nonsmokers within the same air space may reduce, but does not eliminate, the exposure of nonsmokers to ETS. Another major review on involuntary smoking was released in 1986 by the Nation- al Research Council (NRC). This report concluded that the risk of lung cancer is ap- proximately 30 percent higher for nonsmoking spouses of smokers than it is for non- smoking spouses of nonsmokers (NRC 1986). Since release of the 1986 Surgeon General’s Report, five additional studies examin- ing ETS exposure and lung cancer in nonsmokers have been published (Brownson et al. 1987; Dalager et al. 1986; Humble, Samet, Pathak 1987; Gao et al. 1987; Pershagen, Hrubec, Svensson 1987). All five noted a correlation between ETS exposure and lung cancer among nonsmokers. Thus, of the 16 epidemiologic studies in the scientific literature, 14 have noted a positive association. Smokeless Tobacco In 1979 the Surgeon General’s Report included, for the first time, a review of the health consequences of using smokeless tobacco (snuff and chewing tobacco) (US DHEW 1979). In 1986, a special Surgeon General’s Report, The Health C. onsequen- ces of Using Smokeless Tobacco (US DHHS 1986b), reviewed smokeless tobacco in depth and concluded that it can cause cancer in humans. The relationship between smokeless tobacco use and cancer is strongest for the use of snuff and for cancer of the oral cavity. Smokeless tobacco can also cause oral leukoplakia, which may progress to neoplastic transformation with continued use of smokeless tobacco. Addiction to Smoking The 1964 Surgeon General’s Report referred to tobacco use as habituating. Fifteen years later, the 1979 Report concluded that smoking was “the prototypical substance abuse dependency” (US DHEW 1979). The entire 1988 Report (US DHHS 1988) was dedicated to an exhaustive review of tobacco use as an addiction. The 1988 Report concluded: 1. Cigarettes and other forms of tobacco are addicting. 2. Nicotine is the drug in tobacco that causes addiction. 3. The pharmacologic and behavioral processes that determine tobacco addiction are similar to those that determine addiction to drugs such as heroin or cocaine. 78 These findings are discussed in greater detail in Part I] of Chapter 5 on determinants of smoking behavior. PART II. THE PHYSICOCHEMICAL NATURE OF TOBACCO The 1964 Surgeon General's Report on Smoking and Health (US PHS 1964) gave impetus to intensified investigations on the physicochemical nature and composition of tobacco smoke and the identification of biologically active agents in tobacco and tobacco smoke and their modes of action. In 1936 Briickner listed 120 known components in tobacco smoke. This number grew to about 450 in 1959 Johnstone and Plimmer 1959). to about 950 in 1968 (Sted- man 1968), to 3,875 in 1982 (Dube and Green 1982), and to 3,996 in 1988 (Roberts 1988). Today, the estimated number of known compounds in tobacco smoke exceeds 4,000, including some that are pharmacologically active, toxic, mutagenic, or carcinogenic (US DHEW 1979; US DHHS 1983). Such diverse biological effects of cigarette smoke constituents provide a framework for understanding the multiple adverse consequences of smoking. Since about 1960, both the composition of cigarette tobacco and the components and shape of the cigarette itself have undergone significant changes that effected reductions in standardized measurements of tar, nicotine. and other toxic agents in the smoke (Nor- man 1982). Perhaps the greatest advances have been made in understanding the pharmacology and toxicology of nicotine (Benowitz 1986: US DHHS 1988) and in de- lineating the nature and mode of action of the major carcinogens in tobacco smoke (US DHHS 1982; Hoffmann and Hecht, 1989). Processed, unadulterated tobacco contains at least 2,550 known compounds (Dube and Green 1982). The bulk of the dried tobacco consists of carbohydrates and proteins. Other important constituents are alkaloids (0.5 to 5 percent). with nicotine as the predominant compound (90 to 95 percent of total alkaloids), and terpenes (0.1! to 3 per- cent), polyphenols (0.5 to 4.5 percent), phytosterols (0.1 to 2.5 percent), carboxylic acids (0.1 to 0.7 percent), alkanes (0.1 to 0.4 percent), and alkali nitrates (0.01 to 5 per- cent). In addition, tobacco contains traces of aromatic hydrocarbons, aldehydes, ketones, amines, nitriles, N- and O-heterocyclic compounds, pesticides. and more than 30 metallic compounds (Wynder and Hoffmann 1967; US DHEW 1979). The composition of the processed tobacco in cigarettes influences the chemistry and toxicity of the smoke. Cigarettes manufactured in the United States are made with blends of bright. burley, and oriental tobaccos that generate weakly acidic mainstream smoke (pH 5.5 to 6.2) in which nicotine occurs in protonated form in the particulate matter. The sidestream smoke (SS) of these cigarettes is neutral to alkaline (pH 6.5 to 8.0), and part of the nicotine in SS is present in unprotonated form in the vapor phase (Brunnemann and Hoffmann 1974). These observations are important because un- protonated nicotine is readily absorbed through the buccal mucosa (US DHHS 1988). The 400 to 500 mg of mainstream smoke (MS) freshly emerging from the mouth- piece of a cigarette is an aerosol containing about 10'° particles per mL; these range in diameter from 0.1 to 1.0 jum (mean diameter 0.2 sm) and are dispersed in a vapor phase (Ingebrethsen 1986). About 95 percent of the MS effluents of a nonfilter cigarette are composed of 400 to 500 individual gaseous compounds with nitrogen, oxygen. and 79 22.5 mg. 500 mg. 67.5 mg. 6.75 mg. WHOLE VAPOR TPM (Wet SMOK a PHASE TESTERS ------ . ----~-- 1.5 ACIDS 45 | _---- -" [omen 2 METHANOL r oo 2 HETEROCYCLIC COMP’DS A 435 9 |, Compos ', n i H,0 NITRILES SMOKE PIGMENT ; ; =o 75 | misc. comeps MISC. COMPDS ! \ \ ALKANES ; y \ 12. | KETONES TERPENOID HYDROCARBON ; \ \ PHENOLS ; N | \ ESTERS ~e2 |} \ OTHER ALKALOID DER. i \ \ 20, | ALDEHYDES ‘ ‘ NICOTINE i \ co , ' : \ ALCOHOLS ! \ ~80 ‘ \ 1 ALDEHYDES & ; \ ‘ KETONES i 1 1 \ i \ \ | 45 | HvDRocARGONS CARBOXYLIC i \ \ ACIDS ' 0; \ 4 ~13 \ \ 1 WATER | ~16 TE 4 cho, ‘ \ 1 Crea Total Cigarette Smoke Percentage of Smoke Weight FIGURE 13.—Composition of cigarette mainstream smoke SOURCE: Dube and Green (1982), carbon dioxide as major constituents: the particulate matter of MS contains at least 3.500 individual compounds (Figure 13. Dube and Green 1982), Like ail organic combustion products. tobacco smoke contains free radicals, highly reactive oxygen- and carbon-centered types in the vapor phase, and relatively stable radicals in the particulate phase. The principal of the latter appears to be a quinone/hydroquinone complex capa ble of reducing molecular oxygen to superoxide, and, eventually, to hydrogen peroxide and h ydroxyl radicals (Nakayama, Kodama, Nagata 1984: Church and Pryor 1985). For chemical analysis, the smoke is arbitrarily separated into vapor and particulate phases. Those smoke components of which more than 5 phase of fresh MS are considered v phase components (Figure 13), Ta tifted and their estimated concentr Hoffmann and Hecht 1989). 0 percent appear in the vapor olatile smoke constituents: all others are particulate bles 5 and 6 list the major types of components iden- ation in the smoke of one cigarette (US DHHS 1982: The quantitative data presented here were obtained by machine smoking of cigarettes under standardized lab oratory conditions using the method of the Federal Trade Commission (Pillsbury et al. 1969): therefore, the data do not fully reflect the human setting. This applies especially to smokers of low-yield cigarettes who tend to compensate for the ow nicotine delivery by drawing smoke more intensely and inhaling more deeply (US DHHS 1988). Table 6 does not contain information about the natu 30 metals in the smoke. These com re and concentration of at least the metals in tobacco pounds are not listed because less than | percent of are transferred into the smoke and constitute together only <80 ug/g Jenkins, Goldey. Williamson 1985). Tables 5 and 6 also lack descriptions of the 80 TABLE 5.—Major constituents of the vapor phase of the mainstream smoke of nonfilter cigarettes Compound" Concentration/cigarette Nitrogen 280-320 my (56-64%) Oxygen 50-70 mg (11-14) Carbon dioxide 45-65 mg (9-134") Carbon monoxide 14-23 mg (28-bacy Water 7-12 mg ( 14-240") Argon Smeg ( 1.0%") Hydrogen 0.5-1.0 mg Ammonia 10-130 pg Nitrogen oxides (NO\) Hydrogen cyanide Hydrogen sulfide Methane Other volatile alkanes (20) Volatile alkenes (16) Isoprene Butadiene Acetylene Benzene Toluene Styrene Other volatile aromatic hydrocarbons (29) Formic acid Acetic acid Propionic acid Methy! formate Other volatile acids (6) Formaldehyde Acetaldehyde Acrolein 100-600 pg 400-500 Le 20-90 pg 1.0-2.0 mg 1.0-1.6 mg 0.4-0.5 mg 0.2-0.4 mg 25-40 ug 20-35 pg 12-50 pg 20-60 pg 10 pe 15-30 pie 200-600 Lg 300-1.700 py, 100-300 peg 20-30 pig 5-10 pet 20-100 ug 400-1400 pg 60-140 pg 8] TABLE 5.—Continued Compound" Concentration/cigarette Other volatile aldehydes (6) 80-140 pg Acetone 100-650 pg Other volatile ketones (3) 50-100 pg Methanol 80-180 Lg Other volatile alcohols (7) 10-30 pg* Acetonitrile 100-150 peg Other volatile nitriles (10) 50-80 g* Furan 20—40 pg Other volatile furans (4) 45-125 pg* Pyridine 20-200 pg Picolines (3) 15-80 pg 3-Vinylpyridine 10-30 pg Other volatile pyridines (25) 20-50 pe® Pyrrole 0.1-10 peg Pyrrotidine 10-18 pg N-Methylpyrrolidine 2.0-3.0 pg Volatile pyrazines (18) 3.0-8.0 pg Methylamine 4-10 pg Other aliphatic amines (32) 3-10 pg “Numbers in parentheses represent individual compounds identified in a given group. bh, . - Percent of total effluent. “Estimate. SOURCE: Hoffmann and Hecht (1989). chemical nature and concentrations in cigarette smoke of agricultural chemicals and pesticides, which originate from the residues of such compounds in tobacco. There are many variations in the qualitative and quantitative aspects relative to such agents in tobacco from region to region and from year to year. Overall, the use of agricultural chemicals has also been greatly reduced (Wittekindt 1985). Nevertheless, it is fairly certain that commercial tobaccos contain up to a few parts per million of DDT, DDD, 82 TABLE 6.—Maior constituents of the particulate matter of the mainstream smoke of nonfilter cigarettes Compound* ug/cigarette Nicotine 1,000-3,000 Nornicotine 50-150 Anatabine 5-15 Anabasine 5-12 Other tobacco alkaloids (17) NA Bipyridyls (4) 10-30 n-Hentriacontane (n-C11 Hoa) 100 Total nonvolatile hydrocarbons (45)° 300-400" Naphthalene 24 Other naphthalenes (23) 36 Phenanthrenes (7) 0.20.4" Anthracenes (5) 0.05-0.1° Fluorenes (7) 0.6-1.0° Pyrenes (6) 0.3-0.5° Fluoranthenes (5) 0.3-0.45° Carcinogenic polynuclear aromatic 0.1-0.25 hydrocarbons (11)° Phenol 80-160 Other phenols (45)° 60-180° Catechol 200-400 Other catechols (4) 100-200° Other dihydroxybenzenes (10) 200-400° Scopoletin 15-30 Other polyphenols (8)? NA Cyclotenes coy 40-70° Quinones (7) 0.5 Solanesol 600—1,000 TABLE 6.—Continued Compound? Lig/cigarette Neophytadienes (4) 200-350 Limonene 30-60 Other terpenes (200-250)" NA Palmitic acid 100-150 Stearic acid 50-75 Oleic acid 40-110 Linoleic acid 60-150 Linolenic acid 150-250 Lactic acid 60-80 Indole 10-15 Skatole 12-16 Other indoles (13) NA Quinolines (7) 24 Other N-heterocyclic hydrocarbons (55) NA Benzofurans (4) 200-300 Other O-heterocyclic hydrocarbons (42) NA Stigmasterol 40-70 Sitosterol 30—40 Campesterol 20-30 Cholesterol 10-20 Aniline 0.36 Toluidines 0.23 Other aromatic amines (12) 0.25 Tobacco-specific N-nitrosamines (4) 0.34-2.7 Glycerol 120 NOTE: NA. not available. “Numbers in parentheses represent individual compounds identified in a given group. Estimate. . “See Table 7 for details. SOURCE: Hoffmann and Hecht (1989). 84 and maleic hydrazide; fewer than 20 percent of these contaminants are transferred into the smoke stream. The 1964 Surgeon General's Report listed five polynuclear aromatic hydrocarbons (PAHs) and three N-heterocyclic hydrocarbons as known carcinogenic smoke con- stituents (US PHS 1964). By the criteria for carcinogenicity of chemicals as set by the International Agency for Research on Cancer (1986), the carcinogens identified to date in tobacco smoke include | 1 PAHs, 4 N-heterocyclic hydrocarbons, 9 N-nitrosamines, 3 aromatic amines, 3 aldehydes, 6 volatile carcinogens, 6 inorganic compounds, and the radioelement polonium-210 (Table 7; Hoffmann and Hecht 1989). The Changing Cigarette As discussed in Part I. epidemiologic studies have documented a dose-response relationship between the number of cigarettes smoked and the development of cancer of the lung, larynx, oral cavity, esophagus, pancreas, bladder, and kidney (US DHHS 1982: IARC 1986). Bioassays for tumorigenicity with whole smoke and with tar have also demonstrated a dose-response relationship (US DHHS 1982). As tar and nicotine yields in cigarette smoke gradually declined, other toxic and tumorigenic agents, such as CO, volatile N-nitrosamines, and carcinogenic PAHs, were also successfully reduced (Hoffmann, Tso, Gori 1980; Hoffmann et al. 1984; US DHHS 1981). However, it was soon realized that the smoker of low-yield cigarettes tended to compensate for reduced nicotine delivery by intensified smoking (US DHHS 1988), and therefore exposure may not actually have been lowered. Based on values generated by smoking machines under standardized conditions, Figure 14 shows the reduction in sales-weighted tar and nicotine delivery of the average U.S. cigarette. Arrows in the graph point to the introduction of technical changes in the manufacture of cigarettes at various times. These changes have influenced the machine-measured sales-weighted average nicotine and tar deliveries (Norman 1982). Technical issues in the machine measurements of delivered tar and nicotine yields also arose during 1982; modifications of the testing procedure were suggested (Federal Trade Commission 1984). The data shown in Figure 14 are based on the consistent testing procedures. Since 1981, the tar delivery of U.S. cigarettes has averaged between 13.0 and 12.7 mg, while nicotine delivery has remained stable at 0.9 mg per cigarette. (See Chapter 5, Table 26.) In the smoke of popular U.S. low-yield cigarettes, the reduction of nicotine, the primary pharmacologic factor in tobacco addiction (US DHHS 1988), has not occurred to the same extent as has the reduction of tar. The same development has been observed with cigarettes in the United Kingdom (Jarvis and Russell 1985). Some modifications in the makeup of commercial cigarettes have led to a selective reduction of toxic and tumorigenic agents. Filter tips of cellulose acetate, the most com- mon cigarette filter material, can selectively remove phenols and volatile N- nitrosamines from the smoke stream. Perforated filter tips selectively reduce CO and hydrogen cyanide (HCN) levels, and charcoal filters may selectively reduce volatile al- dehydes and HCN. The incorporation into the tobacco blend of reconstituted tobacco sheets, expanded tobacco, and tobacco ribs has also contributed to a selective reduc- tion of PAHs in cigarette smoke. The incorporation of ribs and stems and the utiliza- 85 TABLE 7.—Tumorigenic agents in tobacco and tobacco smoke Evidence for IARC evaluation Processed tobacco vemoke of carcinogenicity Compounds (per gram) (per cigarette) In lab animals In humans PAH Benz(a)anthracene 20-70 ng Sufficient NA Benzo(b)fluoranthene 4-22 ng Sufficient NA Benzo(j)fluoranthene 6-21 ng Sufficient NA Benzo(k)fluoranthene 6-12 ng Sufficient NA Benzo(a)pyrene 0.1-90 ng 20-40 ng Sufficient Probable Chrysene 40-60 ng Sufficient NA Dibenz(a,h)anthracene 4ng Sufficient NA Dibenzo(a,i)pyrene 1.7-3.2 ng Sufficient NA Dibenzo(a,|)pyrene Present Sufficient NA Indeno(1,2,3-c,d)pyrene 4-20 ng Sufficient NA 5-Methyichrysene 0.6 ng Sufficient NA Aza-arenes Quinoline 1-2 pg NA NA Dibenz(a,h)acridine 0.1 ng Sufficient NA Dibenz(a,j)acridine 3-10 ng Sufficient NA 7H-Dibenzo(c,g)carbazole 0.7 ng Sufficient NA N-Nitrosamines N-Nitrosodimethylamine ND-215 ng 0.1-180 ng Sufficient NA N-Nitrosoethy! 3-13 ng Sufficient NA methylamine N-Nitrosodiethylamine ND-25 ng Sufficient NA N-Nitrosopyrrolidine ND-360 ng 15-110 ng Sufficient NA N-Nitrosodiethanolamine ND-6,900 ng ND-36 ng Sufficient NA N’-Nitrosonomicotine 0.3-89 pg 0.12-3.7 pg Sufficient NA 4-(MethyInitrosamino)- | - 0.2-7 pg 0.08-0.77 Lig Sufficient NA (3-pyridy!)- |-butanone N’-Nitrosoanabasine 0.01-1.9 pg 0.14-4.6 pg Limited NA N-Nitrosomorpholine ND-690 ng Sufficient NA 86 TABLE 7.—Continued Evidence for IARC evaluation Mainstream of carcinogenicity Processed tobacco smoke Compounds (per gram) (per cigarette) In jab animals In humans Aromatic amines 2-Toluidine 30-200 ng Sufficient Inadequate 2-Naphthylamine 1-22 ng Sufficient Sufficient 4-Aminobiphenyl 2-5 ng Sufficient Sufficient Aldehydes Formaldehyde" 1.6-7.4 pig 70-100 pg" Sufficient NA Acetaldehyde* 1.4-7.4 mg 18—1,400 mg* Sufficient NA Crotonaldehyde 0.2-2.4 pg 10-20 peg NA NA Miscellaneous organic compounds Benzene 12-48 pg Sufficient Sufficient Acrylonitrile 3.2-15 pe Sufficient Limited 1, t-Dimethylhydrazine 60-147 peg Sufficient NA 2-Nitropropane 0.73-1.21 Lg Sufficient NA Ethylcarbamate 310-375 ng 20-38 ng Sufficient NA Vinyl chloride 1-16 ng Sufficient Sufficient Inorganic compounds Hydrazine 14-5! ng 24-43 ng Sufficient Inadequate Arsenic 500-900 ng 40-120 ng Inadequate Sufficient Nickel 2,000-6,000 ng 0-600 ng Sufficient Limited Chromium 1,000-2,000 ng 4-70 ng Sufficient Sufficient Cadmium 1,300—1,600 ng 41-62 ng Sufficient Limited Lead 8-10 peg Sufficient Inadequate Polonium-210 0.2-1.2 pCi 0.03-1.0 pCi NA NA NOTE: ND, no data; NA, evaluation has not been done by IARC. “The Fourth Report of the Independent Scientific Committee on "Smoking and Health” (1988) published values for the 14 leading U.K. cigarettes in 1986 (51.4 percent of the market) of 20-105 ig/cigarette (mean, 59 pg) for formaldehyde and 550—-1,150 wg/cigarette (mean, 910 jg) for acetaldehyde. SOURCE: Hoffmann and Hecht (1989). 87 Sales-weighted tar (mg) Sales-weighted nicotine (mg) 40 4.0 # 1957—reconstituted tobacco 304 '959—porous paper + 3.0 \ 1967—expanded tobacco ‘ 1971—ventilati 00 4 . ¥ ventilation Log 10. oo ta 1.0 Nicotine 0 I T t v qT T 0.0 1955 1960 1965 1970 1975 1980 1985 FIGURE 14.—“Tar” and nicotine content of U.S. cigarettes, sales-weighted average basis, 1957-87 NOTE: Nicotine values for 1957-67 are estimates. SOURCE: 1957-67, Wakeham (1976), fourth-quarter estimates for each year: 1968-81. PTC (1984): 1982-87, derived from FTC data tape of annuul cigarette company submiss.ons to the FTC. This database is the same as thal used for the on- going FTC tobacco report series. Since 1981, these reports have not listed the sales-weighted tur average. Historical events are noted in R. J. Reynolds (1988), tion of more burley varieties in the tobacco blend have led to an increase in the nitrate content of the U.S. blended cigarette from 0.5 percent to between 1.2 to 1.5 percent. This development brought about a reduction of the smoke yields of tar, phenols, and PAHs, but has caused an increase of the nitrogen oxides in the smoke and thus has in- creased the potential for N-nitrosamine formation (US DHHS 1981. 1982; Hoffmann et al. 1984). The development of the low-yield cigarette has also necessitated an en- richment of the flavor “bouquet” in the smoke either by tobacco selection or by addi- tion of natural or synthetic flavor compounds. These facts and the practice of smoking low-yield cigarettes more intensely make it difficult to evaluate whether these new types of cigarettes are in fact less hazardous to the smoker (see Chapter 8). Changes in the market share of filtered cigarettes, lower yield cigarettes, mentholated cigarettes, and longer cigarettes are presented in Chapter 5. Environmental Tobacco Smoke SS is the smoke generated during smoldering of tobacco products between puffs. When it is obtained under standard laboratory conditions, undiluted SS contains far higher amounts of toxic and tumorigenic agents than MS, which is drawn puff by puff through the unlit end of the cigarette. Table 8 presents data for those toxic agents in SS that are known carcinogens, tumor promoters, and cocarcinogens. The release of volatile N-nitrosamines and aromatic amines into the SS is remarkably higher than that into MS (US DHHS 1988; Guerin 1987). Whereas filter tips, especially perforated 88 TABLE 8.—Some toxic and tumorigenic agents in undiluted cigarette sidestream smoke Amount in Type of sidestream smoke sidestream s ie Compound toxicity (per cigarette) mainstream smoke Vapor phase Carbon monoxide T 26.8-61 mg 2.5-14.9 Carbony! sulfide T 2-3 ug 0.03-0.13 Benzene c 400-400 ig 8-10 Formaldehyde Cc 1,500 pg 50 3-Vinyipyridine sc 300-450 pg 24-34 Hydrogen cyanide T 14-110 peg 0.06-0.4 Hydrazine Cc 90 ng 3 Nitrogen oxides (NOx) T 500-—2,000 pg 3.7-12.8 N-Nitrosodimethylamine c 200-1,040 ng 20-130 N-Nitrosopyrrolidine Cc 30-390 ng 6-120 Particulate phase Tar Cc 14-30 mg 1.1-15.7 Nicotine T 2.146 mg 1.3-21 Phenol TP 70-250 pg 1,3-3.0 Catechol CoC 58-290 pg 0.67-12.8 o-Toluidine Cc 3 ug 18.7 2-Naphtylamine c 70 ng 39 4-Aminobipheny] Cc 140 ng 3h Benz(a)anthracene Cc 40-200 ng 24 Benzo(a)pyrene Cc 40-70 ng 2.5~20 Quinoline c 15-20 pg 8-11 NNN Cc 0.15-1.7 pg 0.5-5.0 NNK Cc 0.2-1.4 pg 1.0-22 N-Nitrosodiethanolamine Cc 43 ng 1.2 Cadmium Cc 0.72 wg 72 Nickel c 0.2-2.5 pg 13-30 Polonium-210 Cc 0.5-1.6 pCi 1.06-3.7 NOTE: C, carcinogenic; CoC, cocarcinogenic, SC, suspected carcinogen: T, toxic: TP, tumor promoter: NNN, N’-Nitrosonornicotine; NNK,4-(methylnitrosamino)-(3-pyridy])- l-butanone. SOURCE: Hoffmann and Hecht (1989). 89 ones, can significantly reduce the concentration of toxic and tumorigenic agents in MS, they have no reducing effect on the agents emitted into the SS (Adams, O’Mara-Adams, Hoffmann 1987). SS is the major source of ETS. The smoke diffusing through the cigarette paper, the smoke emerging from the burning cone during active smoking, and that portion of MS that is exhaled also contribute to ETS. Table 9 presents some data for toxic agents resulting from tobacco combustion in indoor environments (US DHHS 1988: Hoffmann and Hecht 1989). The concentrations of toxic agents in ETS appear low in comparison with their levels in undiluted cigarette MS. With regard to exposure factors, one needs to take into account the fact that the active inhalation of MS is limited to the time it takes to smoke each cigarette, whereas the inhalation of ETS is constant over several hours spent in the polluted environment. This is reflected in the results of measurements of the uptake of nicotine by active and passive smokers (US DHHS 1988). Smokeless Tobacco As noted above, the special Report of the Surgeon General, The Health Consequen- ces of Using Smokeless Tobacco, has shown that tobacco chewers and snuff dippers face an increased risk for cancer of the oral cavity (US DHHS 1986b). In the United States the four primary smokeless tobacco types are plug tobacco, loose leaf tobacco, twist tobacco, and snuff. The composition of processed, unadulterated tobacco has been discussed. Chewing tobacco and snuff are made with various flavor additives (LaVoie et al. 1989). It is of special significance that the preparation of smokeless tobacco products, which en- tails curing, fermentation, and aging, occurs under conditions favoring the formation of tobacco-specific N-nitrosamines (TSNAs) from nicotine and other tobacco alkaloids such as nornicotine, anatabine, and anabasine (Figure 15). Of the six identified TSNAs in smokeless tobacco, N’-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3- pyridyl)-t-butanone (NNK) are strong carcinogens in mice, rats, and hamsters, induc- ing benign and malignant tumors of the oral cavity, nasal cavity, esophagus, lung, liver, and pancreas (Hecht and Hoffmann 1988; Rivenson et al. 1988). Table 10 presents chemical—analytical data for TSNAs in U.S. smokeless tobacco products (Hoffmann and Hecht 1988). The concentrations of carcinogenic nitrosamines in smokeless tobac- co exceed those in other consumer products by at least 2 orders of magnitude (US DHHS 1986b). During tobacco chewing and snuff dipping, additional amounts of car- cinogenic TSNAs are most likely also formed endogenously in the oral cavity (Hoff- mann and Hecht 1988). Carcinogenic TSNAs have been regarded as a major factor for the association of snuff-dipping with oral cancer in humans (Craddock 1983). Other carcinogens identified in smokeless tobacco are volatile nitrosamines (N- nitrosodimethylamine, <215 ppb), N-nitrosomorpholine (<40 ppb), N-nitrosodiethyl- amine (<6,800 ppb), formaldehyde (<7,000 ppb), crotonaldehyde (<2,400 ppb), and benzo(a)pyrene (<90 ppb), as well as traces of the radioelement polonium-210 (<0.6 pCi/g) (US DHHS 1986; Hoffmann et al. 1987; Chamberlain, Schlotzhauer, Chortyk 1988). 90 TABLE 9.—Some toxic and tumorigenic agents in indoor environments polluted by tobacco smoke Pollutant Location Concentration/m? Nitric oxide Workrooms 50-440 pg Restaurants 17-270 jig Bars 80-520 pe Cafeterias 2.548 ug Nitrogen dioxide Workrooms 68-410 pg Restaurants 40-190 Lig Bars 2-116 pg Cafeterias 67-200 ug Hydrogen cyanide Living rooms 8-122 pg Benzene Public places 20-317 pe Formaldehyde Living rooms 23~50 pg Acrolein Public places 30-120 pig Acetone Public places 360-5,800 pg Phenols (volatile) Coffee houses 74-Li.S ng N-Nitrosodimethylamine Restaurants, public places 0-240 ng N-Nitrosodiethylamine Restaurants, public places 0-200 ng Nicotine Public places 1-6 Lg Restaurants 3-10 pg Workrooms 1-13.8 pg Benzo(a)pyrene Restaurants, public places 3.3-23.4 ng SOURCE: Hoffmann and Hecht (1989). 91 OF é CH. N 3 NICOTINE et NN Wo lion] oor yo Ot NNA REDUCTION CHy N-NO or on on™ iso-NNAL WNAL N ANABASINE FIGURE 15.—Formation of tobacco-specific N-nitrosamines TABLE 10.—Tobacco-specific N-nitrosamines in U.S. smokeless tobacco (ppb) Product NNN NNK NAT NAB Loose leaf tobacco 670-8 ,200 (6°) 380(1) 2,300 (1) 140 (1) Plug tobacco 3,400-4,300 (3) Snuff—moist 3.120-135,000 (26) 100-13,600 (25) 1,340—339,000 (20) 10-6,700 (16) Snuff—dry 9000-52000 (3) 1, 800-13.000 (3) 18,000-38,000 (3) 60-60,000 (3) NOTE: NNN, N’-Nitrosonomicotine: NNK. 4-(methy!aitrosamino}- 1-(3-pyridyl)- | -butanone: NAT. N‘-nitrosoanatabine: NAB. N’-nitrosoanabasine. “Number in parentheses is the number of samples analyzed. SOURCE: Hoffmann and Hecht (1988). Toxicity and Carcinogenicity of Tobacco Smoke Undiluted tobacco smoke is too toxic to be tolerated by laboratory animals primari- ly because of the acute toxic effects of CO. CO in cigarette smoke increases with as- cending puff number from 2 to 5 volume percent (the average CO content of cigarette smoke is 3.5 to 4.5 volume percent). The acute toxicity of tobacco smoke is also due to HCN, nicotine. and volatile aldehydes. In vitro short-term exposure to cigarette smoke causes ciliastasis, an effect primarily attributable to HCN (300 to 500 Lg/cigarette) and volatile aldehydes (500 to 2.000 Lig/cigarette). The long-term expo- sure of laboratory animals to diluted cigarette smoke causes impairment of mucociliary clearance. mucus hypersecretion, and epithelial lesions. Cigarette smoke constituents responsible for this effect are both the gas phase, primarily HCN and volatile aldehydes. and the particulate phase (US DHEW 1979: US DHHS 1984). Long-term inhalation of diluted cigarette smoke by mice has resulted in adenomas and adenocarcinomas of the lung. whereas such inhalation in rats has only led to a few isolated tumors of the lung. In Syrian golden hamsters, long-term smoke inhalation studies have regularly induced benign and malignant tumors of the larynx and only a few lung tumors. These observations strongly suggest, and studies of particulate deposition and determination of carboxyhemoglobin (COHb) and nicotine-cotinine in the blood of the smoke-exposed animals have confirmed, that laboratory animals do not inhale the smoke deeply. Intratracheal instillation of cigarette tar and one of its fractions has resulted in lung tumors, including bronchogenic carcinomas (Mohr and Reznik 1978: Dalbey et al. 1980: US DHHS 1982). The particulate matter (more often called “tar”) suspended in organic solvents has in- duced carcinoma in the rat after subcutaneous injection and benign and malignant tumors in the skin of mice and rabbits after topical application, The major tumor in- itiators reside in the PAH-enriched neutral subfractions. whereas the tumor promoters and cocarcinogens are found in the weakly acidic fraction as well as in the polaric neutral subfraction (Wynder and Hoffmann 1967: Mohr and Reznik 1978: US DHHS 1982: Hoffmann and Hecht 1988). As discussed earlier, combined chemical—analytical studies have led to the identifica- tion of several organ-specific carcinogens in cigarette smoke. The diversity of these carcinogens and those identified as contact carcinogens may cause ambiguity as to which among them are most important. Table 11, which is based on extensive laboratory studies, lists the likely causative agents associated with the increased risk of cigarette smokers for cancer of the various organs (Hoffmann and Hecht 1988). Nicotine It is generally held that nicotine is the active pharmacologic agent in tobacco that determines the addictive behavior of the tobacco smoker (US DHHS 1988). Nicotine, together with CO, is also regarded as a major contributor to cigarette smokers’ increased risk of cardiovascular disease (US DHHS 1983. 1988). In addition to nicotine. tobac- co contains various other alkaloids, most of which are 3-pyridy] derivatives. In the blended U.S. cigarette. nicotine constitutes 85 to 95 percent of the total alkaloids. During the smoking of a nonfilter cigarette, about 15 percent of the nicotine appears in the MS, 35 to 40 percent appears in the SS, 15 to 20 percent is deposited in the butt, and the remainder is broken down into pyrolysis products. The major pyrolysis products of nicotine are CO, carbon dioxide, 3-vinylpyridine, 3-methylpyridine, pyridine, myosmine, and 2,3’-dipyridyl (US DHHS 1982). As discussed earlier. the absorption of nicotine from tobacco smoke is pH depend- ent. When tobacco smoke reaches the small airways and alveoli of the lung, nicotine is rapidly absorbed. In chewing tobacco and snuff with their alkaline pH, nicotine is primarily absorbed through the mucous membranes of the oral cavity. Nicotine enters the blood and is rapidly transported to the brain, which has specific receptor sites for 93 TABLE 11.—Likely causative agents for tobacco-related cancers Organ Initiator or carcinogen Enhancing agents Lung, larynx PAH Catechol (cocarcinogen) Weakly acidic tumor promoters NNK Acrolein, crotonaldehyde (?) Polonium-210 (minor factor), acetaldehyde, formaldehyde Esophagus NNN Pancreas NNK(?) Bladder 4-Aminobipheny] 2-Naphthylamine Oral cavity (smoking) PAH Ethanol NNK, NNN Oral cavity (snuff dipping) NNK, NNN Irritation (?) Herpes simplex (7) Polonium-210 NOTE: PAH, polynuclear aromatic hydrocarbons; NNK, 4-(methy|nitrosoamino)- | -(3-pyridyl)-1-butanone: NNN. N’-Nitrosonornicotine. SOURCE: Hoffmann and Hecht (1989), the drug. The effects of nicotine on the central nervous system are associated with the development of tobacco dependence (US DHHS 1988). Nicotine is metabolized primarily in the liver and, to a smaller extent, in the lung. About 10 to 15 percent of the absorbed nicotine is excreted unchanged in the urine. The primary metabolites of nicotine are cotinine and nicotine-N’-oxide. Cotinine is further metabolized extensively, with only 17 percent of it appearing unchanged in the urine (Benowitz 1986; Neurath et al. 1987; US DHHS 1988). Cotinine measurements in saliva, serum, or urine serve as an indicator for nicotine uptake by tobacco chewers, active smokers, and involuntary smokers. It takes 18 to 20 hr to eliminate one-half of the cotinine present in an active smoker through renal excretion; an involuntary smoker shows a considerably slower rate of elimination (Sepkovic, Haley, Hoffmann 1986; US DHHS 1988). Biological Markers Techniques for the determination of current and lifetime exposures to tobacco products include the examination of medical records and data from prospective and 94 case-control studies as well as the utilization of biological markers. The development of highly sensitive and reproducible methods has led to increased use of biological markers for uptake of tobacco smoke constituents. Table 12 lists those biochemical markers that are currently used to determine ex- posure to tobacco smoke components after active inhalation of MS and also after in- voluntary uptake of ETS. Some of these markers are also the basis for measuring the transfer of smoke constituents from the maternal bloodstream to a developing fetus. The tobacco-specific alkaloid nicotine and its major metabolite, cotinine, are most frequently used as serum and urine indicators of the uptake of tobacco smoke by active smokers and also to indicate ETS exposure in nonsmokers. Unlike CO, nicotine is not TABLE 12.—Biochemical markers for the uptake of tobacco smoke Smoke Biochemical , Critical constituent marker Substrate Method Sensitivity value Nicotine Nicotine Serum GC 1 ng/mL 0 Urine Serum RIA 0.2 ng/mL 0 Urine Cotinine Saliva Gc 5 ng/mL 0 Serum Urine Saliva RIA 1 ng/mL 0 Serum Urine Carbon monoxide COHb Blood Oximeter 40.1% 0.9 £0.7% (CO) co Exhaled Gc +1 ppm 5.6 $2.7 ppm air Hydrogen cyanide § Thiocyanate Saliva Autoanalyzer +5 pmol/L 100 pmol/L (HCN) (SCN) Serum (color Urine reaction) Nitrogen oxides Nitrosoproline Urine GC/TEA +0.4 pg/L 2.0 +1.5 (NOx) g/24 hours Ethylene Globin-adduct Blood GC tSpmol/gHb 58 +25 (CH2=CHz2) pmol/gHb 4-Aminobipheny] Globin-adduct Blood Gc ? <70 pe/gHb Tobacco-specific Globin-adduct Blood Gc ? hitrosamines Not established *Critical values, values measured in nonsmokers. SOURCE: Intemational Agency for Research on Cancer (1987). 95 only taken up by inhalation but also is absorbed through the mucous membranes in the oral cavity. Therefore, it is possible to determine user uptake of hydrophilic agents from chewing tobacco and snuff by means of nicotine—cotinine measurements. The analytical assessment of nicotine and cotinine in physiological fluids is done primarily by gas chromatography and radioimmunoassay (IARC 1986). Both methods are high- ly sensitive (between 0.2 and 5 ng/mL), and there is little or no interference by other smoke components. After environmental exposure, the average nicotine and cotinine levels in saliva, plasma, and urine of nonsmokers vary from 0.5 to 4.0 ug/mL, whereas the average amount of nicotine in the serum of cigarette smokers ranges from 15 to 40 ug/mL and lies between 500 and 2,000 pg/mL in saliva and urine. Cotinine concentra- tion varies from 150 to 350 g/mL in plasma, from 150 to 400 g/mL in saliva, and can go up to 2.000 pg/mL in urine (Jarvis et al. 1984; US DHHS 1988). In snuff dip- pers and tobacco chewers, plasma nicotine levels were found between 3 to 22 pe/mL and plasma cotinine was 200 to 400 ug/mL (US DHHS 1986). One of the oldest methods for estimating the inhalation of tobacco smoke is the deter- mination of COHb in blood. Since some CO is endogenously formed, the background values for COHb in the blood of nonsmokers without occupational exposure to CO range from 0.5 to 1.5 percent (National Research Council 1977). Smoking only a few cigarettes per day elevates COHb levels to 2.0 percent. In a study of men aged 34 to 64 years, cigarette smokers had average COHb concentrations of 4.7 percent, cigar smokers, 2.9 percent; and pipe smokers, 2.2 percent (Wald etal. 1981: Wald and Ritchie 1984). The COHb values of nonsmokers after ETS exposure do not markedly exceed 1.5 percent; thus, COHb cannot serve as an indicator of exposure to ETS (NRC 1986). Since CO is only slowly released from the blood in the process of exhaling, the smok- ing intensity of a cigarette smoker can also be assessed by the analysis of CO in the ex- haled breath. The critical value for CO, the value above that of a nonsmoker, is 5.6£2.7 ppm in exhaled breath; again this method is not applicable to the dosimetry of non- smoker ETS exposures. HCN, a major tobacco smoke constituent (>100 Hg/cigarette), is absorbed upon in- halation and is detoxified in the liver, yielding SCN~. Since SCN~ can also originate from dietary intake, only values above 100 mol of SCN~ per L of serum as measured for cigarette smokers are meaningful for dosimetry of uptake. In general, the average cigarette smoker has SCN” levels between 100 and 250 uUmol/L of serum (US DHHS 1987). A number of studies have clearly demonstrated that the mutagenic activity of the urine of cigarette smokers is higher than that of nonsmokers (IARC 1986). The most widely applied method for determining mutagenic activity of urine samples was developed by Yamasaki and Ames (1977), using a resin to concentrate the body fluid and, upon metabolic activation, measuring the mutagenic activity on bacterial tester strains TA98 and TA1538. In general, the urine of cigarette smokers exhibits at least twice the mutagenic activity of that measured in nonsmokers’ urine. In summary. there are several biochemical indicators that enable investigators to assay the uptake of tobacco smoke by individuals or by groups of individuals. Whereas analyses of exhaled CO, of COHb, and of SCN” and nicotine-cotinine in saliva, serum, and urine are well suited for determining the smoking intensity of an active smoker, 96 only nicotine and cotinine determinations in serum and urine can also serve as indicators for the exposure of nonsmokers to ETS. Summary The 1964 Surgeon General's Report was a landmark study that reviewed and assessed the available epidemiologic. clinical, pathological, and experimental literature for evidence linking cigarette smoking to disease. The principal findings of that Report are summarized in Table 13. In men, cigarette smoking was found to increase overall mortality and to cause lung and laryngeal cancer. Several other important conclusions were also drawn (Table 13). Since 1964, 20 reports of the Surgeon General (including this Report) have been released on tobacco and health that substantiate and strengthen the original conclusions of the 1964 Report. These reports have also established associations between smoking and disease in areas for which data did not exist, shed light on pathogenetic mechanisms of tobacco-related disease, and added scientific depth to areas mentioned only briefly in the 1964 Report. A review of Table 13 allows the reader to survey quickly the state of knowledge on cigarette smoking and health in 1989 and to compare it with what was known in 1964. Of the 27 principal effects presented in Table 13. 13 were first noted in 1964, among those 13 effects, many have been strengthened since 1964. Recent reports of the Sur- geon General have also covered important topics not even mentioned in the 1964 Report. For example, these reports have concluded that involuntary smoking can cause disease, including lung cancer. in healthy nonsmokers and that smokeless tobacco can cause oral cancer. The most recent Surgeon General's Report also concluded that the use of cigarettes and other forms of tobacco is addicting (US DHHS 1988). Much progress has been made in understanding the physicochemical nature of tobac- co smoke. Today, the estimated number of compounds in tobacco smoke exceeds 4,000, including some that are pharmacologically active, toxic, mutagenic, or car- cinogenic. The diverse biological effects of tobacco smoke constituents provide a framework for understanding the multiple adverse consequences of smoking. For ex- ample, the identification of 43 different carcinogenic substances in tobacco smoke helps explain why cigarette smoking can cause cancer at different sites including the lung, larynx, oral cavity. and esophagus: why cigarette smoking is a contributory factor for the development of cancer at different sites including the bladder, kidney, and pancreas, and why cigarette smoking is associated with cancer of the stomach and uterine cervix. The central role of cigarette smoking as a massive. preventable personal and public health problem can now be better appreciated. In the United States, it is a major cause of CHD. this country’s most common cause of death; cigarette smoking is estimated to account for 2] percent of all CHD deaths. Cigarette smoking is the major cause of lung cancer, the most common cause of cancer death in the United States: smoking ts es- timated to account for 87 percent of lung cancer deaths and 30 percent of all cancer deaths. While lung cancer death rates for women who are nonsmokers have not in- creased since the early 1960s, comparable death rates for women who smoke cigarettes have increased more than fourfold. In 1986, lung cancer and breast cancer were the 97 86 TABLE 13.—Summary of the principal effects of cigarette smoking Effect first discussed in Surgeon General's Reports Mortality and morbidity Overall mortality, increased in men Overall morbidity, increased Cardiovascular CHD, mortality increased in men Cerebrovascular disease (stroke), mortality increased Atherosclerotic aortic aneurysm, mortality increased Atherosclerotic peripheral vascular disease, risk factor Cancer Lung cancer, the major cause in men Laryngeal cancer, a cause in men Oral cancer (lip), a cause (pipe smoking) Esophageal cancer, associated with Bladder cancer, associated with Pancreatic cancer, increased mortality Renal cancer, increased mortality Gastric cancer, associated with Cervical cancer, possible association with Year first discussed in a Surgeon General’s Report 1964 1967 1964 1964 1967 1971 1964 1964 1964 1964 1964 1967 1968 1982 1982 Current knowledge in 1989 Overall mortality increased in men and women Overall morbidity increased A major cause of coronary heart disease in men and women A cause of cerebrovascular disease (stroke) Increased mortality from atherosclerotic aortic aneurysm A cause and most important risk factor for atherosclerotic peripheral vascular disease The major cause of lung cancer in men and women The major cause of laryngeal cancer in men and women A major cause of cancer of the oral cavity (lip, tongue, mouth, pharynx) A major cause of esophageal cancer A contributory factor for bladder cancer A contributory factor for pancreatic cancer A contributory factor for renal cancer An association with gastric cancer An association with cervical cancer 66 TABLE 13.—Continued Effect first discussed in Surgeon General’s Reports Year first discussed in a Surgeon General's Report Current knowledge in 1989 Pulmonary Chronic bronchitis, the major cause Emphysema, increased mortality Women Low-birthweight babies, associated with Unsuccessful pregnancy, associated with Other effects Tobacco habit, related to psychological and social drives Involuntary smoking, irritant effect Peptic ulcer disease, associated with Occupational interactions, adverse Alcohol interactions, adverse Drug interactions, adverse Nonmalignant oral disease, associated with Smokeless tobacco, associated with oral cancer 1964 1964 1964 1980 1964 1972 1964 1971 1971 1979 1969 1979 The major cause of chronic bronchitis The major cause of emphysema A cause of intrauterine growth retardation A probable cause of unsuccessful pregnancies Cigarette smoking and other forms of tobacco use are addicting A cause of disease, including lung cancer, in healthy nonsmokers A probable cause of peptic ulcer disease - Adverse occupational interactions that increase the risk of cancer Adverse interactions with alcohol that increase the risk of cancer Adverse drug interactions An association with nonmalignant oral disease Smokeless tobacco is a cause of oral cancer leading causes of cancer death in U.S. women, accounting for approximately equal numbers of cancer deaths. Cigarette smoking is the major cause of COPD, an effect that far outweighs all other factors: smoking is estimated to account for 82 percent of COPD deaths. (See Chapter 3.) The 1964 Report of the Surgeon General stated that death rates from cerebrovascular disease (stroke) were increased in cigarette smokers compared with nonsmokers, but it drew no conclusions concerning causality. In the current 1989 Report, for the first time, cigarette smoking is cited as a cause of stroke. the third most common cause of death in the United States. Stopping smoking reduces the risk of stroke, The effect of smoking on pregnancy was briefly mentioned in the 1964 Report. Many studies have subsequently shown that cigarette smoking causes fetal growth retarda- tion and is a probable cause of unsuccessful pregnancies. Table 13 summarizes other important smoking associations with several diseases, in- cluding atherosclerotic aortic aneurysm, atherosclerotic peripheral vascular disease, and peptic ulcer disease: it also includes occupational and alcohol-related interactions with smoking that increase the risk of cancer. Finally, the reports of the Surgeon General have emphasized the benefits of quitting tor smokers of all ages. CONCLUSIONS Part I. Health Consequences 1. The 1964 Surgeon General's Report concluded that cigarette smoking increases overall mortality in men, causes lung and laryngeal cancer in men, and causes chronic bronchitis. The Report also found significant associations between smok- ing and numerous other diseases. 2. Reports of the Surgeon General since 1964 have concluded that smoking increases mortality and morbidity in both men and women. Disease associations identified as causal since 1964 include coronary heart disease, atherosclerotic peripheral vascular disease, lung and laryngeal cancer in women, oral cancer, esophageal cancer, chronic obstructive pulmonary disease, intrauterine growth retardation, and low-birthweight babies. 3. Cigarette smoking is now considered to be a probable cause of unsuccessful preg- nancies, increased infant mortality, and peptic ulcer disease; to be a contributing factor for cancer of the bladder. pancreas, and kidney: and to be associated with cancer of the stomach. 4. Accumulating research has elucidated the interaction effects of cigarette smoking with certain occupational exposures to increase the risk of cancer, with alcohol ingestion to increase the risk of cancer, and with selected medications to produce adverse effects. 5. A decade ago, the 1979 Report of the Surgeon General found smokeless tobacco to be associated with oral cancer, In 1986, the Surgeon General concluded that smokeless tobacco was a cause of this disease.