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i ~use for report: ibel W. ~acher,, wncx S. dildred CHAPTER 1i I ntroduction and Summary

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INTRODUCTION AND SUMMARY Cigarette: smoking continues to be a major health problem in the: Unitedi States today. It is still too early to tell whether the increas- ing rate of'giving; up smoking by adults during the years 19'67; 1968„ 1969; and early 1970 and the plateauing, of this effect during the past year have had any: measurable effect, on the morbidity: and' rnortalit'y associated with smoking. At the same time that the majorr health professions, voluntary health agencies, and public service agencies concernedl have joined with governmentagencies to reduce the magnitude of this problem through education,, research efforts devoted to understanding, how cigarette smoking affects biological function to produce disease continue at a high levell. This report is largely concerned with reviewing, the research re- ports which have become availablie in the past year. In this chapter; brief summary statements are presented of the state of'knowledg.e in severall areas. These are followed,, where appropriate, by a"high, light" statement of significant ad'ditions to knowledge made as a result of the new research presented in greater detail in the~ body of the report. The state of knowledge! in three areas;, whichi have not been re+ viewed previously, is also presented in the report. These areas are:. Allergy, Public Exposure to Ai'r Pollution from Tobaceo Smoke, and'the Harmful Constituents of Cigarette Sinoke: SUMMARY : CORONARY HEART DISEASE. Cigarette smokers have higher death, rates from coronary heart disease (CHD) than nonsmokers.. This relationship is stronger for men than women. Cigarette smoking markedly increases ani individ- ual's susceptibility to earlier death from CHD'. Cigarette smoking,, hypertension, and elevated serum cholesterol are major risk factors contributing to the development of CHD ; cigarette smoking acts both independently and conjointly with these other factors to in- crease the risk of' developing CHD. Cigarette smoking may con- tribute both to the development of CHD and to the exacerbation of preexistent CHD ;, both nicotine and carbon monoxide are thought to~ contribute to these abnormal processes. Cigarette smoking is associated with a significant increase in atherosclerosis of the aorta. i

and' coronary arteries. Cessation of smoking is associated with a decreased risk of death from CHiD. The risk of CHD~ incurred by pipe and cigar smokers is appreciably less than that incurred by cigarette smokers. FilTighl'2ghtsof' 1~972 ' Report: Coronarg, Heart Disease 1. Recent epidemiological! studies from severall countries confirm that cigarette smoking, is one of' the major risk factors con- tributing,tothe!developmentof'CHD: Avoidance of cigarettesmoking is of importance iln the primary prevention of CHiD. 2: Studies in man and animals have shown a greater myocardial arteriole walli thickness in smokers than nonsmokers: 3. Experimental and epidemiological investigations implicate the elevationi of carboxyhemoglobin levels in smokers as a contributor to the develbpment of CHD and arteriosclerotic peripheral vascular disease., 4: Cigarette smoking, is considered to be the major cause of' pul- monary heart disease (cor pulmonale) in the United States in that it is the most important cause of chronic non-neoplastic bronchopulmonary diseases. Avoidance of cigarette smoking, is of importance in the primary prevention of pu'1i.nonary heart disease. SUIVIIVIARY : CEREBROVASCULAR DISEASE' Cigarette smokers have higher death rates from cerebrovascular disease than nonsmokers. SUMIVIARY : NONSYPHILITIC AORTI.C' ANIEURYSM* Cigarette smokers have higher death rates from nonsyphilitic aortic aneurysm than nonsmokers. SUMIVTARY: PERIPHERAL VASCULAR DISEASE Cigarette smoking is a likely risk factor in the development of peripheral vascular disease. Cigarette smoking appears to aggravate preexistent peripheral vascular'disease. •Thissummarysdatement~ is the samee as that.appearing.inprevious.t reports,, because neww studies adding,to the understanding of'this.area.have not'appearedi.Consequently, the Iiteraturein this area is not reviewedland the statementl is only, included to complete this summary chapter. 10 ~. 21 ~ ob 0

fated with a incurred' by ,incurred'by tease j ries confirm factors con- of cigarette ion of CHD.. h myocardial ers: ? is implicate nokers as a eriosclerotic ;ause of pul- ~ed States in p-neoplastic jtte smoking ! pulmonary brovascular SUMIVIARY :: NON-NEOPLASTIC BRONCHiOPUIl.IVIONARY DISEASES Cigarette smoking is.the most important cause of'chronic obstruc- tive bronchopulmonary disease (COPD) in the United States. Ciga- rette smokers have higher death rates from pulmonary emphysema and chronic bronchitis and more frequently have impaired pul- monary function and pulmonary symptoms than nonsmokers:, Ex- cigarette smokers have lower death rates from, COPD, than do con- tinuing smokers. Cessation of smoking is associat'ed! with improved ventilatory function and decreased pulmonary symptom prevalence.. For most of the Unitedi States population, cigarette smoking is a more important cause of COPD1 than, air pollution or occupational exposure; cigarette smoking may also act conjointly with occupa, tional or environmental exposure to produce greater COPD mor- bidity and mortality. An infrequent genetic: error,, homozygous alpha,-antitrypsin, deficiency,, has beeni commonly associ~atedl with the early development of severe, panacinar emphysema. Whether or, not cigarette smoking acts together with the i- -1mozygous or hetero- zygous deficiency states to increase the risk, of developing either panacinar emphysema or the more common forms af COPD, has not been adequately studied. Cigarettie smoking, exerts an, adverset effect on the pulmonary clearance mechanism. Respiratory infec- tions are more prevalent and severe, among cigarette smokers,, par- ticuIarly among heavy smokers; than among nonsmokers. The risk of developing or dying from COPD among pipe or cigar smokers is probably higher than that among, nonsmokers: but is clearly less& than that among cigarette smokers. Flighl'ights of'the 1972' Reportr 1'Non-rueoplicstic Bronchopulmonary Diseases L. Recent epidemiological and clinical studies, from several CRYSiVI* nonsyphilitic 2. EASE relopment of 3'. to aggravate 4. rts, because new tly,, the literature . ummary cHapter., countries confirmt'hat rnen~and women cigarette smokers have an increased prevalence of respiratory symptoms and have diminished pulmonary function compared~ to~ nonsrnokers.. Investigations of high school students have demonstrated that abnorrnaii pulmonary function and pulmonary symptorns are more common in smokers than nonsmokers., Recent occupationall studies confirm that cigarette smoking is an important cause of, COPD; acting both~ independently andd in: combination with occupationali exposure.. Recent experimentall studies confirm t'hat cigarette smoking exerts an adverse effect, on pulmonary clearance and macro- phage function. 3 4 b

5, Pulmonary macrophages obtained frorn cigarette smokers ex- hibit characteristic rnorphologic differences when compared to those obtainedi from nonsmokers: SUMIVIARY : CANCER ~ II Cigarette smoking,i's the major cause of lung cancer in men andla6 significant cause of lung, cancer inwomen. The risk of developing f lung cancer in both men and women is directly related to an individ- ual's exposure as measured by: the number of cigarettes smoked, ' duration of smoking, earlier initiation, depth, of'inhalat'ion, and the i` amount of "tar" produced by the cigarette. The risk of developing !i lung, cancer diminishes with cessation of srnoking., Smokers of pipes ': or cigars have a lower risk of developing lung cancer than cigarette i' smokers. Certain occupations are associated' with an increased risk of developing lung cancer. In these occupatianal settings cigarette smoking, appears& to exert an effect that produces much higher lung cancer rates than those resulting, either fromi the occupational ex- , posure alone or from smoking alone. Factors associated with urban living result in an, increase in the risk of' developing lung cancer;~ this effect, however, is minor compared to, the overriding effect of cigarette srnoking,The smoking of cigarettes, pipes, and cigars is a significant factor in the development of cancers of'the larynx andl oral cavity., Pipe smoking, is causally relatledl to cancer of the lip. The significant asso- ciatilon between smoking and the development of cancer of the esophagus i'ssornewhat stronger for ci'gar.ettes than forpipe& oreigars andl the combined~ exposure to alcohol and cigarettes is asso- ciated with especially high rates of cancer of the esophagus. Ciga- rette smoking, is associated with cancer of the urinary bladder in menL There is also an association between cigarette smoking andd cancer of the pancreas. Hiyhlights of'the 1972 Report: Cancer 1. Preliminary result's from a major prospective epidemioJogicall study in Japan demonstrate a st'rong,association between, cig- arette smoking and lung cancer.A dose-response relationship, was demonstrated for the number of cigarettes smoked. These findings in an Asian population withi distinct genetic and cul- tural characteristics confirm the: major importance of' ciga- rette smoking in the causation of lung cancer, ai conclusion which up to now has been based largely on studies of Cauca-0 siani populations in the United States, Canada„ and! Europe. I , 4 r~ WR ~ ~ ~

2.Ex-srnokers have significantly lower death rates for lung can- cer than continuing smokers. The decline in risk following cessation appears to be rapid both for those who have smoked for long, periods of time andl for those with a shorter smoking hsstory,, withi the sharpest reductions taking place after the 3. en andla Ueloping individ smoked, , ; and thee veloping, . of pipes ;igarett'e lsed risk °igarette her lung 'lonal ex- Gh urban cancer; . effect of it factor 6. iy. Pipe unt asso- r of the 1pesoris asso- . s. Ciga- dder inn ting and iiolbgical Veen cig- t,tionship 4 These and cul of ciga- clusion Cauca- urope. first two years of cessation. The risk of developing, lung, cancer appears to be, higher for smokers who have chronic bronchitis. Though both conditions are directly related to the: amount and duration of smoking, an additional risk: for lung cancer appears to exist for ciga- rette smokers with chronic bronchitis which is independent of' age and'r number of cigarettes consumed. Experimental stud'ies on animals have demonstratedl that the particulate phase of tobacco smoke contains certain chemical compounds which can act as complete earcinogens, tumor initiators, or tumor promot'ers.Recently, other compounds have been described that have no i'ndependent activity in two- stage carcinogenesis but accelerate the carcinogenic effects of polynuclear aromatic hydrocarbons in the initiator-promoter system. Additionall epidemiological evidence confirms a significant as- sociation between the combined use of cigarettes andl alcohol, and cancer of the esophagus. Epidemiological studies,have demonstrated a significant asso- ciation between cigarette smoking and cancer of the urinary bladdsr, in both men and women. These studies demonstrate that the risk of developing: bladder cancer increases with in- halat'ion~ and the number of' cigarettes smoked. Epidemiological evidence demonstrates a significant associa- tion between cigarette smoking , and cancer of the paner.eas., S'UMiMARY : PREGNANCY Maternal smoking during pregnancy exerts a retarding influence on fetal growth as manifested by decreased infant birth weight andd an increased incidence of prematurity, defined by weight.. There isi increasing evidence to support, the view that women who smoke. during pregnancy have a significantly greater risk of an unsuccess- ful pregnancy than those who db not. SUiIIMARY~: GASTROINTESTINAL D~ISGRDE~~R& Cigarette smoking males have an increased prevalence of peptic ulcer disease as compared to nonsmoking rnales and a greater peptic

ulcer mortallity ratio. These relationships are stronger for gastric ulcer than for duodenal ulcer. Smoking appears to reduce the effec- tiveness of standard peptic ulcer treatment and to slbw the rate of ulcer healing. Highlights of the 1972' Report: Ga,strointestinr,cl Disorders 1. A possible link between cigarette smoking, and peptic ulcer has been demonstrated in dbgs in which nicotine was found to inhibit pancreatic and hepatic bicarbonate secretion. This could lead to peptic disease by depriving the duodenum of sufficient alkaline secretion to neutralize gastric acidity. 2. Ani investigation in human volunteers has suggested that cig= arette smoking decreases the effectiveness of the lower- esophageal sphincter as a barrier against gastro-esophageal reflux.. SUIVIMARY : TOBACCO AMBLYOPIA* Tobacco amblyopia is presently a, rare disorder in the United. States. The evidence suggests that this disorder, iis related to nutri- tional or idiopathic deficiencies in certain detoxification mecha- nisms, particularly in the rnetabolism, of the cyanide component of tobacco smoke. SUMMARY: NON-NEOPLASTIC ORAL DISEASE* Ulceromembranous gingivitis, alveolar bone loss, and stomatitis nicotina are more commonly found among smokers than among nonsmokers, The influence of smoking, on periodontal disease andd gingivitis probably operates ini conjunction with poor oral hygiene.. In addition, there is evidence that smoking may be associated with edentulismi and delayed socket healing. While further experimental and clinical studies are indicated, it wouldl appear that nonsmokers have an advantage over smokers in terms of't'heir oral health. The information contained in the follo2cing three summarg state_ ments: Allergy, Public Exposure to Air Pollution from Tobacco Smoke, and Harmful Constituents o f Cigarette Smoke, is ne2v and appears for the first time. • This summaryy statementt is the samease that appearingg in previous reports, because new stNdies.addingtotheunderstandingofthis;area have not appeared. Consequently;.ttieliterature, in this area.is.not reviewed and the statement.isonlyincludedto~complete this summarychapter.y b F 4..~

~ gastric he effec- ~'rateof lers ~ic ulcer found to pn. This enum of 4:that cig- ~ lower- Pphageal. e United ; to nut'ri- ~ mecha~- ~onent of I 9E* Etomatitis ~ among ~Iease and Jhygiene. [ated with jerimental insrnokers ealth. uxry state- ~t Tobacco s nezv and 1I because new the literature mary, cbaPter. SUMMARY OF' THE' 1'972' REPORT : ALLERGY 1. Tobacco leaf, tobacco pollen„ and tobacco smoke are antigenic in man andl anincrals, 2. (a) ~ Skin sensitizing, antibodies specific for tobacco antigens have been found frequently in smokers and nonsmokers. They appear to occur more often in allergic individuals. Precipitating antibodies specific for tobacco antigens have also been found in both smokers and nonsmokers:, (b) A delayed type of hypersensitivity to tobacco has been demonstrated in man. (ic) ' Tobacco may exert an adverse effect on protective mech- anisms of'the : immune ! system~ in manand animals.3'. (a): Tobacco smoke can, contribute to the discomfort of many individuals. Itexerts complex pharmacologic, irritative, and allergic effects, the clinical manifestations of which may be indistinguishable from one another. (b) Exposure to tobacco smoke may produce exacerbation of allergic symptoms in nonsmokers who are suffering from allergies of' diverse causes. 4. Lit't'le is known about the pathogenesis of tobacco allergy and its possible relationship to other smoking-related diseases. ;SUMMARY OF THE 1972 REPORT: PUBLIC EXPOiSURE TO AIR POLLUTION FROM TOBACCO SMOKE , 1. An atmosphere contaminated withi tobacco smoke can con- tribute to ithe discomfort of many individuals. 2.. The level of carbon monoxide attained in experiments using rooms filled with tobacco smoke has been shown to equal„ and! at times to, exceed, the legal' limits for maximum air pollution permitted for ambient air quality in several localities and can also exceed the occupationali Tlireshold Lianit Value for a nor= mall work period presently in, effect for the United States as a whole. The presence of suchi levels indicates that the effect of exposure to carbon monoxide rnay: on occasion, dependh'ng, upon the length of exposure, be sufficient to be harmful to the health of an exposed person. This would be particularly sig- nificant for people who are already suffering, from chronic bronchopulmonary disease and coronary heart disease., 3, Other components of tobacco smoke, such as particulate mat- ter andl the oxides of nitrogen, have been shown in various 7

concentrations to affect adversely animal pulmonary and cardiac structure and functiom The extent of the contribu- tions of these substances: to illness in humans exposed to the concentrations present in an atmosphere contarninatedl with tobacco smoke is not presently known., SUMMARY OF THE 1972' REPORT: HARMFUL CONSTITUENTS OF CIGARETTE SIVIOKE' A number of substances or classes of substances found in ciga- rette smoke are identified as those which are judged to be con- tributors to the health hazards,of'srnoking. These constituents are further divided into the most likely contributors to these health hazards (carbon monoxide, nicotine, and tobacca "'tar'''), sub- stances which are probable contributors„ and those which are sus- pected contributors. The recommendations for controli in this area are to seek progressive reduction of all harmful constituents in cigarette smoke with priority being given first to the most likely contributors named and second to the.probable contributors, to the health hazards of smoking. Th.ese~ judgments represent the consen- sus of experts based on current knowledge and are subject to modi- fication and further elaboration as more knowledge becomes available. 8

~ionary and ~e contribu, posed to the inated with SMOKE and in ciga- I to be con- tituents are fiese health tar'''), su' ach are sus Xn this are stituents i. , most 1ike1 utors to th I the consen ect to modi. ~e become I CHAPTER 2 Cardiovascuil6r Diseases

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/ Contents Page Coronary Heart Disease Introdhzction ................................... 13' Epidemiological Studies ..... . ........... . ........ 14. Interaction of Smoking, and Other Risk Factor& ....... 16 Autopsy Studies ................................ ]i9 Experimental Studies .............. . .... . ...... . . Nicotine and Cigarette Smoke .............. . .. Carbon Monoxide ............................ Stnoking and Thrombosis .................... Cholesterol Content of Tobacco and Tobacco Smoke: Cor P~ulmonale (Pulmonary Heart Disease)~ . . ........... Cerebrovascular Disease ................................... , Peripheral Vascular Disease . . . ......................... Oral Cbnt'raceptives, Thrombophlebitis„ and Srnoking....... Highlights of Current Cardiovascular Information . ........ References ............................. LIST OF TABLES Table 1.-Incidence (1963-1970) of heart infarct in relationn to tobacco consumption, ini "'The Men Born in 1913,,' Goteborg,Sweden ...................................... Table 2'. Cigarette smoking at entry and'subseqnent 20-year CI-IiD incidence, among Minnesota men .................. Table 3.-Human autopsy study. Comparison of the thick- ness of' myocardial arteriole walls in smokers andl non- smokers ................................................ Table 4.-Average values of carboxyhemoglobin and serum cholesterol in Danish smokers and nonsmokers in control group and'l gxoup, of patients with arteriosclerotic cardio- vaseular disease .......................................... 21 21 21 23 24 24 24. 25 26' 27 27 15 15 19 23 0 ~. 1 Y 4+ V C~^~ W I

LIST OF FIG'[JItLS' ii L Page Figure 1..-C'anihe autopsy study. Comparison of the thick- ness of myocardial arteriole walls in 32 smoking dogs killed after 875 days and 8 nonsrnoking, dogs ........... 20 . 12 00w

ek- )gs Page 20 IhTTRO!DUCTIION In the United States more people die from coronary heart disease (CHD)'~ than from any other disease; furthermore; CHD is the single most important cause of excess death among cigarette smokers (54, 57). The 1'9'71 report, "The Health Consequences of Smoking" (56) , outlined the growing magnitude of t'his problem and summarized the relationship between smoking and coronary heart disease as follows : 1. Data from numerous prospective and retrospective studies confirm the j udgment that cigarette smoking is a sigmsficant risk factor contributiilg to the development of coronary heart disease including fatall CHD' and its most severe expression, sudden and unexpected death. The risk of CHD incurred by smokers of pipes and cigars is appreciably less than that by cigarette smokers, 2. Analysis of' other factors 'associated with CHD (high serum cholesterol, high blood pressure, andl physical inactivity) shows that cigarette smoking operates independently of these other factors and can act Jointly with cert,'ain of them to in- crease the risk of CHD appreciably. 3. There is evidence that cigarette smoking may accelerate the pathophysiological changes of pre-existing, coronary heart disease and't'herefore contributes to: sudden death from CHD. 4. Autopsy studies suggest that cigarette smoking is: associated w ith a significant increase in atherosclerosis of the aorta, and coronary arteries. 5: The: cessation of smoking is associated with a decreasedi risk of death from CHD. 6'. Experimental studies in animals and' humans suggest that cigarette smoking may contribute to the development of CHD: and/or its manifestations by one or more of the followTingg rnechanisrns : a. Cigarette smoking, by: contributing to the release of cat'echolamines, causes increased myocardial wall tension, cont'ractioni velocity, and heart rate, and thereby increases the work of' the heart and the myocardial demand for oxygen and other nutrients. 1'3

b. Among individuals with coronary atherosclerosiis; ci~ga- retite smoking, appears to create an imbalance bet'ween, the increased needs of the myocardium and an insufficient in- crease ini coronary blood flow and oxygenation. c. Carboxyhemogl'obin, formed from the inhaled carbonn monoxide, diminishes the availability of oxygen to ~the myo- cardium and rnay: also contribute to the development of atherosclerosis. d. The impairment of pulmonary function caused by cigarette smoking may contribute to arterial hypoxernia, thus reduc- ing, the amount of oxygen available to the myocardium.e.. Cigarette smoking may cause an increase in platelet adhe- siveness which might contribute to acute thrombus for- mation. Recent epidemiological, pathological, and experimental studies add to the understanding of the relationship between smoking and, CHD. These studies point to cigarette smoking as one of the major risk: factors leading to CHD and help, clarify some of the biomech- anisms through which t'his occurs. EPIDiE1VDI0'1LOGTCAL STUDIES A prospective study of 973' men born in 1913 in Goteborg,. Swed~ens was, undertaken in 1963~ (51, 52) ~. The proportion of myo- cardial infarctions among cigarette smokers was sigpRficantly greater than among nonsmokers (P <.05)', and the incidence of myoeardial infarction rose: with increasing cigarette consumption (tab1E! U. afthe 35indivildu~alswho experienced a myocardial in- farction between 1963' and 1970, only two, had been nonsmokers ; in the whole population of: men borni in 1913, 56 percent were smokers. Although angina pectoris was more common in smokers than nonsmokers, the difference was smaller than for myocardial in.- farction and was not statistically significant (52) 1. Paffenbarger, et al. (.42) reported on the health experience of. 3,263 longshoremen st'udied' over the past 18 years. During this in- terval 1,098 were known to have died, 350 dying from CHD'. Long- shoremen who smoked more than 20 cigarettes a day faced al risk of coronary death which was more than twice as great as that of: the group:made up of both nonsmokers and smokers of less than 20 cigarettes a day ( P' < .0i1)' . Keys, et al. (30) analyzed the 20-year CHD incidence among 279 Minnesota, men aged 47 through 57 years who were CI-ID free at entry into the study. The relationship of cigarette smoking habits at the start of'the study to the subsequent incidence of CHD was examined. The originally: published' table of results was incorrect 14

i. sis, ciga- ~ween the Ficient in, : i I carbon i the myo- pment of cigarette us reduc- rdium. ~let adhe- ' abus for- t1 studies oking, and he major biomech~- Goteborg, ' k of'myo- nificantlly idence of Isumption ardiall in.- kokers ; in j smokers. • ~ers than ardial in- I E"rience of ug this in- ~D: Long- : eed a risk m that of is than 200 mong 27'9I Dfree at ng habits CHD was incorrectt and the authors have supplied a corrected table which appeared in a later issue of the', same jaurnal (table 2). The morbildity! ratio for "'hard CHD"' (CHD deaths pius myocardial infarctions not resulting in death) among those smoking more than ]0 cigarettes a TABLE 1.-Incidence (1963-1'9?'n)~ of' heart infarct in relation to tobacco cons2urnpt'ion in ".T'he Men Born in 1913," Goteborg; Siveden.n = 855 clAssification Sinoking Heart infarct Never smoked n= 207 Stlopped' smoking n=168' Cigarette smokers 1-14 cig/day n = 234 15-24!cig/day n = 138 ?2'5cig/,day n=33 Pipe/cigar n=75' Number Percent ( 2') 1.00 ( 2'), 1.00 (13) 6~0 ( 9) 7:0 ( 4) 1i2:0 (,5) 7A SOURCE:: 'Eibblin, G., Wilhelmsen, L, (51).. TABLE 2.-Cigarette smoking at entry and'subsequent' 20-year CHD incidence : among Minnesota men.l Iwl~umber. Smoking~habit (cigarettes/day)~. A'gee of'men~ Item Never~ Stopped. C1A. 10~-19~ }20~. 47,48 53 % with, habit 23' 19 9 19 30 49,50 51 % with habit 33 20 14 10 23 51,52 69 % with habit 33' 26I 14 14 13. 53„54 53' % with habit 36 30 8 13 13. 55-57 51 % with habitl 24 33' 8 18 17 47-57 277 Number of'men 83 71 30 41 52' 47-57 277 Hard CHD rate (~c)' 12.0 15.5 10:0 17.1 21.2' 47-57 277 Hard CHD rate (SE) ± 3.6 + 4.3' ± 5.5 ± 5.9 ± 5:7 47-57 277 Hard CHD Morbidity Ratio 1.00 1,29 .83' 1.43' 1'.77. -17-57' 277' .!Y11 CHD:rat'e (~lo) ±2r.7 ±21.1 ±16.7' ±19.5 ±26.9' -17-57' 277, All CHD rate (SE) ± 4l5 ± 4.8 ± 6.8' ± 612' ± 6.1 47-57 277: All CHD1 Morbidity,Ratlio 1.00 .97: .77 .90 1.24 t Cigarette, smoking habits~, by~age~at.start of'the~.20-year~follaw-up~„ 20-year~..incidence rates (per.100 men)~.,,and.st'andardlerrors (SE)', of thexates.,"Hard CEID"-CHD death~and~h myocardiali infa~reta,. "All1'~-angina pectoris and other CH~.D~D diagnoses.. "Deaths"-from all causea except~ I ~i6lence:. SOURCE: Modified from Keys, A.,,et al., (i30). 15. GJ

day is similar to that reported from the large prospective studies. However, with the small number of cases in each smoking, cat'egc,ry,, there are no statistically significant differences in the incidence of CHD between the categories, either singly or combined!. Retrospective studies of CHD have recently been reportedi fromi Czechoslbvakia, Sweden, Norway,, and India which, corroborate earlier studies linking cigarette: smoking with excess CHD morbid- ity and mortality. The Prague study (19) included 443 men between the ages of 600 and 64 years. Significantly more (P <.05) ) individuals with a. "probable" myocardiali infarction were found among, cigarette smokers than among nonsmokers or pipe and cigar smokers. The smoking habits of 120 patients with myocardial infarctionn who were hospitalized in Gateborg were compared with those of thee entire "men born in 197 3" population sampUe (17, 62). A signif- icantliy (P <.01)~ greater number of smokers and heavy smokers (more t'han 15 cigarettes & day) were found in the myocardial in- farct'ioni group than in tlie population sample., The Bergen, Norway, cross: sectional study of 2,117 women and 2,472 men documented a relationship between smoking and CHD1im men, which was most marked in the 5'0' to 59'. year old age group (16). No effect of smoking, on the prevalence of CHD' in women was demonstrable in this study, and the effect in men did not appear to be related to the daily number of cigarettes smoked. In! New Delhi, 100 "well 'documented" cases of ischemic heartt disease were compared with an equal number of control cases (8)',.. In this study, significantly rnore ( P' <.01) of the case group smoked cigarettes regularly than the control group, (1WTorbidity Ratio = 2.1) . Mu1'cahy,et al. (40) recently foundla positive associatibn between coronary heart disease mortality rate and calculated per capita cig- arette consumption in 21 countries. He interpreted the results as being, consistent with the hypothesis that cigarette smoking is a significant risk factor in CHD': mortality. Stamler, et al. (50) found that for both men and women the 1964 CHD mortality rates in 17 7 developed countries were.related to aver- age annual per capital cigarette consumption. INTERA:CTION OF SMOKING AND! OTHER RISK FACTORS The Report of'the Inter-Society Commission for Heart Disease Resources summarized the evidence indicating that three risk fac- tors (hypercholesterolemia, hypertension, and cigarette smoking) are properly designated major risk factors for premature CHD (,28)i. Other possible risk factors including, obesity,, physical inac- tivity, diabetes mellitus, elevated resting heart rate, electrocardio- i W ,6

ludies:. egory, nce of G from )orate orbid.- ~of60' 7ith a Iarette I irction of the ,ignsf- aokers ial in- mi and HDin group !n was ~ppear i heart s (8). moked. = 2.1). Aween ta cig:- ults as. lg, is a .e 1964 3 aver- TORS )isease ;k fac- Aimg') I CHD' L inac- tardio- graphicabnormalities, a positive family historyof'premature CHD, ; ~1d psycholbgic and social factors have also been, described (54, 55,56) . in the study of 973 men born in 1913! in Goteborg, Sweden, sev- eral coronary risk factors including elevated serum, chol'esterol;, ele- vatedl serum triglyceride, low physical' activity at work,, and' smok- ing were found tobe related to an increased risk for the development of coronary heart disease during the subsequent years of'the study. Failure to find a relationship between hypertension andl an, in- creased risk of CHD may have been due to the fact that all patients -,Vithi hypertension in 19!63' have been under treatment since thatt tiihue~ Tibbliniand Wilhelmsen (52)' found!that as:a patient accumulated more risk factors his chance of' developing, CHD1 became substan- tially greater. Werko (61)' reportedl from the same GReborg study that patients who were smokers; had sedentary jobs, and had both tlevatedicholesterol and triglycerides experienced a 4-year incidence ofrsew coronaryevents: of about 20 percent;, t'he4Lyear incidence arnongthose who exhibited only one or two risk factors was much lower, ranging fromi 0 to 3 percent. ECG changes andl anginal pain \vere included in the definition of new coronary events., Paffenbarger, et al.(.4.2)'. evaluated coronary risk factors in the stud~ of 3,263 longshoremen. They found that,, with the exception of diagnosedl heart disease, smoking was the most important factor predictive of'higlii risk for coronary rnortality:, I Keys, et A (30) im the, study: of 279 Minnesota men, concluded ; that al positive, cold pressor test, elevated', serum cholesterol, andd elevated systolic blood pressure had major predictive power for ('HD, death or infarction;! in their analysis smoking seemed less important. S'tamler (49) ~ has analyzed the data on 13' deaths.occurring dur- ing, the first years of the Chicago Coronary Prevention Evaluation Program,, which originally consisted of 519'. coronary-prone male volunteers aged 40, to 59 who were free from clinical CHD'. Eleven of the 13 decedents had three or more coronary risk factors at entry into the program, and at least S' were cigarette smokers at the time of death. Forty-three men, who were cigarette smokers at entry into the Coronary Prevention Evaluation Program, gave up smok- ing andl have remained active ini the program. There have beeni no~ dpaths fromi cardiovascular causes in this group. Stamler (49)) commented :°`Etven though the number of deced'ents was small,, these data, strongly suggest that continued cigarette smoking is as= sociated with very high risk of premature death for very coronary- P rone men,, and that other preventive measures are by: themselves of limited vallue for them as long as they fail to give up cigarette smoking."' i 1 17

r As described in the 1971 report, "The Health Consequences of. Smoking"' (56),, some studies have indicated that smokers show inereasedl leveIs, of serum lipids while others have not. Such contra- I dictory results are also present in recent studies from Germany, Poland~ and Sweden (,21; 39, 53). After ai patient suffers a myocardial infarction, he frequently gives up smoking (17, L6) . Only fragmentary data are avaiiable on, what effect the cessation of' cigarette smoking might have oni the '. likelihood of ai recurrent myocardi~al, infarction ( 9;,34, 43). ~Ninety- two survivors of a first myocardial infarction were studied over a 3!-year period by Paras Chavero, et all (43). During this time, 37 patients continued smoking, and 12 of them (32 percent) experi- enced a second myocardial infarction. The 51 patients who did not smoke during this 3-year period included 39 ex-smokers and 12' pa- tients who had!never smoked. Eight of the nonsmokers (16'percent) experienced a second myocardial' infarction. The smoking habits of' four of' the patients were not known. Although the continuing smokers experienced a greater rate of recurrent myocardial infarc- tioni than the nonsmokers, the difference was not statistically sig- nificant (P =.07). The role of genetic factors in the development of' CHD and' the difficulties associatedl with the use of twin studies were discussed in the 1971 report, "The Health Consequences of' Smoking" (56)~. Mailed', questionnaires were used to establish the diagnosis of angina pectoris in ai study by i,undtrnan, et all of twin pairs discordant wit'hh respect to smoking habits and in a study by Liljefors of twins with CHD. Lundman, et al. (36) recently investigated 69 male twins with the diagnosis of angina pectoris established by questionnaire. Only 22 percent of'these diagnoses could be verifiedl byy clinical examina- tion. In a study of CHD, Liljefors (35)' studied 91 pairs of twins fromm the Swedish Twin Registry ofl' 1967: The twins ranged in age' from 42'to 67 years, and 511 pairs were monozygotic. Smoking habits were not significantly different in pairs discordant for the probable presence of' CHD. However, Liljefors noted that ". .. in many pairs the smoking habits were similar and that the material included few pairs discordant with respect to~ smoking, so that it does not pro- vide a suitable basis for conclusions as to the causal importance of smoking for CHD'."' As observedl in the 1971 report, "'The Health Consequences of Smoking"' (56), it would be surprising if' genetic factors did not play a role in heart disease; however, it is open to question whether findings from twin studies can be used to dis- tinguish between ". . . the hypothesis that genetic factora govern the level of host susceptibility or resistance to the effects of an exo. genous influence such as cigarette smoking and the hypothesis t'hat't genetic factors `cause" both heart disease and smoking:"' ta ( I

I I iuences of. ~ers show eh contra, Germany, f requently Failable on we on the ). Ninety- ied over a s tirne, 37 t)~ experi- ho did not I ind 12'pa-l ~ percent), ' t habits of :ontinuing ial infarc+ {iically sig- I , ~ and the ~discusSed ng" (56)'. i~of angina 'idant with. Itwins with Ywins with jai're. Only I examina,- wins from ~ age from abits were e probable hany: pairs Ciuded few n not pro- iartance of "he Health i if genetic !is open to sed to dis- ims govern ~'of an exo- ~hesis that AUTOPSY STUDIES In previously reported autopsy studies, Auerbach, et al. foundd that aortic and eoronary; atherosclerosis in man were more common and severe among smokers than among nonsmokers (5). They have now extended their investigations to the myocardial arterioles of men and beagle dogs (6). In a study of 1,184 meny they foundlthat the thickness of myocardial arteriole walls was greater, on the average, in smokers than nonsmokers (table 3). The thickness in- creased witfii the number of cigarettes smoked' per day and with age: The thickness was less; on the average; among cigar and pipe smokers than among cigarette smokers, but it was greater than in, rnen who had never smokedl regularly. TABLE 3.-Fluman autopsy stzcdy, Comparison, ofthe thickness, of myocardial arteriole walls in smokers and nonsmokers.' Number of: Men Percent of Men ?:ge. $Grade $GradeIGrade $Grade tGrade, jGrade(year) Smoking Total 0 1 2.3 Total 0 1 2;3~ < 45: None 22' Cigar, pipe 41 Cig.1-19 50 Cig.20-39 85 Cig. ?40 29 2 19 1 100.0 9.1 1 85.4 4.5 - 1 3 100.0 - fi25,0 -i75:0 1 31 18' 100.0 2.0 62A1 36:0 4, 35 46 100.0 4.7 41.2'54.1 - 10 19 100.0 - 34.5: 65.5 45-59 None 15 Cigar, pipe 13 Cig.1-19: 33 Cig.20-39 99 Cig. ?40 50 60-69 None 56 Cigar, pipe 35 Cig.1-19' 92 Cig,20-391 193 Cig. >_40 87 f-~! 70 None 32 Cigar, pipe 40, Cig, 1L-19 30: Cig.20-39 46' Cig, ? 409~ 1 112' 2 100.0 647 80.0 13'.3 - 8' 5 100:0 - 61.5 38.5 ~ - 17 16 100:0 - 51.5 48.5 - 35' 64 100.0 - 35,4 64.6 - 11 39 100:0 - 22.0 78.0 4' 36 16' 100.0 - 22' 13 10Q:0 - 44' 48' 1100.0 - 58 135 1100.0 - 21 66' 100.0 7.1 64.3' 28.6 - 62.9 37.1 - 47.8 52.2 - 30.1 69.9 - 24L1 75.9 2' 18 12' 1100.0 - 19 21 100.0 - 12' 18 100.01 - 12' 34 1100.01 - 3 & 100.01 6.3 56.2I 37.5 - 47.5 52.5' - 40.0 60.0~ - 26.1 73.9 - t3!3.3' t66.7 In the right ventricular wall of 1,020 men by age and smoking habits. t Percentagesi based on less.than.ten.eas~ss., I Four Paint Scale for the Thickness ofI Myocardial hrteriale Walls: 6-normal thickness; 1-sdight thickneset 2-moderate thickness; 3-great thicknesa. SOURCE: Auerbach, 0., et al!, (6). 19'

In one: experiment, beagle dogs inhaled cigarette smoke daily through tracYieostomae. Twenty-eight dogs that died between days 57 and 875: formed one group; 32; dogs that were killed after 875 days formed another group. Eight control dogs were not exposed. Beagle myoeard'iaLarteriole walls were found'to~be thicker in smok-, ing, than nonsmoking dogs, in dbgs smoking many cigarettes than in dbgs smoking,fewer cigarettes; and in dogs smoking nonfilt'er cig- arettes than in dbgs smoking filter-tip cigarettes (figure 1). Also;, the thickness of arteriole~ walls increased with the duration of smoking., Group N : : No smoking • 8 Dogs GroupL Nonfilter Cigarettes • « (%=,asmanY cigarettes ) i c i . Group F ;'; . . . Filter,Tip, Cigarettes U0 Dogs ..« ..« j Group H «.. • • Nonfilter .. • • Cigarettes ... 12 Dogs r. « ..« .«. ««. «.. Grade of © ~ 2 Hickne Each dot represents one seetionL The three dots on a line represent the three sections from a,particular dog. FIGURE 1.-Canine : autopsy study. Comparison of the thickness of myocardial' arteriole walls in 32' smoking dogs killed after 875 days and 8 nonsmoking dbgs. Souxe>z: Auerbachi 0., et al. (6).

EXPERIMENTAL STUDIES NICOTINE AND CIGARETTE SMOKE' Sehievelbein, et al. (47) investigated the effect of oral nicotine administration over a 20-rnonth period on lipid metabolisrni in 35 rabbits. Even though lipoprotein lipase! levels and calcium content of the aorta were sigtlificantly greater in the group given nicotine than in the control group, the histological changes of' arteriosclero- sis were found with equal frequency in both groups. The authors concluded that the epidemiological correlations between CHD and cigarette smoking could not be explained by the pharmacologic ef= fect of nicotine alone: A study of the interaction of chronic nicotine administration and acute hypoxiai in 280, rats was performedl by Wenzeli and Richards (60). Pretreatment of the rats with nicotine increased the mortality during hypoxia, but the difference was not statistically signiificant. Pretreatment with the nicotine also, was associlated! with marked variability of regression of hypoxic heart lesions. The interaction of nicotine pretreatment and the hypoxic insult produced variable effects on myocardiall enzymes. Aronow (1), recently studied the effect of' cigarette smoking on the A wave of the apexcardiogram in 20 men with CHD. The A wave reflects the lefti ventricular filling wave assoc'iatedl with the impact of blood upon the ventricular wall during, left atrial contraction. He found that the mean maximum increase in A wave ratio after smoking was 34 percent for high-nicotine c'igarettes; 13 percent for the low-nicotine cigarettes, and 6' percent for the non-nicotine ciga- rettes. He ascribed these changes to increased myocardial ischemiaa produced by cigarette smoking, which was reflected by a larger AA wave ratio in the apexcardiogram. While nicotine appears to have produced most of these changes, the observation that ai 6 percentt increase occurred in the absence of nicotine suggests the possibility that carbonimonoxide plays a role in this effect. CARBON MONOXIDE Because cigarette smoke contains from 2.7 to 6' percent carbon monoxidis, (CO), sign'ifi~cantl:yhighercarboxyhemoglobin (CO!Hb')) levels are found in smokers than, nonsmokers (13, 20; 2k',, 63). COHb levels in nonsmokers are usually less than 1 percent, while those in smokers average around 4 percent andl may: exceed' 15 percent (.4,,. 20, 561). Heavy smokers and those who inhale show the highest carboxyhemoglobin levels (,20)!. Haebisch (24) found that a smoker with a daily consumption of 35 to 40! cigarettes easily attains and maintains for hours an alveolar 21

CO concentration of 50 p.p.m., which reaches or exceeds legalTy- established ambient air quality standards (1k,18, 23, 24)i. Cohen,, et a1.(13) and Aronow, et al. (2) have shown that there: is no significant difference in mean expired air carbon monoxide levels after patients have sInokedl tobacco or Iett'uce leaf' cigarettes. Although pipe and cigar smokers in, the United States are reported to have lower exposure to CO than cigarette smokers (,20 ), CO in- toxication has been reported in cigar smokers (25)1. C0' exerts its adverse effects on, the cardiovascular system of smokers through; one or more of the following mechanilsms :(a) re.- duction of the amount of hemoglobin available for oxygen trans-, port; (b) shift of the oxygen-hemoglobin dissociation curve to the left with consequent interference in oxygen release at the tissuee level; and (c) induction of arterial hypoxemiaL C0 may interfere with the homeostatic, mechanism by which 2,3-DPG controls the affinity of hemoglobin for oxygen, (56). CO has also, been implicated in experimental atherogenesis in animals (56). Ayres, et a1L (r), recently studied' 41 patients during diagnostic cardiac catheterizations at which time they inhaled either 5 percent or .1 percent C0: Arterial and mixed venous oxygen tensions were, d'ecreasedl by administration of either concentration. In patients with CHD;coronary artery 0~ extraction decreased 7:9 percent after inhalation of .1I percent CO' and 30.5 percent after inhalation of 5' percent C0. Some of the patients with CHDi experienced changes in lactate and pyruvate metabolism indicative of inadequate myocar- dial oxygenation. The higher level of CO' inhalation in this experi- ment is comparable to that experienced intermittently by cigarette smokers.. Brewer and his colleagues, (11); investigated cigarette smoking as& a cause of hypoxemiaa in residents of Leadville, Colorado; at an altitude of 3,100 meters. The arterial' pOz of 8 smokers was signif- icantly lower (P < .05) than that of 12: nonsmokers, but this, was reversible upon, cessation of smoking. They concluded that the ad- verse effect of cigarette srnoking on 01, transport may be especially pronounced at high altitude, andl may restrict an individual's ability to adapt to reduced 0:, tensions (11, 12).. Kjeldsen (31, 32) examined 993' industrial, workers, about one- half of whom were tobacco workers. Fifty-nine cases of' arterio- sclerosis were documented by such clinical symptoms as anginaa pectoris and intermittent claudication or by a previous history of'f myocardial infarction.While. 20!.9 percent of the 934! "controN' in- dividuals were nonsmokers, only 2' (3:41 percent) of the.59 patients with arteriosclerosis were: nonsmokers. A significantly higher per- centage of diseased workers were heavy: smokers and inhaledl the smoke. 22 , < O' W

If The diseased smokers had significantly higher carboxyhernoglobin and serum cholesterol, levels than either smoking or nonsmoking control patients:, This was true after standardizing for differences in levels of smoking between controls and diseased patients. As ex- pected, there was a gradient in carboxyhemogl'obin levels from lower llevels& in light smokers to higher levels in~ heavy smokers (table 4).. TABLE 4.-Average values o f carboxyhemoglobin and serum choles- terol in Danish srnokers and nonsmokers in, control group and group of'patients with arteriosclerotic cardiova;scular disease. Carboxyhemo¢]bbin (saturation percentage). Serum cholesterol (mg/TOO0 ml)'. Smoking category controls: MtS.D. patients gignifi- M'LS.D: cance controls M'±S.D: patients IK±S.D'. signifi= eance Smokers 4.2±3!1I 7.0±3.7 p<0.0o1 247±44 290±33 p<oL0q1 (738).1 (57) t-5:52 (738) (57) t-4.89. hlbnsmokers' 0.4,±0:9 0.5±0.7' n.s. 236±49~ 284±56 p<0.02 (196), (2), t-o:16 (196) (2) t-2'.32 Light smokers, 2.5'±2:5' 3.7±2L5 n.s. 24',5±38' 279±67 n.s. (121) (3) t-0:76 (121) (3), t-11,45. Moderate 4.11±3!0 7.3'-!-3'.6' p<0.001 246±45 286±5(l p<0.001 smokers (463) (34) t=4.95 (4'63) (34) t-4.52 Heavy smokers 5.7±310 7.0±4ff n.s. 253±45: 298±53 p<0.05' (154), (20)t-1.45 (T54) (20) t-2.18 pProbab'ility that ~differencee is ~. not ~. duee to ~ chance~.~. t=~ Studemt's t ca)cu7ationi n.s.. = not'.significantL 'Tihee numberr of ~.subjects~~ in.each category ~is~s enclosed in parentheses beneath the ~mean. (M~) ~, and standbrd~deviation.(S.D~.)~.. Sovaca: Kjeldsen, K. (31). Kjeldsen also observed that the COHb levels of 8' to 19 percent seeni in 40 percent of the patients, with arteriosclerosi'swereof'thesame magnitude as those provoking experimental atherosclerosis and cardiac necrosis in animals. SMOKING A;I+iD, THROMBOSIS Previous reports of' the Surgeon GeneraU on smoking and' healthi have reviewedl the effects of smoking' on thrombus formation (54,. 55, 56). The' role of thrombosis in CHD remains an, active area of investigation. kecent studies have not thus far yielded a unifyimg, concept of the effect of smoking on thrombosis (33,, 41',iF8) ., 23

CHOLESTEROL CONTENT OF TOBACCO' AhTD! TOBACCO SMOKE Cholesteroll glucoside has not previously been reported in tobacco, or in any other plant (10). Bolt and Clarke (10) investigated the sterolini and sterol fraction of flue-cuired tobacco and found' that cholesterol i's one of the major component&of the sterol fraction. More recently, Grunwald, et al. (22) have confirmed that choles- terol accounts for 10 percent of the total sterol in cigarette tobacco. They also found that 8.6 percent of the total sterol content of' ci'ga- refte smoke condensate was cholesterol. Thirteen percent of the cholesterol present in cigarette tobacco was& transferred to the condensate. The biological significance of these findings remains, to be determined. CQR PULMONALE (P'ULMONARY HEART DTSEASE)~ The relationship between cigarette smoking and chronic obstruc- tive bronchopulirnonary disease (COPD) with cor Ixiimonale was& discussed' in the 1968 Supplement to "'The Health Consequences of Smoking" (55).. Although the extent of morbidity and mortality due to cor pulmonale andl right heart failure is difficult to determine, CO!PD' is often complicated by these conditions (27). The Pulmonary Heart Disease Study Group~of the Inter-Society Commission: for Heart Disease Resources recently summarized the evidence linking cigarette smoking, with CO!PDD and concluded: "'Cigarette smoking is the major cause of pulmonary heart disease in that it is the most important cause of the chronic non*neoplastic bronchopultnonary diseases in the United Stat'es"' (28). CEREBR'OVASCULAR DISEASE The 1971 report, "The Hlealth Consequences of Smokiing"' (56), summarized the dlata linking smoking, to cerebrovascular disease as, follows : 1. Dat'a from numerous prospective studies indicate that ciga- rette smoking is associated with increased mortality from cerebrovascular disease., 2l Experimental evidence concerning the relationship of smok- ing and cerebrovascular disease is at present insufl"icient to allow for conclusions concerning, pathogenesis. However, some of the pathophysiological considerations discussed con- cerning CHD may also pertain to the relationship of smoking and CVD; particularly cerebral infarctionL 24

li In the interim, additional reports have been published. Dyken (15) performed a retrospective study on 285 patient's tivith eerebrovascular disease in Elkhart„ Indiana. Even though low ciga- rette consumption was noted ini all groups, males who had cerebral infarctions smoked significantly more than controls. Paffenbarger, et al. (42) found that smokers of more than 20: cigarettes a day: faced a slightly increased but not significantly greater risk of' dying from a stroke than those: smoking lesser arnounts.. After 16 years follow-up, male cigarette smokers in the Framing= ham study had more than three times the nonsmokers' risk of'devei- oping a cerebral infarction (29). However, Ra:nnel' commented: "It is not clear that smoking actuaTly affects the rate of cerebral athero- genesis, and some other mechanism may be involved."' PERIPHERAL VASCULAR DISEASE 3 f e The 1I&71 report, "The Health Consequences of Smoking" (56)!, summarized the data relating smoking, to: peripheral vascular dis- ease as follows: 1. Data from a number of retrospective studies have indicated that cigarette smoking is a likely risk factor in the develop- ment of peripheral vascular disease. Cigarette smoking also: appears to be a factor in the aggravation of peripheral vascu- lar disease. 2. Cigarette smoking has been, observed to alter peripherall blood flbw and periplieral vascular resistance. Newly published studies add to our understanding of the effect of nicotine or tobacco smoke on the peripheral circulatibn andl of the significance of smoking, in peripheral vesseli atherogenesis. Martz, etal. (37)1 observed that some! oftheappar~entlycon- fllicting data on t'lie effects of nicotine upon the peripheral vascula- ture may result from interpretations based upon indirect measure- ments of microcirculatory; variables. Hence, they studied vascular changes in a bat wing under direct microscopic observation. They notiedl a marked increase in the diameter of innervated, minute arteries with intraperitoneal nicotine administration, but this effect was abolished with sympathetic denervation. Asano and Branemark (3) installed a direct, microscopic obser- vation chamber in the connective tissue of two human~ volunteers. I~I One volunteer was ai "healthy" 20-year-old male nonsmoker: The other volunteer was a diabetic who had'& been a smoker for five years and who "_ . had no, apparent diabetic vasculopathy. " The effects of tobacco~ smoking on the microcirculation of these volunteers in- 25

cluded: ". .- vasoconstriction, decrease in blood fl'ow: rate and fre- quency of' plasirra spacing, blocking, of' blood flbw in varyiug num- bers of' nutritive capilllaries, shunting, of blood from arterioles too venules...." These rniierocirculatory changes were said to result in a decrease of nutritive blood flow in tissue. As mentioned in the discussion of CHD, Kjieldsen ( 31, 32)~ stu& ied several smoking patients with occlusive peripheral' vascular disease whose COHb levels were significantly higher than those of' control smokers. The levels of COHb in many of these patients were comparable to those associated with experimental atherosclerosis in animals. Astrup, et a11 Whave suggested that prospective stud- ies shouldi be performed to investigate the rela.tionshiR between COHb levels and the incidence of arterial disease., In the Prague study (;1'9)' intermittent claudilcation was signif- icantly (P' < .01) more commoni among cigarette smokers than non- smokers, Twenty percent of' the rneni ini the age group of 60 to 641 who were heavy srnokers (more than 25 cigarettes a day) had' inter- mzttent claudilcation. Raf (44)i reported' that all but 4 of the 98 patients admitted for peripheral vascular surgery at the Karoline Hospital, Sweden, were smokers. 1Vlathi,esen, et al. (38) in Denmark, followed' the spontaneouss course of arterial'insufficiency in 211 patients. Cessation of smoking increased the number of patients displaying spontaneouls improve- ment. ORAL CONTRACEPTIVES, THRCYMB'0!PHJ.EBIITIS, AND SMOKING Ini two studies from Great Britain and one fromi the United States, it was reported that the use of'oral contraceptives was asso- ciated with a significantly increased risk of d'eveloping venous thromboembolism (.46; 58, 59). The British investigators also noted in their initial report thatthe affected patientswere, on the average,, heavier smokers than controls (58). Hbwever, after an additional year of study„ a similar effect was not noted, and they concludedl (59)i : ". .. the earlier difference between the smoking, habits of'the two groups~can thus reasonabiy be attributed to chance (P' = 0.08') ." The American investigator (45) found ". .. no evidence that smok- ing, acting either independently or in conjunction with oral contra- ceptives, is a factor in idiopathic thromboembolism." Cigarette smoking has not been clearly demonstrated to be a fac- tor that contributes to the.risk of idiopathilctlirornboembolism asso- ciated with the use of oral contraceptives. Nevertheless, the possibility that it may act to increase that risk has not yet been completely ruled out. 26

HIGHLIGHTS OF CURRENT CAR'DIiOiV'ASC'ULAR' INFORMATION In addition to the comprehensive summary from the 1971 report,. "The Health Consequences of Smoking'"' (56), cited earlier in this chapter,, the following statements are made to emphasize the most recent dleveloprnents in, the field : ll. Recent epidiemiological studies from several countries con* firm that cigarette smoking is one of the major risk factors' contributing to the dlevelopment of' CHD. Avoidance of ciga- rett'e smoking is of importance in the primary preventioni of CHD. 2, Studies in man and animals have shown a greater lnyocardial' arteriole wall thickness in smokers than nonsmokers. 3. Experimentai and' epidemiological investigations implicate the elevat!ion, of carboxyhemoglobin levels in smokers as a, contributor to, the development of CHD and arteriosclerotic peripheral vascular di'sease.. 4L Cigarette smoking, is considered to be the major cause of pulmonary heart disease (cor pulmonale) in the United States in that it is the most important cause of chronic non- neopiastie bronchopulmonary diseases. Avoidanee of ciga- rette smoking i's of importance ini the primary prevention of pulmonary heart disease. CARDIOVASCULAR REFERENCES (1) ARONOw;, W., S. The eff'ect of smoking cigarett'es oni the apexcardiogram in coronary heartl di'sease: Chest 59(4)::~ 365-368,,Apri1 1971.. (2) ARONOW, w'. S., DENDINGER, J., ROKAW, S. N. Heart rate: and carbon: monoxide levell after smoking, high-, low-, and1nont-nicot'ine eigaret'tes. A study in male patients witlh, angina pectoris. Annals of Internal Medicine 74 (5) : 6971-702„ May 1971. (i A,SANO;, M.,, BRANEMA;RK, P:-I'„ Cardiovascular and microvascular re< sponses to smoking in man. Advances in, Microcirculation 3:, 125-158, 1970.. (4) ASTRUP;, P., KJELDSEN', K., WANSTRUP, J. Effects of carbon monoxide exposure on, the arteria], walls. Annals of the New York Academy of Sciences 174(1):: 294, 300; October 5, 1970.. (5) AUERBACH, O1, HAMMOND, E. C., GARFINKEL,, L. SInoking, in relation to atherosclerosis of the coronary arteries. New FinglandlJournal of Med. icine 273(15) : 775-779, Octbber 7, 1965. (6) AUERBACH, 0., HAMMOND, E. C., GARFINKEL, L., KIRMAN, D. Thickness of wallsi of myocardial arterioles in relation, to smoking and age. Archives of Environmental Health 22'(1) : 20-27, January 1971., (7) AYRES, S, M., GYANNELLIS S., J!R, MUELLER, H. Myocardial and systemic responses to carboxyhemoglobin. Annals of the New 7Gork Academy of Sciences 174(1):,268-293; October 5, 1970: 27'

(8) BAN6AL, R'. D.,,CHAaLANIy T. D., GULATI„P. V. An~epiderniologieallstudy of ischaemic heart disease ini patients attending, the cardiology clinic at the AIIMS; New Delhi. Indian Medical Journal 64(4) : 84L92, April 1970. (9) BIERENRAUM„M. L., FLEISCHMAN, A. I.,,GREEN„D. P'., RAICHELSON, R. I., HAYTON; T., WATSON, P. B.,, CALDWELL„ A. B! The 5-year experience of' modifiedl fat diets'. on~ younger men with coronary: heart disease: Circulation 42 (5):: 943-952, November 1970.. (10) BOLT, A. J. N., CLARKE, R, E: Cholesteroll gltrcoside in tlobacca: Phyto- chemistry 9(4) : 819-822, April 1970.. (11)', BREWER, G. J., EATON, J. W., GROVER'y R. F., WEIL, J. V., Cigarette smoking as a cause of hypoxemia in man at altitude.Chest 59'(5 Sup- plement) : 30S-31S„May 1'971. (12), BREWER;, G. JL,, EATON, J. W.,, WEIL, J. V., GROVER, R, F. Studies~Of redl cell glycolysis andl interactions: with carbon monoxide;, smoking, andl altitude. Advances ini Experimental Medicine andl Biology 6: 95-114, 1970: (13) COHEN4 S. I., PERKINS, N., M.,, URY,, HL K., GOLDSMITH, J. R., Carbon monoxide uptake in, cigarette smoking. Archives of' Environmental Health 221(1) : 55-60, January 1971.(1Y,',) DUBots, A. B. Establi'shmentof "threshold"'CO exposure levels. Annals of the New York Academy of Sciences 1174!(1) : 425-428, October 5,, 1970. (15) DYKEN, M. L. Precipitating factors, prognosi's, and demogxaphy of'cere< brovascular disease in an Indiana communit'y: A _ review of all pa- tients hospitalized from 1963 to 1965 with neurological examinationn of survivors. Stroke 1(4!) : 261-269;, July-August 1970: (16) EILERTSEN, E., SULHEIM, O. ROkning och koronarsjukdom (3) : Bergen- stiudien. (Smoking, and coronary disease (3) : The Bergen Study.) Lakartidningen 67 (2): 145-149„ Ja nuary 7, 1970:. (17), ELMFELDT, D: Rolkningach koronarsj,ukdom, (8). Rokvanor hos patienter medi hjartinfarkt. (Smoking and coronary disease (8): , Smoking habits of patients with heart infarctions.) Lakartlidningen 67(2): 168-169, January 7;, 1970. (18), ENYIRONMENTAI. PROTECTION AGENCY. National primary and Secondaryy ambient air quality stand:ards. Federal Register 36 (84) : 8186-8201, Apri113D, 19711. (19)! FODOR, J.: Rokning och koronarsjukdom (4) : Pragstudien. (Smoking and coronary disease (4) : The Prague Study.) L'akartidningen 67 (2),: , 150-152, January 7;, 1970.. (20)', GOLDSMITH, J. R. Contribution of motor vehicle exhaust, industlry,, and cigarette smoking to community: carbon monoxide exposures: A,nnals~ of the New York Academy of Sciences 174(1) : 122-134,, October 5, 11970. (21)', GROSS, W., BIALEK, R., SCHADE, G., JUCHEMS, R. Serumlipid-Verande- rungen beim Rauchem (,Serum lipid changes: in smoking.) Deutsches: Medizinisches Journal 21(6) : 368-374,, March 20, 1970. (22), GRUNWALD, C., DAVIS, D. L., BUSH, L., P. Cholesterol in cigarette smoke cond:ensate.:Journal of Agricultural and Food Chemistry 19(1),: 138- 139, January-February 1971!. (23) GRUT, A.,, ASTiRUP, P'.,, CHALLEN, P. J. R., GERHARDSSON',, G: Threshold, limit vallzes for carbon monoxide. Archives of Environmental Health. 21(4),: 542-544, October 1970: 28' r t l

A. (24) HAEBISCH, H. Die Zigarette als' Kohlenmonoxydijuelle. (The cigarette as a source of carbon monoxide.) Archiv fur Toxikologie 26(3) : 251- 267, August 26, 1970. (25) HAMILL, W., ONEILL, R. P:, Carbon monoxide intoxication~ in cigar smokers. Irish Journal of' Medical Science 2'(6) : 273-277, June,1969. (26) HAY, D. RL, TuRBOTT, S. Changes in smoking habits~ in men under 65 years after myocardial infarction and coronary insufficiency. British. Heart Journal, 32'(6) : 738-740; N'ovember'1I970. (27) INTER-SbCIETY COMMISSION FOR HEART' DI',SEA'SE RESOURCES. Pulmonaly' Hieart Disease Study Group. Primary prevention ofl pulmanary heart disease. Circulation 41(6) : A17=A23;, June 11970., (28) INTER-SOCIETY COMMISSION. FOR, HEART DISEASE RESOURCES. Atherd- sclerosi's Study Group. Epidemiology S#ludy Group. Primary preven~ tiion of the atherosclerotic diseases. Circulation 42(6) : A55-A95, De- cember 1970.. (29)KANNEL, W. B'., Current status of the epidemiology of braini infarction associatledl with occlusive arteriali disease. Stroke 2(4),: 295-318,, July-August 1971. (30) KEYS; A., TA:YLOR; H. L.,, BLACKBURNy H., BROZEK, J'., ANDERSON; JL T.,. St'MONSON, E. Mortality and coranaryy heart disease among,men stud- ied for 23 years. Archives of Internal Medicine 1128(2): 201~-21'4; Augustl 1971. (~Table 2' modified by personal communication October 1971.) (31) KJELDSEN, K. Carboxyhemoglobin and serum cholesterol levels in, smokers correlated to the incidence of' occlusive arterial disease. IN : Jones; R: J. (Editor). Atherosclerosis., Proceedings of the Second Internationall Symposium. Chicago, I2linois; November 2-5, 1969. New Yark„ Springer-Verlagy 1970. ppi 378-3971. (32) KJELDSEN, K. Rokning, och koronarsj;ukdorn (12): CO-eksposition og aterosclerosefrekvens. (Smoking andl coronary' diseases (12) : Ex- posure to carbon monoxide and frequency of atherosclerosis.) Lakar- tidningen 67(3) : 262-265, January 14, 1970:(33) KoxSAN-BENGTSEN'„ K. Rpkning och koronarsjukdom (S4) :&oagula- tions'-effekter och riakning: ( Sinoking and coronary diseases (14) : Coagulation effects and smoking.) Lakartidninggn 67(3) r 272-277,, January 14, 1970. (34) LERENS P: The Oslo dieti-heart study. Eleven-year report. Circulation 42 (5) : 935-942, November 1970: (35) LII .IEFORS;, I. Coronary Heart Disease in, Male Twins. Hereditary and, Environmental Factors in Concordant and, Diseordant, Pairs. Actla Medica Scandinavica ( Supplementum, 511), , 1970., 90! pp, (16)ILUNDMAN4 T.,, LILJEFORS, I., CEDERLOF;, R:, FRI;BERC; L. Thevalid"i'tyof'e thequestionnairediagnosis.Archives'of Envi;ronmental Health 22'(5) 597-599; May 1971. (37) MARTZ, R. C., YOUKILIS, E. J.,, HARRIS, P. D!,, FORNEY, R. Bl,, NICOLL, P. A. Effects of nicotine on the subcutaneous microcirculat!ion of the bat. Proceedings of' the! Society for Experimental Biology and Medi- cine 133(',1) :, 153-159;, January 1970. (38) MA,THI'ESEN'„ F: R., LARSENy, E. E., WULFF,, M. Some factars' influencing the spontaneous course of arteriallvascular insufficiency. Aotal Chirur- gicai Scandinavica 136(4) : 303-308,, 1970. (39) MOnZELEwsxI4 A., MALEC„A. Zachowanie sie niektorychlipidbwwe Krwi, u palaczy. (Patlterns of certain blood lipids in smokers.) Wiadomosci, Lekarskie 22'(3') : 229-233; February 1, 1969., 29.

(40) MULCAHY, Rl, McGtuvRAY, J. W., HICKEY, N. Cigarette smoking related to geographic variations in coronary heart disease mortalitly and to expectation of life in the two sexes: American Journal of Public Health and the Nation's Health; 60(8): 1515-1521, August 1970., (k1); ©GSTON, D., BENNE'rr, N: B., OGSTON, C. M. The influence of cigarette smoking on the plasma fibrinogen concentration. Journal of Athera+ sclerosis Research 111(2) : 349-352, M!arch-April 1970. (4'2), PAFFENBARGER, R. S~, JR:,, GIIWIA, A. S'.,, LAUGHLIN, M. E.,, BLACK, R. A. Characteristics of longshoremen related'to fatal coronary heart disease and stroke. American Journal of'Public Health and the Nation's Health 61(71); : 1362=1370, July 1971. (43)' PARiS CHAVERO, E., MERCADO CbNTRERAS, E., QUINirERO NOVELLA, A., Tabaquismo y cardiopatia coronaria. Tobaccoi'smand coronary cardfio- pathy). Archiivos del Institluto de Cardiologia de Mexico 15(2) : 128- 134, March=Apri1„ 1970:. (44) RAF, L. E. Medicinska skadekerkninger av rakning. Rakning och perifera. karlsjukdbmar. (~Harmful clinical effects of' smoking. Smoking and diseases of' the peripheral vessels.) Social-Medicinsk Tidskrift 2 (Special No.) : 67-71, February 1971. ('l,5) SARTwELL, P.E. Oral eontraceptiives and thromboembolism: A further report. American Journal of Epidemiology 94(3) : 192r201, September 1971. (JN6)SARTWEI,L„ P:: E:, MASII, A. T.,, ARTHES, F: G., GREENE,, G. R., S$'L'I1PiH, H: E, Thromboembolism and oral contraceptives:, An epidemiologic case-control study. American Journal of Epidemiology 90 ('5)' : 365- 380, November 1969; (47) SCHIEVELBEINy H., LONDONG, V., LONDONG, W., GttUNIBACH, H.,, REM'PLIK, V. Nicotine and arteriosclerosis. An experimental contribution to the influence of'nicotine on fat metabolism. Zeitschrift fur Klinische Che- mie und Klinische Bioehemie 8(3) : 190-196i May 1970. (48) SeH:OENDORF, T., WILKENSNG, J., CLIFFTON, E. E. Influence of cigarette smoking on some blood coagulation~ tests. Journal of Medicine 1:: 117- 128„1970. (49) STAmLER;, J. Acute myocardial infarctionr--progress in primary preven- tion. British Heart Journal, 33'( Supplementl),: 145-164, 1971. (50)i STAMLER, J., STAMLER, R, SHEKELLE, R. B'. Regional differences in prev- alence, incidence and mortality from atherosclerotic coronary heart disease. IN:: deHaas; J., H., Hemker, H. C;, Snellen, H. A. (Editors). Ischaemic Heart Disease. Leid'en, The Netherlands„ Leiden University Press, 1970: pp. 84-1'27. (51) TIBBLIN, G., WiLHELMSeN'„ L. Rokningen som riskfaktar.(Smaking, as a risk factor.) Lakartidningen 68 (7) r, 687-689, February: 10, 1971. (52) TIBBLINi, G., WILHELI4ISEN, L. R(ikning och koranarsjukdam (5) : 1913 ars man. (Smoking and coronary disease (5')i:' Men born in 1913.) L'akartidningen 67 (2) : 153-155, January: 7, 1970. (58) TIBBLIN, G., WILHELMSEN, L. Rokning och koronarsjukdom (S5) : 1913 ars man-rdkare och icke-rokare: ( Smaking, andl coronary d'isease (15J : Men born in 1913-smokers, and nonsmokers:) L'akartidninggn 67 (3)' : 278--281,: Janua:ry14, 197,0i (54) lI. S, PUBLIC HEAZ.TH, SERVICE. The Health Consequences of'~ Smoking. A Public Health Service RRview:~ 1967:, Washington„ U. S. Depart- ment of Health, Education, and Welfare, Public Health Service Pub- lication No. 1696, 1967. 199 pp. (55)' UIS. PUBLIC HEALTH SERVICE. The Health, Consequences of Smaking. 1968 ' Supplement to the 1967 Public Health Service Review. Washing- 30 30 Q ~ CD T

/ ton, U.S. Department of'. Health,, Education, and Welfare, Public Healtih~ Service: Piiblication No: 1696, 1968. 117 pp4 (56) U.S. PuBLIC HEALTH SERVICE. The Healt'h Consequences of Smoking. A Report of' the Strrgeon General: 19711. Washington, U.S., Depart- ment of Heaith, Educations, and Welf'are, DHEW Publication No. (iHSM) 71-7513, 1971. 458 pp.. (57) U.S, PUBLIC HEALTH SERVICE. Smoking and Health. Report of the Ad- visory Committee to the Surgeon General of the Public Health: Service. Washington, U.S. Departmentl of Health, Educationy and Welfare, Public Health Service Publication No. 1103, 1964'. 387 ppi (58) VESSEy, M. P'., DOLL, R. Investigation of relation~ between use of oral contraceptives andl thromboembolic disease. British Medical Journall 2: 1I99 -205, April 27, 1968. (99) ViJssEy', M. P'., DOLL, R. Investigation of relation between use of orall contraceptives and thromboembolic disease. A further report. British, Medical Journal 2(5658) : 651-657, June 14, 1969. (60) WENZEL, D'. G., RiCHABDS,, M. H. Effects of' chronic nicotine, acute hy- poxia, and their interact'ions on myocardial enzymes. Toxicology and Applied Pharmacology16'(3) : 6'S6'r667y May 1970. (61)1 WeBxo;, L Can we: prevent heart disease?' Annals of'Internal Medicine 74 (2) : 278-288, February 1971. (62) WILHELMSEN, L. The myocardial infarct,ion clinic in Goteborg-or- ganization and preliminary results. Pehr Dubb Journalen, 3: 43-54',. 1969. (63) WYnDEx;, E. L., HoFFn-rANrr, D. Tobacco and Tobacco Smoke. Studies in Experimental Carcinogenesis. New York, Academic Press, 1967. 730 pp: s 31

Q:. rC• tT~ L (= O!

CHAPTER 3 Non-neo~plastiic Bnonchopulnnonary Diseases

/ Contents „ Page Introduction ...................... 37 Epild'emiologiical' Studies, ................ . . . . ........... 38 COPD Mortality ................................. . . . . . 38' CCyPD,Mbrbidity ................................... 39 Cessation of Simoking, ................................ 41 Occupational Hazards ................................ 42 Genetic Factors, ................................... 44 Pathological Sti'udies . . . . . . . . . . . . . . . . . . . 45 Experimental Studies ..................... 45 Human Studies . . . . . . . . ............. 4!5 Animal Studies . . ................. ............... 46 flveraff Clearance ................................... 47 Phagocytosis .......................................... 47 The Surfactant System .............. .............. 48 Other Respiratory Disorders ............................ 48' Highlights of Current Bronchopulmonary Information .... 48 References ............................................... 49'. 35

INTRO'.DUCTI OIV Chronic bronchitis and emphysema are the chronic bronchopul- monary: diseases of greatest healtlii importance in the United States (71). The 1971 report,, "'The Health Consequences of Smoking" (70), summarized the relationship between smoking and these dis- eases as' foldows : 1. Cigarette smoking is the most important cause of chronic obstructive bronchopulmonary disease in, the United States.. Cigarette smoking increases the risk of' dying from pulmo- nary emphysema and chronic bronchitis. Cigarette smokers show an increased prevalence of respiratory symptoms, in- cliiding cough„ sputum production, and breathlessness, when compared with nonsmokers. Ventilatory function is. de- creased in smokers when compared with nonsmokers:. 2. Cigarette smoking does not appear to be related to deat'h from bronchiall asthma although it may increase the fre- quency and severity of asthmatic attacks in patients al- ready suffering from~ this disease. 3. The risk of developing or dying from CCIPD among pipe and/or cigar smokers is probably higher than that among nonsmokers while clearly less than that among cigarette smokers.. 4. Fx-cigarette smokers have lower death rates from C0!PD'1 than do continuing srnokers. The cessation of cigarette smok- ing is associated' withi improvement in ventilatory function and with a decrease in pulmonary symptom prevalence. 5. Young, relativeNy asymptomatic„ cigarette smokers show I measurably altered ventilatoryfunetion whenicomparedlwith nonsmokers of the same age. 6. For the bulk of the population of the United States, the im- portance of cigarette smoking, as a cause of COPD is much greater than t'hat of atmospheric pallutioni or occupational exposure. However, exposure to excessive atmospheric pol lution or dusty occupational materials, and cigarette smoking may act jointly to produce greater COPD, morbidity and mortality. 37

/ 7. The results of experiments in both animals and humansIave demonstrated that the inhalation of cigarette snaoke, is asso- ciated with acute and chronic changes in vent'ilatory fune- t'ion and pulmonary histology. Cigarette smoking has been~ shown to: alter the mechanism of pulmonary clearance and adversely affect ciliary functiion~, 8. Pathological studies have showni that cigarette smokers who die of diseases other than COPD have histologic clianges characteristic of COPD in, the bronchial tree and pulmonary parenchyma more frequently than do nonsmokers. 9i Respiratory infections are more prevalent and severe among cigarette smokers, particularly heavy smokers, than, among nonsmokers. 10. Cigarette smokers appear to develbp, postoperative pulmo- nary cornplications more frequently than nonsmokers.. Recent epidemiologieal, autopsy, and experiinent'al, studies con- firm and extend'the foregoing statements. EPIDEMIOLOGICAL STUDIES COPD IIWIORTALITY Over ai period of 4t'o 8'8 years, Burrows and Earle (10), studied 200 patients with symptomatic COPD whose mean FEw,, was 1.0,t 0.4 liter. Ninety-seven percent of these! patients had a, history of ciga- rette smoking; the average consumption for the entire group of 200 individuals was 23' eigarettes a day over a period of 41 years. Upon, entry into the study, 59 percent were still regµlar smokers and 8'88 percent had discontinued smoking. Eighty-nine percent of the group were males and the:mean, age was 59'.1, years. A 47 percent 5-year mortallity: was observedl in these 200 patients,, and most deaths were ". . . directly attributable t'o, the underlying lung disease or one of its complications.'"' The relationship, of con'- tinued smoking to the course of the disease was difficult t'o! interpret. Patients who stopped smoking prior to ~ entry into the study had a poorer survival than those who continued to use cigarettes. This was related to a tendency for patient's to give up smoking when their illness was severe, and ". .. the apparent advantage.of smokers was eliminatedlwhen patients with similar FEVI levels were compared.'"' The authors reported no reduction, of' mortalit'y in the group 1 of pa- tients who stopped& smoking, even when smokers and ex-smokers with similar FEVI levels were compared. 38 , 4 ra st: ti; IVc na wi in,% . thi fur. C ~ ~

~o- m- 9ou 0!.4 tga- 200, pon ' 138 ;onpi :nts„ ,yingg con- pret, Iad a 1 1vvas their I was Ted1" I pa- tikers. E Reduction of cigarette smoking was associated with a history of reduced expectoration, smaller measured sputum volume, and ". .. a favorable course of the vital, capacity (P <.01).. .." The 1971 report, "The Health Consequences of Smoking" (70), included an analysis of the variety of' ways in which smoking may be related to, disease. COPD was cited as an example in which smok- ing, probably initiates a disease process by producing progressive, irreversible damage. The 200 patients reported by Burrows and! Earle (10„ 11) may be represent'at'ive of patients who have experi- enced' progressive and irreversible pulmonary damage after many years of exposure to cigarette smoke: In such cases, ". . . cessation of'smoking leaves impaired functioni which does not improve appre- ciably but does not continue to deteriorate from continued exposure to cigarette smoke. However, such, function rnay deteriorate through aging or through exposure to other harmful' agents" (7CJ ). COPD' MORBIDITY New reports of chronic broncl'iopulnaonary disease prevalence support the findings of earlier studies in which a greater prevalence was found among smokers than~ nonsmokers. A repeat study of a Berlin, New Hampshire, population sample, which included more than 1,500 individuals, was earried out in 1967 by Ferris,, et aL (27) . In both thi& survey and the earlier 11961 1 sur- vey, a greater prevalence of chronic nonspecific respiratory disease was found in cigarette smokers than nonsmokers. The 1967 E'erlin~ study demonstrated that cigarette smokers whoo inhaled deeply or moderately had generally higher prevalences of chronic nonspecific respiratory disease than those who did not inhale or inhaled only slightly. After, standardization for age, sex, and smoking habits, the pre- valence of chronic nonspecific respiratory disease in the 1967 survey sample was slightly lower than in 1961. IThis may be accounted for by a decrease in air pollution. In a random sample of 609 residents of Glenwood Springs, Colo- rado, a high prevalence of chronic bronchitis was found to be strongly related to smoking, partieularlyof cig~arettes,,and this rella- tilonship was independent of age, sex, or history of dust exposure at work (52). Chronic airway obstruction was found to be predomi- nantly a disease of elderly male smokers and increased in frequency with increasing age after 49 ~ years. The Tecumseh study is a well-known continuing epidemiologic investigation of the entire community of Tecumseh, Michigan. In this study the relationship of parental longevity to ventilatory function and prevalence of' chronic nonspecific respiratory disease 39'

among sons was recently anal~zedi (17). D'eath, before age 6'5 of' either parent was related to low valuesof 1-second forced expiratory volume among the sons.lVlaternal deathi before age 65 was also asso- ciated with increased prevalence of chronic bronchitis and emphy- sema among sons. Some, but not all, of' these relationships were accounted for by differences in smoking habits of the sons. The authors also concluded: "The evidence strongly suggests that con- stitutional factors are involved" (17). A higher prevalence of chronic bronchitis was found among smokers than nonsmokers (iP' <.011) in a study of 710 Vugoslaviani workers (43). There was a direct relationship between the lifetime number of cigarettes smoked and the presence of'chronic bronchitis: Several papers have been published recently comparing respira- tory symptoms such as cough and sputum production among smokers and nonsmokers in different populations. Two of the new studies were prospective investigations (15, 38). In all instances, symptoms were more common among cigarette smokers than non- smokers (1, 6, 8, 15, 3,8, 52, 63, 75)': In the three studies which re- ported on pipe and cigar smokers, the frequency of' respiratory symptoms inthis group was, in general, intermediate between those of cigarette smokers and nonsmokers (6, 1'5, 52). Results of studies of' pulmonary function ini representative sam- ples of different populations ('6,,17, 38, 63), surveys of employees (15, 43, 57), and normal volunteers (75) indicate that cigarette smokers have lower average pulmonary function than nonsmokers. Pulmonary diffusing capacity was found by Van Ganse, et al. (72) ' to decrease in men and women with aging and with an increase in current or lifetime cigarette consumption. In general~ a dose-response relationship between cigarette con- sumption and the development of respiratory symptoms and/or im- paired pulmonary function was found in both men and women; as cigarette consumption increased, these abnormalities were found more frequently (6; 38, 52,, 72; 75)1. Woolf'andl Suero (75), studied the respiratory effectis of cigarette smoking in 298 normall women. The prevalence of cough,, sputum productions wheezing, and shortness of breath increased progres- sively with, inereasedl cigarette smoking. The results of the follow- ing tests of pulmonary function were significantly lower in smokers than in nonsmokers : forced vital capacity, forcedl expiratory vol- ume in one second, maximal mid-expimatory flow, arterialized capil- lary blood oxygen tension at rest, specific conductance, and pulmo- nary diffusing capacity andl fractional uptake of' carbon monoxide during exercise. Seely, et al. (63) examined 365 high school' students in the New Haven area. They found that students with 1 to 5 years"smoking ex- perience had excessive cough, sputum production, and shortness of ao.

of pry so- ere he )n- )ng ian ,me tis. ira- ong ew ces, ion- . re- ;ory iose .eems- otte :ers. al. ease Con- ~im- r;. as pundl rette ztum gres- llow- jkers vo1- ;api1- ilmo- )xide New g ex- ,ss of breath. These young smokers also had lower flow rates at mid-vital capacity and at lower lting volumes than~ nonsmoking students. The authors have raised the questioni of whether smoking by high school students may lead to development'all arrest of the lung. They feel that follow-up pulmonary function studies in adolescents who stop smoking will help clarify this questiom In al study of 556 high school, students from Oklahoma, City, Addington, et al. (1), report'ed, that respiratory symptoms were sig.- nificantly more frequent in smokers than nonsmokers, but no signif- icant differences were noted in the FEV1 and the mean vital capacity. Snider, et al. (65), investigatedl 1„403 patients with dbcumented pulmonary tuberculosis for the presence of obstructive pulmonary disease. Airway obstruction was found in 62 percent of white, men, 37 percent of nonwhite men„ 36 percent of white women, and 17 percent, of nonwhite women., Sixty-eight percent of the patients were current smokers and 15 percent were ex-smokers, Heavy smoking had less effect on the presence ofa2rway obstruction than advanced tuberculbsis or older age. These data: were interpretedl as showing the predominant importanee of' tuberculosis as a factor leading to airway obstruction in~ tuberculous patients. However, the authors also conclludedl: "The present data suggest the possibility ofani additive effect ofsmoking with tuberculosis in producing air- way obstruction.'"' CESSATION OF SMOKING The salutary effect of stopping cigarette smoking on COPD mor- tali'ty and morbidity has: been noted in previous reports of the SlZrgeon General (69; 70):. A recent statement from the "'Pulmonary Heart Disease Study Group''" of the Inter-Society Commission for Heart Disease Re- sources (41) also emphasized this point: "The overwhelming cause and effect relationship between smoking, bronchitis-emphysema and~ pulmonaryheart disease is such that there is little doubt that a radi- cal reduction or elimination of the cigarette habit would result in al greatly lbwered incidence of the chronic respiratory diseases and cor pulmonale "' In recent studies, a decrease in the prevallence of respiratory symptoms among ex-cigarette smokers has beeni demonstrated (10; 15, 75) . Higgins, et al. (38) interpreted data from 1957 and 1966 surveys of'chronic respirat'ory disease in England as suggestingthat the benefits of giving up smoking on respiratory symptoms are: less in those who have smoked for many years than in those who have smokedl for shorter periods. Baker, et al. (5) undertook a therapeutic program for previously 41

/ unrecognized mild to moderate cases of COPDi.. One hundred t'hirty- four men were included in this study. Eighty-five percent of these men were cigarette smokers, 11 percent were ex-smokers, and 4 per- cent were nonsmokers. At the 6-month follow-up, 61 subjects were still in the treatment program. Patients were encouragQd to stop smoking, and at the 6-month follow-up 34 percent of the cigarette smokers had stopped smoking, while 34 percent decreased their cigarette consumption by at least half. At the follow-up evaluation, approximately two-thirds of those who either gave up smoking or decreased their cigarette consumption showed improvement in symptoms. Thirty percent of those whose smoking habits did not change showed improvement in symptoms. No significant differ- ences were found in the pulmonary function studies at the fol'low-up. evaluation. A]t'erationi of smoking habits was the single factor most closely related to symptomatiie improvement. OCCLTPATTOIQAL I`IAZARDS' As observed by Bouhuys and Peters (7), the relative contribu- tions of cigarette smoking and industrial' exposure to the loss of lung function may at times be difficult to determine. Recent studies ini wool,,textile; grain elevator, shipyard, pulp mill',, steel, andlundergroundlmining industries have documented a higher prevalence of chronic bronchitis among cigarette smokers than non- smokers (9, 13; 19„20, 39, 42, 47, 50). Similar, sstudies in steell„ pulp mill, machine shop, and welding industries indicate a greater fre- quency of respiratory symptoms and/or diminished pulmonary function in smokers than in nonsmokers (22, 23, 30, 39)~. Japanese investigators recently reported that former employees of a poison gas factory had a high prevalence of chronic bronchitis and' expiratory slowing; a history of chronic bronchitis was ob- tained from 67 percent of smoking rnen and 47 percent of nonsmok- ing men who had manufactured mustard gas or lewisite ( 5.4 ). In recent months severall articles have been published on coall workers" pneumoconiosis. Because coal miners are not allowed to smoke at work, they must smoke their cigarettes during a short'er period of time thani non*miners ; nevertheless, the average coal miner smokes as many cigarettes a day as does the non-miner (51)'.. Thus, his exposure tends to be more intense during the periodi ini which he is smoking. Allso, the documentledl hazard of chronic expo. sur'e to coal dust may be compounded by the deleterious effect of smoking on ciliary function. Ashford, et al. (4)i studied approximately 30,000 working, coal miners in Great Britain. Their data suggest that smoking and pneu- moconiosis act, independently in the ! production of pulmonary symp- toms. az

11 l A tota.l of 801 working, anthracite coal miners from Pennsylvaniaa were investigated by Tbkuhata, et all ( 68 )., Twenty-four percent of the smoking miners had pulmonary function impairment as com* pared with 11 percent of miners who did: not smoke. Because the smokers developedi their pulmonary function abnormalities after a much shorter underground work exposure, the, authors suggested that smoking may significantly accelerate the: development off pneumoconiosis among coal miners:Rasmussen and'. 1Velson (61) studied 368' soft-coal miners from the Southern Appalachian coal fields., Al'll workers includedl in the study had' been involved in the coal industry for at least five years. Miners with a smoking history of 30, pack-years or more showed a significant (P <.011), reduction of FEVI when compared to non- smoking miners. Impairment of oxygen, transfer was greater in bothi the 15 to 29I.9 pack-year group and the 30' plkzs pack-year group than among the lifelong nonsmokers ( P' G.01) . One hundred sixty-two dyspneic soft coal miners, who gave his- tories of lifelong abstinence from cigarette smoking, were examined by Rasmussen (60). Of these patients, 85.6: percent had some X-ray evidence of pneumoconiosis. The group as a whole was ". .. not rep- resentative of all coall miners, nor of all symptomatic coal miners."' Even thou~gh 56 percent of these, miners had "normal" ventilatory capacities, i.e:, an. FEV', whichi was 75 percent or greater of the predicted normal vital capacity, more than 90' percent had an alveolar-arteriall oxygen gradient during exercise which exceeded. 19.9 mmHg. In more than 95 percent of the "'normal" group„ this gradient was not associated with significant arterial oxygen, desatu- ration during exercise: The loss of pulmonary function in the entire group of'non-cigarette smokers was somewhat less than that found in a group of miners composed of cigarette smokers and non- smokers; nonetheless, these find~ings demonstrate that, in the ab- sence of cigarette smoking, coal dust exposure may be associatedd with abnormalities in oxygen transfer during exercise, despite the. presence of a normal FEVl, An autopsy study of 144 Appalachian coal miners was carried out by Naeye, et al. (53). Several parameters of cardiac and pulmonary structure were examined with regard to the effect of' smoking. The. volume of pulmonary macules and nodules contain2ng, coall dust and the concentration of' silica cryst'als and collagen in these macules. and nodules were unrelated to srnoking. Right ventricular, hyper- trophy, defined according to an index developed by Naeye, was pres- ent in all groups of'rniners but was more! severe in the bituminous& workers wha smoked cigarettes. The emphysema index, which is a measurement of the percent of llung tissue comprised of' abnormall air space,, was determined only in bituminous coal miners. It was 43

significantly greater in cigarette smokers than in nionsmokers. Goblet ce11'1 hyperplasia, which appeared to be present in the entire group, was somewhat greater in the bituminous coal rniners who smoked than in the nonsmokers, but the differences were not statis- tically significant. Several investigators have concluded that eigarette smoking by: itself is more important in the production of respiratory disease, other than pneumoconiosis, among coal miners than is exposure to coal, dust (24, 34, , 58y 68). Rasmussen questions this view (60)i. There is no consensus in recent publications on what role cigarette smoke may play in the development of coal workers'' pneumoconio- sis (2k',, 5l', 53, 58, 6'8)~. Weiss (73')' examined 10'0, asbestos textile workers and found aa greater prevalence of pulmonary fibrosis among; cigarette smokers than nonsmokers. The prevalence increased' with increasing amount and duration of cigarette smoking and with increasing durationi off exposure to asbestos. GEIVETIC FACTORS An infrequent genetic error, homozygous alpha,-antitrypsin de- ficiency, has been commonly associated with the premature develop- ment of severe; panacinar emphysema. It is postulated that alpha,- antit'rypsin is essential to protect the lung against the destructive action of' naturally occurring proteinases (36). Related questions of current interest deal with the!prevallence and significance of' the heterozygous deficiency state (intermediate serum antitrypsin deficiency)' and the, interaction of' smoking with the severe! and intermedliate deficiency: states. Mittman, et al. (49) recentl reviewed the limited data available on the smoking habits of' patients with alphal; antitrypsin deficiency; the cigarette smoke ex- posure of patients with the intermediate deficiency appears to be greater than that of'patienta's with the severe deficiency. Cigarette smoking has been reported to be a possible precipitating; factor in the development of COPD in the homozygous deficiency state (40). Some studies (26,, 44, 49, 67) have demonstrated an association between the heterozygous deficiency state and the devel- opment of COPD', while other studies have not (35,62)~. Mittmans et al. (49), have suggested that the intermediate deficiency may predispose to lung disease by accent'uat'ing an individualPs suscepti- bility to the harmful effects of external' irritants. Whether or not cigarette smoking acts together with the hornozygous or hetero- zygous deficiency states to: increase the risk of developing either panacinar emphysema or the more common forms of'COPD has nott been adeqlaately studied. 4'A dafto-

Y ~ 10 11. ;e a r's it ' A ad. 1e ith 9). of ~x- , be ing acy an. 7eL ;an, 7ay p6- not ro- her not PATHO'LOGI!CAL STUDIES fn previous investigations, a correlation has been found between cigarette smoking and the histologiic changes characteristic of bronchitis and! emphysema (;70) . An autopsy study of' 60, patients with COPD was performed by Cullen, et al. (16). Although they did not find a correlation between the smoking history, total emphysema score, type of emphysema, or bronchiali histologic features,, the authors noted that only three pa- tients were non-cigarette smokers. These three patients were pipe! or cigar smokers. Eight patients who had stopped smoking three. years before death had the same bronchial histologic abnormaliities: as those who continued smoking until death. This suggests that the bronchial abnormalities hadl become irreversible at the time of smoking cessation. Diu~nnill and Ryder ('21') carried out a quantitative study of the relationship, between chronic bronchitis, emphysema, and smoking. The ltings of 353 patients were examined at autopsy, and a smoking history was available in 1'79' cases. A small but significant (P' <.005)i difference was found between smokers andi nonsmokers in the per- centage volume of bronchial mucous glands. Emphysema, mainly the centrilobular type„was found significantly (P <.001) more fre- quently in men and women smokers than nonsmokers, and it oc- curredl at a much younger age in the smokers:. EXPERI'1VI'ENTAL STUDI'ES. HUMAN STUDIES Anderson (3) observed in a few: patients withi andl without COPD that cigarette smoking can produce V/Qi, (ventilation/perfusion) changes resulting in a significant average! drop in PaO, (parti'all pressure of oxygen in arterial blood) . Clarke, et all. (1k) studied the bronchoconstrictor effect of' plain and', filtered cigarettes in 16 men. Filtration of eit'herthe particuTate or vapor phase of the smoke had a similar effect in reducing the bronchoconstrictor response to cigarette smoke inhalation. Using a reference cigarette developed by the University of Kentucky, Diamond, et al. (18) measured pulmonary expiratory resistance immediately after smoking. Heavy smokers, whose con- trol resistance values were significantly higher than those of mod- erate or nonsmokers, had' a. decrease in resistance, while nonsmok- ers had an, increase. Although selected ventilatory function tests did not change significantly after smoking, the author noted that the methods usedl in this studyy are probably not sensitive enough to measure constriction in peripheral airways, where smoking is thought to exert an adverse effect, 45

ANIMAL STUDIES Frasca, et al. (32) made electron microscopic observations in areas of fibrosis and emphysema of' the lungs of dogs, which had been subjected to experimentall cigarette smoking as reporta'ed~ by Hammond, et al. (37). Details of the smoking procedure were re- viewed in the 1971 report, "'The Health Consequences of Smoking"' (70). The maj or findings in the study of Frasca, et al. were : a com- plete lioss ormarked redllctionin the numberof alveolar septallcapiL laries; a marked thickening of the alveolar septa, due to increasedd amounts of collagen,, thickening of the plleural st'roma due t'o large amounts of collagen, and the presence of increased numbers off macrophages in both, the pleura and parenchyma. Many of these macrophages were filled with: pleomorphic cytoplasmic inclusions. Crystalline-like structures were found in membrane-bound inclu, sions and ferritin-like particles occurred both in large membrane- bound aggregates and lying free in the cytoplasmLFlint, et al. (29) reported a siguificant increase in the number of polymorphonuclear leukocytes recoverabl'e from the lungs of guineaa pigs following exposure of these animals to cigarette smoke. B'e- cause no changes in serum alpha,-antitrypsin levels were found~ in this setting, the authors hypothesized that an imbalance mayy occur between proteolytic enzymes released by polymorphonuclear leukocytes an6 the inhibitors of these, enzymes. The stress effects of forced mouth-breathing and inhalation of cigarette smoke on lung rnitochondrial phosphorylation were studied in the guinea pig by Kyle and Riesen (45). Mouth-breathing alone was associated with impaired efficiency of phosphorylation at two mitochondrial loci, while mouth-breathing guinea pigs exposed to cigarette smoke lost efficiency at ondy one of these sites., Aviadb and coworkers have studied! the effects of hormones on the pulmonary response to cigarette smoke inhalation and intra- venous nicotine injection. Subcutaneous progesterone administra- tion, prior to nicotine or smoke exposure, reduced the bronchocon- stri,ctor response in rats (64). A simila.r, eexperiment involving pretreatment of'dogs with glucocorticoids resulted in variable bron- choconstrictor responses after exposure to cigarette smoke (12). Nitrogen dioxide (NOJ, a gas found in cigarette smoke and some! industrially polluted air, can destroy cellular, mmembranes and sub- cellular structures (25). Continuous administration of low concen- t'rations of NO2 in rats has prodt2cedl an emphysema-like disease (66). Falk has suggested'that NO2 may ". .. carry a major responsi bility for the high incidence of emphysema in cigarette smokers"' (25). Stephens, et al. (66) ~ examined ultrastructurallchanges in puhno- nary connective tissue of'rats exposed to 2 to 20 p.p.m. of NO2 for aa.

varying periods of time. In the absence ! of significant cell destruc- tion, striking alterations in both collagen fibri'ls and' basement mem- branes were found. QVERAiLL CLEAItANCE, Pavia, et al. (55, 56) examined'the effect of cigarette smoking,on the mucociliary mechanism of'the human llung. A temporary slow- ing of mucociliary clearance was found in a group of 22' elderly smokers (56). Eight of these subjects had mild restrictive impair- ment and two had airway obstruction. When percentage clearance by elderly cigarette smokers and' nonsmokers was compared, sig- nificant differences were not demonstrable (55). In the latter study,, patients with functional evidence of lung, disease were not included. I3epositioni and clearance of inha~led2/L partieles, of iron oxi~d~ela-beled with 198Au were studied in 19 young, normal subjects by Lourengo, et al. (46). While tracheobronchial clearance began im- mediately after inhalation in nonsmokers,, it was delayed for periods of 1 to 4 hours after inhalation in, smokers. Frances, et al. (31) studiedl the effect of cigarette smoke on par- ticle transport on donkey nasociliary mucosa. This mucosa was found to be much more resistant to the efPects of cigarette: smoke thanthat in the donkey tracheobronchial tree.lVlore recently, Albert,, et a1. (2) published a report that in one of three donkeys tolerance! to cigarette smoke had developedi in the tracheobronchial mucosa. Weissbecker, et alL (74Y examined in vavo mucus flow rates in cats exposed to cigarette smoke gas phase of varied composition. Several compounds, e.g., isoprene and nitrogen dioxide, when addedd in combination to the gas phase, were effective in reducing thes mucus flow, compared to the effect of' th& gas phase alone. Other compounds, e.g., C0, diminished the mucostatic effect of' the gas phase: Compounds producing mucostasis were ineffective when added to cigarette smoke. These experiments indicate that effects observed from pure compounds cannot be used to predict the effect of cigarette smoke on mucus transport. PFIAGOCYTOSIS The recent literature concerning the effect of tobacco smoke : on macrophage function, is reviewedi in the chapter on allergy of this report. Pratt, et al. (59), have extended, their studies on the ultrastruc- ture of' human alveolar macrophages: r1+Iacrophages obtained from smokers tend' to contain more heterogeneous inclusions than those from nonsmokers. Angular and needle-like struct'ures were observed 4z

only in the inclusions of smokers. The authors concludled that these, structures ". .. rnay represent undigested smoke products,..."' In an investigation of early emphysema found in patients who were autopsied, McLaughlini and Tueller (48) found brownish, pig- mented alveolar macrophages in, the intact parenchyma adj acent to areas of emphysema. Such macrophages were not found in normal lungs, but were found in sputum specimens of ". .. apparently healthy cigarette smokers." In heavy smokers many of the macro- phages also contained iron particles. THE SURFACTANT SYSTEIVL Giammona,, et al. (33) measured the surface t'ension of lung ex- tracts andl bronchiall washings of' dogs following exposure to ciga- rette smoke. Elevated minimali surface tension values were found in bronchial washings obtained from three dogs. The values re- mained ellevated for 48' hours after the cigarette smoke exposure; the values obtained one week after the cigarette smoke exposure were normal. The: surface tension, measurements of lung extracts obtained from four autopsied dogs were normai!. OTH!ER RESPIRATORY DISORDERS Finklca„ et al. (~28), studied acute, noninfluenzalrespiratory dis=ease in military cadetsiand found significantly higher incidence rates for acute upper, and lower respiratory illness among cigarette smokers than nonsmokers. Intermediate rates were found for lighter cigarette smokers, cigar, pipe, and ex-smokers: HIGHLIGHTS'. OF CURRENT BRON'CHaP'ULMONARY I'NFOR'1VIATIOIrT In addition to the comprehensive summary from the 1971 report, "The Health Consequences of' Smoking"' (70) ,, cited earlier in this chapter, the following statements are made to emphasize the, most recent developments in the field : 1. Recent epidlemiologicall and clinical studies from several countries confirm that men and women cigarette smokers have an increased prevalence of respiratory symptoms and have diminished pullmonary function compared to nonsmokers. 2. Investigations of high school students have demonstratedthat abnormal pulmonary function and pulinonary symptoms are more common in smokers than nonsmokers. 48

3. Recent occupat'iomali studies confirm that cigarette smoking is an' important cause of COPD, acting both independently and in' combination with occupational' exposure.. 4. Recent experimental studies confirm that cigarette smoking exerts an adVerse effect on pulmonary clearance and rnacro, phage function. 5. Pulmonary macrophages obtained from cigarette smokers ex- hibit characteristic morphologic differences when compared to those obtained from nonsmokers. BRONCHOPULMONARY R'EEERENCES (1) ADDINC'I'ONy, W. W.,, CARPENTER, R. L., MCCoY', JL F., DUNCAN, K. A., MocG; K. The association of cigarette smoking with respiratory symp- toms and pulmonary function in a group of'high school ~ students. Jour- nal of the Oklahoma State Medical Association 63'(11) : 525-529, 1Vovember, , 197,0: (2) ALBERT, R. E., ALESSANDRO, D., LIPPMANN, M., BERGER, J. Long.-term, smoking, in the donkey.! Effectl on~ tracheobronchial, particle clearance. Archives of' Environmental, Health; 221(1) : 12-19, January 1971. (3)' ANDERSON, W. H., Acute exposure to cigarette smoke, as a cause, of' hypoxia, Chest 59; (5, Supplernent)i : 33S-34S, May 1971. (4) AsHFORD„ J. R., MoRGAN,, ID: C., RAE, S., SOWDEN, R'. R'. Respiratory symptoms in British coal miners. American Review of Respiratory Disease 102'(3) : 370-381, September 19701 (5) BAKER, T. R.,, OSCHERWITZ, M., CORLIN,, RI.,, JARBOE, T., TEISCH,, J.,, NICHAM'AN, M. Z. Screening, and treatment program for mild chronic obstructlive pulmonary disease. Journal of'the Ameriean~ Medical As- sociatlion 214!(18) : 1448-1455, November 23, 1970. (6) BOUDIK, F., GOLDSMITH, J. R., TEICHMAN, V., KAUFMANN,, P: C. Epide- miology of'ehronic bronchitis in Prague.. Bulletin of the Worldl Health Organization 42'(5), : 711-722, 1970. (7) BoUHUYS,, A., PE'rERS, J. 1VL Control of' environmental lung disease. New England, Journal of' Medicine 2831(11) : 573-582, September 10, 1970., (8) BRILLE„ D: Frequence de la, bronchite chronique chez 1'a femme. Role du tabac. (Frequency of chronic bronchitis in women. Role of tobacco,) Revue de Tuberculose,et de Pneumologie 33(6) : 794-797; 1969., (19) BRYSIEWI'CZ, K., BULUK, H., CESARZ-FRiONCZYT{, M.,, KORDECKA, J., LES- ZCZYNSKI, B., LUKJAN, Z., SADOKIERSKA, H. Wplyw pracy w warun- kach zapylenia na czestosc wystpowanial przewleklych, zapalen oskrzeli u pracownikow zaklodow' przemyslu welnianego imi Sierzana w Bialy- mstoku. (The effect of occupational, dust exposure on the prevalence of chronic bronchitis among workmen, of Sierzan's wool industry at Bialystok.) Gruzlica i Choroby Pluc 38(7) : 657-661, 1970. (10) BURROWS, B.,,EA'RLE, R. H. Course and prognosis of chronic obstructive lung disease. A prospective study of 200 patients. New England Jour- nall of Medicine 280 (8) : 397-404, February 20, 1969.. (11) BIIRRows„ Bl, EARLE, R. H. Prediction of' survival in patients with chronic airway obstruction. American Review of Respiratory Disease 99(6): 865-871„June 1969. 49'

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Contents. Pag~e Lung Cancer 59 Epidemiologicall Studies ............................. 60 Experimental Aspects ............................... 65 Other Cancers ........................................... 67 Cancer of'the Larynx ............................... 68 Oral Cancer ........................................ 68 Cancerof'the Esophagus .............................. 70 Cancer of the Urinary Bladder .................... 72 Cancer of'the Pancreas .............................. 74 Highlights of Current Cancer Information ................ 74 References .............................................. 75 LIST OF TABLES Table 1.-Some ~iniitiating, agents~ in~ two-stage earcinogenesis~~ 6& LIST OF' FIGURES Figure 1.-Lung cancer mortality ratios of Japanese males by amount smoked ..................................... 61 Figure 2'..-Relative risk: of lung cancer in ex-smokers, of cigarettes by l+ength of cessation before diagnosis ....... 6& Figure 3,-Relative risk of Iung cancer in ex-smokers of cig= arettes, by length of cessation and previous duration of smoking .............................................. 64 Figure 4.-Relative risk of cancer of the oral cavity, pharynx, larynx„ and esophagus associated with smoking and chew- ing in various forms ............................... 70 Figure 5.-Death rates for cancer of't'lie esophagus in Jap- anese males& by smoking and drinking characteristics .... 71 Figure 6. Relative risk of urinary bladder cancer for males by amount smoked ................................... 72 Figure 7.-Relative risk of urinary bladder cancer for fe- males by amount smoked ............................ 73 57

r -00-01

LUNG CANCER . Cigarette smoking has been established as the major cause of lung cancer. The 1971 report,, "The Health Consequences of Stnok- ing"' (39), in summarizing this associationy concluded : 1. Epidemiological evidence derived from a number of' prospec- tive and retrospective studies coupled with experimental and pathoiogiicall evidence confirms the conclusion that cigarette smoking, is the main cause of lung cancer in men. These stud- ies reveal that the risk of developing lung cancer increases with the number of cigarettes smoked per d'ay, the dtzrat'ion~ of' smoking,, and' earlier initiation, and diminishes with ces- sation of smoking. 2. Cigarette smoking is a cause of lung cancer in women but accounts for a smaller, proportion of the cases than in men.. The mortality rates for women who smoke, although signif- icantly higher than for female nonsmokers, are lower than for men who smoke. This difference may be at least partially att'ributed to difference in exposure : the use of fewer ciga- rettes per day, the use of'filtered and low "'tar"' cigarettes;, and lower levels of inhalation. Nevertheless, even when womenn are compared with meni who apparentPy have similar levels of exposure to cigarette smoke, the mortality ratios appear to be lower in women. 3. The risk of deveioping lung, cancer among pipe and/or cigar smokers is higher than for nonsmokers but significantly lower than for cigarette smokers. 4. The risk of developing,lung cancer appears to be higher among smokers who smoke high "tar" cigarettes or smoke in~ such a manner as to produce higher 1levels of "tar" ' in the inhaledd smoke. 5. Ex-cigarette smokers have significantly lower death rates for lung cancer than continuing, smokers. There is evidence to support the view that cessation of smoking, by large numbers of cigarette smokers would be foilowed by lbwer lung eancerr death rates, 99.

6'. Increased d'~eatlii rates from lung, cancer have been observedd arnong urban populations when compared with populations from rurali environments. The evidence concerning the role of air pollution in the etiology of lung, cancer is presently incon clusive: Factors such as occupational and smoking habit dif - ferences may also contribute to the urban-rural difference observed. IDeta2ledl epidemiologic surveys have shown that the urban factor exerts a small infl'uence compared to the over- riding effect of cigarette smoking in the development of' lung, cancer. 7. Certain occupational exposures have been found to be asso- ciated with an increased risk of dying from lung cancer.. Cigarette smoking, interacts with these exposures in the pathogenesis of lung,cancer so as to produce very much higher lung cancer death rates in those, cigarette smokers who are also exposed to such substances. 8. Ekperirnental st'udieson animals utilizing skin painting, tracheal instillation or irnplantation„ and' inhalat'ion of ciga- rette smoke or its component compounds, have confirmed the presence of complete carcinogens as vwell as tumor initiators and promoters in tobacco smoke. Lung cancer has been found', in dogs exposed to the inhalation of cigarette smoke over a period of more than two years. In the interim, additionali epidemiological, pathological, and ex- perimental studies have added to our understanding of these rela- tionships.. EBIDEMIOLOGICAL SrUDIES The majior prospective epidemiolbgical studies to: date, demon, strating associations between cigarette smoking, and specific dis- eases, were conducted primarily in the United States, Canadh, and' Great Britain in Caucasian populations, A large, prospective study currently in progress in Japan adds to the weight of evidence sup- porting a causal relationship between cigarette smoking and lung cancer. It is the first large-scale prospective study to be conducted in a population characterized by genetic, diet'ary,, behavioral, an& cu1.- tural intiuences distinctively different from those in previously ex- amined Western populations. The! 3=year, preTiminary prospective! d'ata~ forlung; cancer f rom this p~opulation of 265,118~ adults in Japan (10) demonstrate overall effeets and dbse-response relationships similar to those observed in previous studies (figure 1) . 60

/ The mortality ratio for male smokers of 1 to 9 cigarettes a day was 2'.7' and rose to ~ 24.8 for smokers of more tfiani 2' packs a day. The mortality ratio was 6.9' for ex-smokers. Of the 122,261 men in the study, 74.3 percent were daily smokers, 3,4 percent were ex- smokers, and 19.1 percent nonsmokers. The percentage of males who were daily smokers decreased with' advancing, age. 26' 24 22 201 18 16 0 2 14 ~. 12.11 10 24.8 9.1 5.7 2:7 1.0 Q_- Non. 1 F9 10-19 20-.24', 25-49 Number of cigarettes smoked per day 6.9 Ex. FicultE 1. Lung, cancer mortality ratios of Japanese males by amount,smoked: SomtcE: Hirayama„T. (10). In a prospective study of 12,322 Czechaslovakian males, Kubik, et ali (19) analyzed various factors associated~ with the develop- ment of lung cancer. During the 31/2-year follow-up period, 61 cases of lung cancer were discovered. The incidence of lung, cancer'among males aged 40 to 64 was 460/1I00,000i among heavy cigarette smokers (more than 200,000 lifetime cigarettes),, 90/100,000 for light cigarette smokers (less than, 200,000 lifetime cigarettes), and 1!0!/100,000 for nonsmokers. There were no cases of l'ung' cancer among, the 222' smokers of pipes and cigars. 61

In tlie past 50 years Poland has experienced a rise in cigarette consumption and, more recently, a sharp rise in the incidence of and mortality from lung cancer (16; 3'4:.). In the 5-year period between. 19'63 and 1967;, the mortalit'y rate fromi lung cancer for men rose from 33'.01 to 49.1 per 100,000. This increase was more pronounced in urban areas. Lung cancer has been the leading, cause of deathh fromi malignant neoplasms in Polish meni since 1959. Additional studies conducted in Germany (26), Lebanon (1'),, Scotland (6), and Sweden, (37) have demonstrated a strong, asso- ciation between cigarette smoking, and lung cancer. Rimington: (28), examined the smoking habits and sputum pra- ductionof 21,579 British males aged 40 an&ollder who were screenedl for lung cancer by X-ray examinatiom During,t'he folllow-up periodl of 36 t'o 56 months, 64 new cases of' lung cancer were identified. Because chronic bronchitis and lung cancer ame both associated withi cigarette smoking, the data were standardized by cigarette con- sumption categories. An increase ini both lung cancer andl chronic bronchitis was demonstrated with increasing consumption, but for each levell of smoking, there was a higher incidence of lung cancer among the: individuals with chronic bronchitis than among, those without this condition. Standardization with respect to age showed that the differences ini lung cancer incidence between those with and without chronic bronchiti's couldl not be accountedl for by the increase seen in these diseases withi advancing age. It was concluded that persons who smoke run a higher risk of chronic bronchitis than nonsmokers and those smokers who develop chronic bronchitis run a higher risk of developing lung cancer than smokers without chronic bronchitis. The relationship between lung, cancer and chronic bronchitis was not demonstrated for pipe, smokers. Graham and Levin (7) examined the: effect of cessat'ioni of ciga- rette smoking on, the risk of' developing lung cancer in a, retrospec- tive study of 700 lung cancer patients. The risk of developing, lung cancer in ex-smokers declined sharply after cessation (figure 2)1. The decline: occurred both in those who smoked for less than 31 years and those who had smoked 31 years or more (figure 3). Those, who had smoked for less than 31 years had a lower risk of lung cancer folIowing cessation than those withi the longer smoking his= tory in each category: of' time follbwing, cessatilon. Although there was an appearance of a somewhat more rapid rate of decline in risk withi time.following cessation for those who smoked for the shorter period, the difference was not statistical'1y significant. The relative risk for the development of lung cancer for pipe and cigar smokers was 2:6. The reduction in risk following cessation of these forms off smoking was not examinedL The relu.tionship of smoking to lung cancer in women, has recently beeni examine& by severall authors. The smoking patterns of 142;857 62', I

. R d n ee d h t- Japanese women were described by Hirayama (10) . Only 10.9! per- cent were daily smokers of cigarettes. Women started smoking at an older age than men and, in contrast to Western populations, there was a higher percentage of smokers in, the older age groups tltan, among younger women. The mortality rates were lower for women than for men, but a dose-response relationship was demonstrated. The lhng cancer mortality ratio for women smokers of 1 to 9 ciga- rettes a day was 2.65 and rose to 3.1!4 for smokers of 20 to 24 ciga- rettes a day compared to nonsmokers. 50' 42'.20. 40 a- pc'- 1g 1). 31 ~se ng is- ;re sk ler ve rs of. 10 10J00 3.33 1.00 Cases 18 65 19 12' 5 2 Controls 346 311 17 23' 29' 30 Months Never 0,'6 7-12 1'3-36 37! 120 >T20 Smoked (Smoked cigarettes only or with other forms, and,stopped alll). FIGURE 2:-ReTative risk of lung cancer in ex-smokers of cigarettes by length of' cessation before diagnosis. SoUttcE. Grahamy S., Levin, M. L. (7). In two recent investigations (3; 13)i, both similar in desigz'1s the authors described higher rates of lung cancer among Jewish women in Pittsburgh and Montreal than among Catholic and, Protestantt controls. The proportion of' epidermoid and anaplastic carcinomas& was found' to be lower for the 87 Jewish women with lung, cancer, in these studies than for the non4ewish women. A survey of smoking 63 23.300 ni

habits in~ t'he twa cities suggested that the increased incidence of' lung, cancer in Jewish women coulld~ notbe entirely attributed to' variations in smoking patterns. A low: incidence of lung, cancer was foundl among', Jewish males, and this was correlated with their low cigarette consumption. 80 74.4 70 60 50 40 N [Y 30 ~ 20 12.4 10 L 0 Cases 93 20 Controls 24 31 Years. 0-1 Smoking,duration before cessation Wlore than 31 years. Less than 31 years 1'9:9' 29 1.7 34 28 2-10 ISmoked cigarettes only or with other forms and stopped all.) 4.8 0 4 >10 16 0.0 0 34 FcGUttE 3.-Relative risk of lung cancer in ex-smokers of cigarettes by length of cessation and previous durat'ion of' smoking, SUU1tCE: Grahamj S., Levin, M. L. (7)~., The' increased risk for the development of lung cancer among uranium miners is well, established. The 197,1 report,, "The Health Consequences of Smoking" (39), summarized the recent investiga- tions in this area.The'. histologic types o'fl' 121 cases of lung cancer in Ameriican uranium miners were studied by Saccomanno,, et all.(3Q) using the WHO: classification of lung tumors. A markedl in- crease was noted~ ini the small celll undifferentiated types with in- 64

f P s W creasing radiation exposure. The author examined the role of tobacco in the etiology of these tumors stating, ". .. among uranium miners, cigarette smoking is a potent co-earcinogen in the cause of lung cancer, but exerts little,, if any,, influence on the cell type of lung cancer-. .'" EEXPERIMENTAL ASPECTS ) I of ng th ;a- er al. n- .n Chemicals present in the particulate phase of tobacco smoke have been tested for their carcinogenic potent'ial ini experimental animals and/or tissue and organ cultures and have been grouped according to the type of activity observed. On mouse skins certain chemicalss induce tumor formatiion and are called complete carcinogens; others appear to act only: in conjunction with additionat treatment, andd are referred to as incomplete carcinogens. They include tumor initi- ators and tumor promoters: Tumor initi•ators induce an irreversible, change in epidermal cells which causes them to respond to subse- quent applications of tumor promoters with the development of skin tumors. This two-stage mechanism of carcinogenesis, welli known for mouse skin, has not been demonstrated in other animal species or tissuesund'er comparablecondit'ions., Hoffmann and Wynder (11, 44) discussed the major initiators i and promoters found in cigarette smoke and described ani additionall property of acceleration possessed by: N-alkylated carbazoles, N-alkylat'ed' indales, and Transr4„ 4'-dichlorostribene. ( DCS) which ; is al pyrolysis product of the insecticides DDT and DDD: These compounds are inactive as complete carcinogens, infrtiat'ors, or pro- moters but accelerate the initiator-promoter activity of polynuclear aromatic hydrocarbons (PAH). The initiating, activity of' polycyclic aromatic hydrocarbons in, two~stage carcinogenesis was investigated and reviewed by Van Duuren, et al. (41). Several compounds previouslythought to be of little or no significance in tobacco: carcinogenesis have been found by Van Duureni and other independent invest'igators to be tumor initiators. Table 1 lists a number of these compounds. Tumor pro- moting agents probably allow these weak carcinogens to express their t'umorigenie potential. Dibenz (a, c) anthracene which was re- ported byV'anDuuren, et al. (414 to be an initiating agent, was found!by Lijinsky, et al. (22) to also act as a complet'e carcinogen in mouse skin experiments. In another investigation, Vani Duuren, et al. (42) confirmeff thatt tobacco smoke condensate is primarily a tumor-prornoting agentt with weak carcinogenic activity. They also found that benzo(a)- pyrene,, a carcinogen in cigarette "tar,'''' acts as a tumor promoter when applied to mouse skin in lbw doses over a long time periodl 65

TABLE 1.-Some initiating agents in two-stage carcinogenesis. Compound'. t Dibenz (a,c) anthracene t Chrysene t Br?nz(a)anthracene t 6-1Vlothylanthanthrene Chloromethyl methyl ether U7-ethaw Triethylenemelamine 1,4-Dimethanesulfonoxy-2-butyne i^ Those found in cigarette emoke: SOURCE: Van Duuren, et al. (41). after the application of' an initiating agent. This supports the obser- vation that the tumor-promoting activity of' cigarette "tar" may represent the summation of carcinogenic activities of the severall carcinogenic aromatic hydrocarbons present in cigarette "tar."' In tobacco carcinogenesis research the choice of`bioassay is of' major importance. Mouse and rabbit skin models have beeni an im- portant source of experimentall data concerning tobacco carcino- genesi's C4k)'. Several relatively rapid screening bioassays have beenn recently suggested. Major (24) examined the effects of tumor pro- mot'ers and initiators on mouse skin, measuring cell numbers, cell size, mitotic index; and epidermall thiiekness. Changes found during, the first five days were characteristic for different agents. The effects of polycyclic aromatic hydrocarbons on the nonspecific: esterase activity in sebaceous glands of mice were examinedl by Healey, et al. (8)i. The changes observed were not entirely specii'ic for carcinogenic activiity and were probably related more, to' the toxicity of the painted substances to the sebaceous gland cells. This suggests that further improvementis neededl in t'his system beforee it can be a practical screening bioassay for potential carcinogenic compounds. Shabad (33) reviewed experirnentallstudies from Russia and else.- where relating tobacco with tumor formation, and concluded, ". .. it is indiicated'that cigarette smoke can actually induce lung cancer in animals." Leuchtenberger and Leuchtenberger (21) have d'escribed adeno- mas and adenocarcinomas in the Iungs of mice chronically exposed to cigarette smoke:Takayama (36) found that subcutaneous, injections of' cigarette"tar'''' in newborn mice produced benign and malignant tumors of the liver, hang, and lymphoid tissue. 66

The compound 7H-Dibenz(c,g)earbazole (7H-DBC), a compo- nent of'cigarette smoke, was tested for its carcinogenic potentiallon the respiratory tract of Syrian golden harnsters using 15' or 30 intra- t'racheal injections per week. Sellakumar andl Shubik (32) found aa high percentage of squamous tumors of the trachea and bronchi in the tested animals andl observed that 7H-DBC appeared to be a potent carcinogen for the respiratory system of' hamsters.. Krasnyanskaya (18) has examined the effects of chronic expo- sure to cigarette smoke on the respiratory tract of 95 rabbits. One, gxoup, was pretreated with ani intratracheal injection of' benz (a)~- pyrene. Although premalignant changes were found! in treated ani- rnal's; no malignancies were observed after four years of exposure.. OTHiER, CANCERS i The relationships between tobacco smoking ini its various forms: and cancers of the oral cavity; larynx, esophagus, kidney, urinary bladder, andl pancreas were summarized in the 1971 report, "'The Healthi Consequences of Smoking" (39). 1. Cancer of 'the Larynx a. Epidemiological, experimental~ and pathol'agical studies support the conclusion that cigarette smoking is a signif- icant factor in the causation of cancer of the larynx.b. The risk of developing laryngeal' cancer among cigarette sm~okersaswell as pipe and/or cigar smokersi& signif- cantly higher than among, nonsmokers. c. The magnitude of the risk for pipe and cigar smokers is about the same order as that for eigarette smokers, or pos- sibly slightly lower. dl Experimental exposure to the passive inhalation of cig- arette smoke has been, observed to produce premalignant and malignant changes in the larynx of hamsters.. 2. Cancer of'the: Oral Cavity a. Epidemiological andlexperimental studies contribute to the conclusion that smoking,is a significant factor in the devel- opment of cancer of the oral cavity and that pipe smoking; alone or in conjunction with other forms of tobacco use,, is causally related to cancer of the lip. b. Experimental studies suggest that tobacco extracts and tobacco smoke contain initiators and promoters of'cancer- ous changes in the oral cavit'y.. 67 ® 0 0

3. Cancer of the Esophagus a. Epidlemiological studies have demonstrated t'hat cigarett'e smoking is associated with the development of cancer of the esophagus. b. The risk of developing esophageal cancer among, pipe and/or cigar smokers is greater than that for nonsmokers and of about the same order of magnitude as for cigarette smokers, or perhaps slightly lower., c. Epidemiological studies have also indicated an association, between esophageal cancer and aleohol consumption andl that alleohol consumption mayint'eract with cilgaretltesmoking. This combination of exposures ils associated with especially high rates of cancer of the esophagus. 4. Cancer o f the Urinary Bladder a. Epidemiologi'cal! studies have dernonstrated an association of cigarette smoking with, cancer of' the urinary bladder amng men. b. The associiation of'tobacco usage, and cancer of the kidney is less clear-cut. c., Clinical and pathological studies have suggested that tobacco smoking may be related to alterations in the me- tabolismi of'tryptophan and may in this way contribute to the development of urinary tract cancer. 5. Cancer of the Pancreas Epidemiologicall studies have suggestedl an association be- tween cigarette smoking and cancer of the pancreas. The significance of the relationship is not clear at this time. Additional relevant epidemiological, pathologiical's and experi- mental data have been reported. CANCER oF'THE LARYNX NTclrTelis and! p75parzai (23) reported 14 cases of carcinoma in situ of the larynx found! among 387 vocall cordl biopsies. Thirteen pa- tients were men and with one exception all, smoked eigarettes, Lavelle (20)' described li1patients with carcinoma of the larynx which occurred as a, second primary cancer at least one year after the suceessfull treatment of an initial primary cancer of the bronchus. "'Although it was not possible to ascertain with certainty the smoking habit of all these patients there were no definite non- smokers among them." 68

ORAL CANICE&. Leukoplakia of' the oral mucosa represents a keratinization of surfaces normally unkeratinized. Over a 23-year period, Sugar and'~ Banoczy (35) observed 53'5: patients with leukoplakia. Of the 324 patients examined in the latest survey,, 96 (30 percent) had leukoplakia for more thani 10 years, Two hundred sixty-nine pa- tients (83 percent) were smokers. Treatment was ineffective in those patients who continuedl to smoke. Oral cancer eventually de- veloped in 13'of 48 patients (27'percent) who had severe leukopla- kia. The initial changesi~n the mou,th, caused by smoking, m~ay: not be: the hyperkeratotic lesions of leukoplakia. Meyer,, Rubinst'ein, and colleagues (25, 29)~ examined the effect'& of smoking, on the surface ! cytology of clinically normal oral mucosa and; in general, foundd that smoking produced changes in cytoplasmi characterized by less mature cell configurations. These changes were most pronounced oni those surfaces most, directly exposed to the streami of cigarette, smoke. Etiological aspects of squamous cancers of' the head: and neck were reviewed by Wynder (43). There was an increased likelihood of a second primary tumor forming, at the site of the: first cancer if a patient had been a heavy: smoker, or if' he continued to srnoke,, after surgical removal of the first primary. From a preventive point of view it was observed that squamous cell cancers of the head and I neck would, be comparatively rare in the.absence of'tobacco andl ex- cessiiae alcoholl consumption. Jussawalila andlDeshpande (15)~ examined various types of smok- ing and chewing habits in a retrospective investigatibn, of 2,0055 patients in Bbrnbay, Iindia, who had histolbgically established can- cers of'the oral cavity, pharynx, larynx; andl esophagus. Smokers used either a manufactured cigarette or the Indian "bidi" whichi contains a small quantity of shredded tobacco rolled in a dried 1eaf, usually of the Texnburnil tree (Dispyros Mela,noxylon). Chewers used "pan" made with betel leaf, lime, and! spices. A small quantity: of tobacco was, on occasions added to this mixture as an optional in- gredient: Smoking and chewing both resultedl in an increased, risk of cancer at, each site examined with a striking, increase in risk ob- served in patients who hadl the combined habits of chewing and srnoking, (figure 4!). Thet independent contributioni of tobacco to: the increased risk of cancer at, each site could not be clearly isolated as there was no eontroll for chewing, when sxnoking, characteristics were examined and vice versaL Intra-oral smoking with the lighted end of a cigar or cigarette inside the mouthi is a custom found in parts of the Caribbean, South America, India, and the Ilslan~d' of Sardinia. Morrow and Suarez 69.

(27) examined 79 intra-oral smokers, most of' whom hadl sought medical attention for reasons other than symptoms associated with smoking-related diseases.A111 but one patient demonstrated "nico- tinic stomatitis"' characterized by hyperplasia, acanthosils; hyper- keratosis~,, and parakeratosis. Sixteen case& of squamou& cellll car6- noma were found. These were located predominantly at the base of the torgue; tonsillar fauces, and adjacent pharyngeal mucosa. Oral Orophaarynx Hypo.pharynx. Larynx, oe5opha9u4 FicuPE,4.-Relative risk of cancer of' the orall cavitg,, pharynx,, larynx, andi esophagus associated with~ smoking, and chewing in various forms. SauxcEC Jussawalla, D. J.,, Deshpande, V'. A. (15). The orall mucosa of many experimental animals appears to be resistant to the induction of cancers. Cohen, et al. (4) failed to: pro- duce any distinctive cancerous or precancerous changes in the mucosal lining of surgically created buccal' pouches of monkeys fill6d with chewing tobacco for varying lengths of time:Homburger (12) exposed the oral mucosa of Syrian golden hamsters to snuff and. 7;12-Dimethylbenz (a) anthracene (D1V1BA) using a bit insertedl 'inn the mouth. Snuff alone failed1to produce any changes that were not also seen in the control animals who had4plain cot'ton plug inserted in the mouth. Benzo (al)' pyrene and DMBA caused! ai few carcinornass of the oral mucosa, but they producedl ai much higher number of'f cancers outside the mouth where the carcinogenic agents had spiilledl onto the perioral skin. The authors observedl that "'. . . skin-painting experiments are more sensitive imdicators of carcinogenicity for the oral mucosa thani applications to the mucosa itself." 70

CANICER OF THE' lu~+'SOPHAGUS' Cancer of the esophagus is associated withi both tobacco: and al- cohol consumption. In, the prospective study from Japan, Hirayama (1a) found no significant association between the use of cigarettes or alcoholl alone and cancer of the esophagus, but there were high rates of esopha- geal cancer among individuals using both cigarettes and alcohol (figure 5). 30 22.5 7.6 4.2 5.1 27.9' 0 0 Drinking Daily + + + 9mokingi Daily + ++ + +'+ Observed 66,080 59,062 48;799 Person-years 95,073 19,4'22' 43,025 FiouRE 5.-Death rates for cancer of the esophagus in Japanese males by smok- ing and drinking characteristics., Souxed: Hirayama,, T. (10). Schoenberg„ et al. (31) , using cohort analysis, examined mart'al'- ity from esophageal cancer in~ the United States. Substantial ethnic, geographic, and ternporal' variations were observed. On, a state-by- state basis; mortality from esophageal cancer was correlated about equally with urbanization, per capita cigarette sales, and per capital 21

alcohol sales.. The correlation with urbanization was partially ex- plained by increased sales of tobacco and alcohol in~ urban~ areas. CANCER OF THE URINARY BLADDER In a retrospective study of 470 confirmed cases of transitional cell or squamouscelll cancers of't'lie biadder;, Cole, et al. (5) found a consistent positive relationship between cigarette smoking and bladder cancer. The relative risk and standard error for the devel- opment of' bladder cancer were 1.89 -±- 0.22 for male smokers and 2:00 ± 0.33 for female smokers., A dose-response relationshsp, was demonstrated for both the number of cigarettes smoked per day (figures 6land' 7) and various degrees of inhalation. Bladder cancer has been sliownto be associated with certain occupat'ional categories such as dye! workers, certain textile workers, tailors,, and nurses (2, 14)1. Cole standardized'the data with respect to occupation andd found that the risk demonstrated could not be explainedl by any: in= direct association with, industrial exposure. Col'e concluded :"The. 3 0 a N cr 2.17 2.01' 1.00 1.03'. r7 7-7-1 Observed 70 36I 140 85 ' Expected 109:5 54.6 109.1 61.4 Number of cigarettes PVonsmoker 1-9 10429 30-49~ smoked per, day MALES FIGURE 6. Relative risk of urinarybladtlernaneer for males by amount smoked. SOURCE: Cole, P:,,et al.(5)., 72'

4 0 1.97 1'.52 1'.00 NA 3:81 Observed 50 13 30, 1i2 Expected 68.2 11'.7 M8 4.3 Nlimber of' cigarettes smoked per day Nonunoker ;_9 FEMALES 1'0-29. 30-49 FIGURE 7.-Relative risk of urinary: bladder cancer for females by amount' smoked. SauRCE': Cole, P., et al. (5), present findings indicate that about 35 percent of cases of cancer of' the'.lower urinary tract in the study population are associatedl with cigarette smoking. If this association is accepted as causal, and if it is generalized to the entire population of'the United~ States, smoking, is associated with about 3,,L00! deaths per year from cancer of the lower urinary tract." No significant association was' found between pipe or cigar' smoking and bladder cancer., Tyrrell, et al. (38) 1 examined several faetors including smoking, history andl occupation in, a group of 2'50 patients treated for uril- nary bladder cancer in, Ireland. No significant association between occupation and bladder cancer was found. This may have' been, due to the low concentration of high-risk industries for this cancer in Ireland. A significant (P < 0.005) association was found in males between cigarette smoking, andi cancer of' the urinary bladder, but. 73'

no significant association was' found for the 50, cases of bladder cancer in females. In ani extensive review of cancer of the urinary tract,, Clayson and Cooper (3) included data that demonstrated an association be+ tween, cigarette smoking, and excessilvemortalityfromblad'd'ercancer., CANCER'~ OF'THEIPANCxEAS~~ Cancer of the pancreas was responsible for 9;696 deaths among men and 7,190 deaths among wornen in the United States in 1967 (40). The United States age-adjusted mortality rate for carcinoma of the pancreas has risen from 2.9 to 8.2 per 1!00;000, from 1920 tto 1965 (17),. In the prospective Japanese study by Hirayama (10), the pre- liminary data showed a pancreatic cancer mortality ratio of 2'.7 for male smokers andi a mortality ratio of 3'.01 for female smokers. In an epidemiolbgic appraisal of cancer of the pancreas, Krai'n. (17) found that cigarette smoking and industrial exposure weree more strongly associated with this disease than either air pollutiionn or genetic factors., HIGHLIGHTS OF CURRENT CANCER INFORMATION Iin addition to the comprehensive summary from the 1971 report, "The Health Conseqnences of Smoking" (39)!, citedl earlier in this chapter,, the following st'at'ements are made to emphasize the most recent developments in the field!: 1. Preliminary results from, ai major prospect'ive epiderniollogi- cal study in Japan demonstrate a strong associationi betweenn cigarette smoking and' lung cancer.. A dose-response relation- ship was demonstratedl for the number of cigarettes smoked. These findings in an Asian population with distinct genetic and cultural characteristics confirm the major importance of cigarette smoking in the causat'ion of lung cancer, a conclu- sion which up to now has been based largely on studies of Caucasian populations in the United States, Canada, and Europe. 2'. Ex-smokers' have significantly lower death rates for lung can- cer, than continuing smokers. The decline in risk following cessation appears to be rapid both for those who have smoked for Iong periods of time and for those.with a shorter smoking 74

history, with the sharpest reductions taking place after thee first two years of'cessation.. 3. The risk of developing lung cancer appears to be higher for smokers who~have chronic bronchitis. Though both conditions are directly related to the amount and duration of'smoking, an additional risk for lung cancer appears to exist for cigarette smokers with chronic bronchitis whichi is independent of age: and number of cigarettes consumed. 4. Experimental studies on animals have demonstrated that the particulate phase of tobacco smoke contains certain chemical compounds which~ can, act as complete carcinogens, tumor ini- tiators, or tumor promoters:, Recently, other compounds have been described that have no independent activity: in two-stage: carcinogenesis but accelerate the carcinogenic effects of polly- nucTear aromatic hydrocarbons ini the initiator-promoter system. 5. Additionall epidemiological evidence confirms a significant as= sociata'ion between the cornbined' use of cigarettes and alcohol, and cancer of the esophagus. 6. Epidemiological studies have demonstrated a significant assa ciationi between cigarette smoking and cancer of the urinary bladder ini both meni andl women. These studies demonstrate that the risk of developing bladder cancer increases with in, halation and the number of'cigarettes smoked. 7: EpidemiologicaI evidence demonstrates a significant associa~- tion between cigarette smoking andl cancer of'the pancreas. CANCER REFERENCES (1)', Asou-DaoUD;, K. T. Smoking habits of'a, Lebanese group and cancer of the lung and larynx. Journal Medical Libanaisi231(1) ; 11-18, 1970. (2) ANTxoNY„ H. M., THOMAS, G. M. Tumors of'the urinary bladder: Ani analysis of' the, occupations of 1,030 patients ini Leeds; England. Journal of the National Cancer Institute 4,5(',5) :, 879-895, November 1970.. (3) CLArsoN„ D. B., COOPER, E. H. Cancer of'the urinary tract. IN r, Klein, G.,, Weinhouse, S. (Editors),. Advances in Cancer Researchs Volume 13.,New York, A:cademic Press, 1970. pp.,271-381. (4')' CoxEN„B., PoswILUo, D! E., WooDs,, D:, A. The effects of'exposure to chewing tobacco on the oral mucosal of monkey and man. A histological and ultrastructural study. Annals of t'he Royal College of Surgeons of England 48'(15) : 255-273, May 197,1. (5) COLEy P., MONSON, R: R., HANING; H., FICIEDELL, G. H:., Smoking and cancer of the lower urinary tract. New England Journal of' Medicine 284 (3) : 129-134, January 21,, 1971. 75'

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tives. Journal of the National Cancer'Instlitute 44 (3)~ : 641-649; March. 1970. (23) McN'ELis,, F. L., EsPARZA', A. R. Carcinoma in situ of the larynx. Laryn- gpscope 81(6) : 924-930„June 1971. (24) MA'aoR, I. R. Cbrrelation ofl initlial changes ini the mouse epidermall celll population with two stage carcinogenesis-a quantitative study. Bri- tish Journal of Cancer 24('1) :~ 149-163, March 1970.. (25), MEYER,, J.,, RLTBINSTEIN,, A. S_ MEDAK, HI, Early, effects' of smoking on surface cytology of the oral mucosa. Orall Surgery, Oral Medicine and Oral Pathology 30(5) : 700-710, November 1970, (26)' Moar[IS„ G.,, ZS¢HO¢H, H., S1rRINGFEI;D, K. Stati,stische Beziehungen: zwischen Rauchen undl Bronehialkarzinom imi Sektionsmaterial. (Sta- tistical relationships'. between smoking, and bronchial carcinoma in autopsy material.), Deutsche Gesundheitswesen 24(51) : 2426-2430, December 18, 1969. (27), MoRRow,, R. C.,, SuAREz, G:, Mucosal changes: and cancer in, intra-orall smoking., Laryngoscope 81(7),:' 1020-1028, July: 19711. (28)~ RihIINGTON; J. Smoking,, chronic bronchitis; and lung cancer. British: Medical Journal 2'(;5758) :, 373-375, May 15, 1971. (29)~ RUBINSTEIN, A. S,,, MEDAKI,, H.,, MEYER, JI, Ear1y , effects of smoking oni surface cyt.ology' of the oral mucosaL I. Regional differences in surf'acee cytology of smokers andl nonsmokers. Oral Surgery, Oral Medicine and Oral, Pathology 30('1):: 131-14!11, July1970, (30) SACCOMANNO, G., ARCHER; V. E., AUERBACH, O:, KUSCH,NER,, M., SAUN- DERS, R. P.,, KLEIN, M. G. Histologic types of lung cancer among:g uranium miners. Cancer 27(3) , :~ 515-523, March 1971. (?1)', SbHqENBER6„ B. S.,, BAII:AR, J. C. (III)„ FRAU&IENI` J. F., JR. Certaini mortality patterns of esophageall cancer in the United States, 1930-67. Journal of the National Cancer Institute 46 (1) : 63-73„ January 1971. (32)~ SkLCAKUIMAR; A. R., SHUBIK, P. Induction of traeheobronchogenic car- cinomas in hamsters with 7H-dibenz(c;g)carbazol:e:, (A'bstract'.) Pro- ceedings of the American Assoeiatiom for Cancer Research, 12!: 98, March 1971. (33)' SIIABAD, L. M. Review of' attempts to induce lung, cancer in experi- mental animals by tobacco smoke. Cancer 27 (1) : 51-55, January 1971. (34) STASZEWSKI, J. Wzxosr umieralnosci z powodki raka pluc w Polsce. (Lung, cancer mortality increase in Poland.) Nowotwory 19I(4):: 263-267,. 1969. (35), S17GAR, L., BaNOCZy, J. Follow-up studies in oral leukoplakia. Bulletin of' the World, Health, Organization 41:, 289-293„ 1969. (36)~ TAKAYAMA, S. Carcinogenic effect of cigarette tar using: newborn ICR' mice. Gann;, Japanese Journal of' Cancer Research 611(3) : 297-298,. June 11970.. (37)', TIBBLi:,N,, G,, WILHEI;MSEN,, L. Rokningen som riskfaktor. (S!moking, as a risk factlor.) Lakartidningen 68'(7) : 687-689, February 10, 19711. (3&)) TYRRELL, A. B'.,, MACAIItT, J. G., McCAUGHEY, W'. T: E. Occupational and non-occupational factors associated with vesicall neoplasm in,Ire- land., Journall of the Irish Medical' Association 64(4!10) : 213-217,. April 22, 1971., (39)', U.S! PUBLIC HEALTH! SERVICE. The HEaltll Consequences of' Smoking.. A Report of the Surgeon Generalr 1971. Washington, U.S. Depart- ment ofl Health, Education, and Welfare„ DHEW Publication No. (iHS'M,) 75-7513, 197'L 458 pp. (40Y U.S. PUBLIC: HEA'LTH, SERVICE. NATIONAL CEN~TER, FOR HEAllTH', STATI~S• TICS. Vital Statistics of the United, St'ates-19fi7: Val. II-Mbrtality, 77 Cdl,

Part A. Washington, i7.S. Department of Health, Education, andlWel fare,, Public Health Service Publication, 1969. (41)i Vn;N DuUREN, B., L., SIvaK, A.,, Gol:DSCHminr, B. M., KxTz,, C., MEI,- cHVONNE, S. Initiating activity: of' aromatic hydrocarbons ini two-stage carcinogenesis. J'ournal, of the National Cancer Ihstitute 44 (5) : 1167= 1173, May 1970. (42), VANi DUUREN, B. L., SIVAK, A.,, KATZ, C.,, MELCH,IONNE, S. Cigarette smoke carcinogenesis: Importance of'tumor promoters. Journal, of'the. National' Cancer Iinstitute 47 (1); : 235-240, July 1971. (43): WYNDER, E. L'., Etiological aspects of' squamous cancers of the head and neck. Journal of' the American Medical Association 215 (3) : 452- 453, January 1Ig; 1971. (44) WYNDEx, E. L., HoFFmnNN; D. The epidermis and the respiratory tract as bioassay systems in, tobacco carcinogenesis. British Journal ofl Cancer 2'4(3) : 574-587, September 1970. 78'

CHAPTER S Pregnancy

Contents Introductiion ............... Effect on Birth Weight ......... ........................ . . Effect on the Outcome of'Pregnancy .................. Congenitall Malformations ................................. Cancer in Children Born to Smoking Mothers ............ Long-Term Effects on, Children Bornto Smoking Mothers .. Experimental Studies ................................. Summary ............. References Page 83' 83 83 87 87 88' 88' 89 89. LIST OF TABLES Table ]i.-Frequency of abortion and cigarette consumption 85 81 »y cn~

0 c.r ~ ~ ~ c,; ~~ 0

INTRODUCTION The 1971 report, "The H'ealth Consequences of' Smoking"' (23'),, summarized the relationship between smoking and' pregnancy as follows : Maternal smoking during pregnancy exerts a retarding in- fluence on fetal growthi as manifeste& by deereasedl infant birth weight and an increased incidence of prematurity, de- fined by weight alone., There is strong evidence to support t'he view thati smoking mothers have a significantly greater num- ber of unsuccessful pregnancies due to stillbirth, and neonatal death, as compared to nonsmoking, mot'hers. There: is insuf- ficient evidence to support a comparable statement for abor- tions: The recently published aecond'i Report of the 1958 British Perinatall Mortality Survey, a carefully designed and controll'ed! prospectivestudyinvolving, l'arge, numbers of pa- tient's; adds further support to; these eonclusions.. New epidemiological, experimental, and patholbgic studies lend support to the foregoing statements. EFFECT ON B'IR'TH WEIGHT Anallysis of data from more than 1'00i,000, births has shown that infants of mothers who srnoke during pregnancy have a mean birth weight of 6.1 ounces (173' grams) less than infants borni to non- smoking mothers (23). Several recent studies confirm this relation- ship (1, 2, 6, 7, 1'0„ 13, 13, 18; 25). EFFECT ON THE OUTCOME OF PREGNANCY New studies have been publfshed concerning the ePfect of maternal smoking on the outcome of pregnancy. Kullander and Kallen (13) performed', a prospective studly: in Sweden involving 6,363 pregnant women. These women completed several questionnaires during the course of their pregnancy, and ini this manner specific information wa& obtained~ on smoking habits for the entire pregnancy. Forty-four percent of the women smoked cigarettes during pregnancy and 97 percent of these! smoked during the whole pregnancy. 83

Stillbirths, neonatal deaths, and deaths occurring before one year of age were recorded to determine a "total death risk."' This risk was approximately 60 percent, higher for children born to smoking mothers as compared to those born to nonsmoking mothers. Deaths occurring before one week of age and also deaths taking place between the: age of one week and one year were significantly more frequent in children bornt'osmoking, mothers. Among children dying before one week of age; significantly more cases of abruptio placentae were found in smoking mothers than in nonsmoking mothers. The higher level of' neonatal mortality in children born ta smoking rn.others was confined to those weighing more than 2,50'G grams. Live-born infants weighing less than 2,5p0 grams had: equally high neonatal mortality rates whether they were born to smoking; or nonsmoking, mothers. The stillbirth rate was greater in smoking mothers than in nonsmoking mothers, but the differencee was not statistically significant. Ani overalliincrea:sed ri'sk of'spontaneou~s abortiorT amongsm~oking women was found, but this was primarily due to an association, be- tween unwanted pregnancy andl smoking. The authors found that significantly (P'<.001) more womeni with unwanted pregnancies were smokers than women vwith wanted pregnanciies; in addition, spontaneous aborrions were significantly (P < .001'I)i more frequent among women with unwanted pregnancies than among women with wanted pregnancies. When, correctioni was made for the mothers' acceptance of pregnancy, the contribution of maternal smoking to, spontaneous abortion was of only borderline significance. Also in the: Kullander and Ka11en study (13), a decreased fre- quency of'preeclampsia among smoking mothers was noted. Mater- nal smoking had no effect on the meani Apgar score of surviving, non-malform,edl children. A prospect'ive study from Sweden of abortions in 4,31,2' pregnan- cies was reported by Pal'mgreni and Wallander (Z7)',. Only those women who smokedlthroughout pregnancy were considered smokers. The lowest abortion rate was found among nonsmokers, 7.8' percent, while the highest rate was found, among heavy smokers, 14.5 per- cent (table 1). The difference is statistically significant (P < .001).. Heavier smokers appeared to abort earlier in pregnancy.. A history of previous abortion, was obtained twice as often in heavy smokers as in nonsmokers. Yerushalmy reported in 1964 on pregnanciies occurring in women participating, in the Kaiser H'ealth Plan of the San Francisco-Oak- land area (2.4 ). , The 19!71 report, "The HealthConsequences of Smoking"' (23)1, commented in detailon that report.. Recently, Yerushaltny published data on 13,0'833 pregnancies occurring in this plan between 1960 and 19'67, which included the 6,800 cases pre- viously reported~. (24, 25). TI 84

TABLE 1.-Frequency of''aoortien and cigarette consumption. Res.,ult't of'the pregnancy Nonsmokers <10:cigarettes >10 cigarettes Total Abortion 177 148 60 385 7.8% 9.11% 14.5% 8.9% Delivery 2,087 1,486 354 3;927 92.2% 90:9%a 85.5% 91.1% Total 2,264 11,634 , 414 4i,312 Souace: Palingren, B,, Wallander, B:.. (17)' As in the 1964 study, he: again found an increase in the incidence of low birth weight infants (less than 2,500' grams): a'mong, srnoking' mothers. These small infants had a significantly' lower neonatal mortality rate and fewer congenitall anomalies than~ the small in fants born to nonsmoking mothers. The neonatal mortality rate for single, live-born infants born to white, smoking mothers was 11.3/1000, while that for single, live-born infants born to white, nonsmoking mothers was 11.0/1000'; the difference is not sign2fi- cant'.. Taylor analyzed' Yeruslialnby's data for the' probability of fetal death andl found no difference between smoking and nonsmoking mothers (22) 1. Some of these! findings are different from those', reported in the other recent, large-scale prospective studies (5, 13, 17, Z9), and some of the differences, may be a consequence of the definition of "smoker" used., In the study of Kullander andlKallen (13'), multiple interviews were performed during, pregnancy which allowed more precise separation of the pregnant women into smokers and non- smokers. In the study reported'' by Ralmgren and Wallander (1'7'),, only those womeni who: smoked throughout pregnancy were con- sidered smokers. The British B'erinatallVTortality Study (5)', which, was discussed in the 197'1 report„ "The Health Consequences of Srnoking"' (23)1, defined "'smokers" as those women who smoked regularly after the fourth month of pregnancy. The smoking history was obtained shortly after delivery of the, infa'nt. In contrast, Yerushalmy (25):, defined "smokers" as women who were smoking one or more cigarettes a! day during the pregnancy,and "nonsmokers'"' as women who, never smoked andd those who stopped smoking either before or during the pregnancy.. Because the smoking history was obtained onlly once, usually early in preg- nancy, some of the women who, were classified as smokers could have gone through a! significant portion of their pregnancy as non- smokers, and similarly some of'the women who were classified as e5 0

nonsmokers could have gone through a significant portion of their pregnancy as smokers. If'smoking by pregnant women increases thee risk of an unsuccessful' pregnancy;, an~ imprecise separation of preg- nant women into: smokers and nonsmokers would tend to diminish the magnitude of any differences found. One Swedish study: (13) and the British Perinatal Mortality Study: (5) seemed'to be at vari- ance in statements about the frequency with which smoking habits vary from one portion of the pregnancy to another. If this is a cul- turally determined phenornenon, there is no way of estimating the extent to which it applies to the pati'ents participating in the! Kaiser Health Plan describedl by I'erushalmy.IVIacMahon, et all (14) commented on~ Yerushalmy's analysis of' mortality rates in low birth weight infants. They observed that there are ". .. factors t'hat affect birth weight without influencing mortality;, for example,, females have lower birth weights than males but not the higher mortalities that might be predicted for them on that account. If cigarette smoking is another such factor, the explanation of the higher weight-specific mortalities for non- smokers becomes immediately clear: it is an artifact of'the analysis. It is meaningful t'o compare category-specific rates only when the specificationi of the category has the same! implication for each, of' the populations compared." Perinatal mortality rates were similar in infants born to smoking and, nonsmoking mothers in a, recent prospective investigation of' 1,300 pregnancies from New Zealand (1). Women were classified as smokers or nonsmokers during their first "'booking" at an ante- natal clinic, and this was not later amended. This methodl of classi- fi'cationi is simiilar to that used~ in the Yerushalmy study. Comstock, et al. (6, 7)1 have reported in 1967 and 1971 on the relationship of maternal smoking to the outcome of pregnancy. In their studies, all peri'natal deaths and samples of live births occur- ring during a 10-year period! among children whose mothers weree residents of Washington County, Maryland, were matched against the records of a special census based on al household interview taken in 1963':Maternal' smokers were defined as women who were smok- ing in 1963 and who had started to smoke prior to the pregnancy inn qaestion; maternal nonsrnokers were women who denied ever hav- ing,smoked. Wh:enit~hisstludyiscomparedltopreviouslycited, studies, (5, 13, 17), the dlatai on the smoking status of the mothers during pregnancy are imprecise, which limits their value. In the 1967 study: (6), maternal smoking was associated with an increased risk of mortality for the child, both in the neonatall period and! for several years thereafter; however, this effect was thoughtt to be related to: factors such as& adequacy of prenatal or postnatal environment and care, rather than a! direct effect of maternal sTnok- ing. Stillbirth rates were similar for smokers andl nonsmokers: 86

a r g ~ d i- in. pd ltt ;al k- 'Il'he more recently published study (7)' includes a 32 percent sample of live-born, low birth weight infants and a 3' percent sam- ple of live-born, larger infants born duriing, the 10-year period pre- ceding the census.. The total births represent'e& by these samples were 4,641 to smokers andl 7,646 to: nonsmokers. The neonatal mor- tality rate, when adjusted for environmental' and socioeconomic factors, was approximately one-third higher among infants born tosmoking mothers than among those born to nonsmoking mothers, (7). The categories of asphyxia, atelectasis, and immaturity ac- counted: for the greater neonatal mortality among infants born to. E I smoking mothers as compared to those born to nonsmoking mothers (?) . CONGENITAL nZALFORMATIO~NS As noted inithe 119,71 report, "The Health Consequences of Smok- ing"' (23)'., the possible teratogenic effect of maternal smoking hass not been adequately evaluated. Addltional studies have been pub- lishe& in the interim, but rather than investigating congenital malr formations in both stillborn and live-born infants,,most of the recent studies have dealt only with live-born infants. Fedrick, et al'. (8) analyzed data from the large British Porinata]' Mortality Study for the incidence of congenital heart disease in still- born and live-born infants of'smoking and nonsmoking mothers.. An incidence of 7:3%1I000 births was found in infants born to: smoki~ng mothers as compared: to 4.7/1000' births for infants born to non- smoking, mothers, a statistically significant difference ( P' <.001) .001). Kulland Kallen (13) noted no t'eratogenic effect of maternal, smoking in children dying before one year, of age or ini children surviving one year of' age: However,, they observedl that published studies have been too srnall' to exclude this possibilYty.In a study of perinatali death, occurring in infants weighing, more than 11,000 grams, Bailey: (1) foundlthat maternal srnoking did not leadi to an increased incidence of congenital anomalies. Yerushalmy (25) reported only on live-born infants weighing less than 2,500 grams and found significantly fewer (P <.02)i anomalies among infants born to smoking mothers. Comstock, et al. (7)' found fewer t'han the expectedi number of congenital anomal'ies, among live-born infants of smoking mothers:, CANCERINi CHILDREN BORN TO SMOKING bZOTHiERS. Neutel and Buck (16) studied" the relationship, between maternal smoking during pregnancy and the development of cancer in the off- spring. The base population was obtained from the B'ritish, and. Ontariio Perinatal Studies andl consisted of 89,302' babies who sur- 87

vived at least seven dlays, There were 65 cancer deaths and 32 can- cer survivors in the period from birth to a minimum: of 7 and a maximum of 110 years of age. Fbr cancer of all sites, the children of smokers' had a relative risk of' 1.3. The authors concludedl: "Al- though these results make it most unlikely that in' utero exposure to tobacco smoke has a broadly: carcinogenic effect on the! fetus, a, re- sponse confined to one tissue', or expressed over a narrow age range cannot be ruled out." ' LONG-TERM EFFECTS' OhI CHILDREN BORN TO SMOKING MOTHERS Goldstein (9)i analyzed data from the British PerinatallVlortality Study to~ determine factors influencing the height of 7-year-oldd cliildren. In the 1958 study, information was collected on, 16,994 singleton births. In 1965, heights were measuredl "to the nearest inch~"oni 13;127 of these children who could be followed up. The data were: analyzed for the influence of parity,, birth weight, length of gestation, maternal age, rnaternall height, social class,, number of younger siblings, and' mat'ernal smoking, habits during pregnancy. Allowance was made for the sex and age of the child at t'he time of measurement. The author's conclusions included the follbwing: "After allowing for the other variables, the children of mothers who smoked 10 or more cigarettes ai day after the 4tlh month of preg= nancy,, are on average about 1.01 cm shorter at age seven than the children of mothers who did not smoke." EXPERIMENTAL STUDIES Becker and 1WIartin (3) continued their experiments concerning the effect of'nscotine on pregnant rats, Offspring of rats given nico- tine weighed significantly less at birth than saline-injected controls: There were fewer live births among the nicotine-injected rats. Kelly andi Roy(12)', using cinephotomi~crography,, demonstrated' that nicotine crosses the mouse: placent'ali barrier in amount's ade- quate to produce a measurable cardiovascular response. Stalhandske, et al. (21) studisdi the in vitro metabolism of'nico- t'ine in livers of fetal, young, and adult mice. Cotinine was found to beth~emajior metabolhte at all ages investigated. Using radioactive compounds, Sieber and Fabro (20) identified ai variety of drugs in the preimplantation blastocyst and in uterine secretions of pregnant rabbits. In anirnals receiving dose levels of nicotine comparable to that encountered in man, significant amounts of' radioactivity were found in the preimplantation blastocyst. A markedly higher concentration of radioactivity was observed in uterine secretion than in maternal plasma. 88i

mn- ~d a Iren `A1- e to re- nge. lity •old 994 rest ata [ of r of. tcy:. p' off hg: kho ;eg- the ;ing ico- ols, ~ted 4de- ico'- 3 to >d a. -ine t of nts A in Juichaui (11) studied the levels of benzpyrene hydroxylase in the placentas of smoking and!nonsmoking women obtained both early in pregnancy and at term. This enzyme.hydroxylates'benzo (a)lpyrene,, a carcinogenic hydrocarbon found in tobacco smoke: Previous stud- ies had shown that placentas, obtained at terrn from smoking women, have a greater ability to hydroxylate benzo (a) pyrene than, the placentas from nonsmokers (23). Juchau corroborated this, but also found very low levels in placental tissues obtained from healthy smokers during first trimester dilatationi and curettage or hystero- tomy for therapeutic abortiom This lack of significant placental drug metabolizing activity during the first trimester was' in- terpreted as a possible hazard to the fetus, particularly if the sub- stance were active in the unmetabolized form. Enzyme levels were undetectable: in placental homogenates of nonsmokers at 8' to 16 weeks gestation.Tlie carcinogenic effect on the newborn of rats receiving, benzo- (a) pyrene during the latter half of'pregnancy was studied by Bulay and Wattenberg Mi. An increased incidence of pulmonary adenoma andl skin papilloma was observed. SUMMARY Maternall smoking during pregnancy exerts a retarding influence on fetal growth as manifested by decreased infant birth weight and' an: inereased' incidence of prematurity, defined by weight. There is increasing evidence to support the view that women who smoke during pregnancy have a significantly greater risk of'an unsuccess- full pregnancy than those who' do not.. PREGNANCY REFERENCES (1) BAiLEY,, R. R. The effect of maternal smoking on the infant birth weight. New Zealandl Mediicall Journall 71(4'56) :~ 293-294, May 1970. (i2), BEAL, V. A. Nutritional studies duringpregnancy: Journal of'the Amer- ican Dietetic Association 58'(14),: 321-326, April 1971. ('3) BECKER, R',. F., MnxT[w, JL C. Vital effects of'chronic nicotine absorptionn and chronic hypoxic stress during, pregnancy and the nursing period.American. Journal of Obstetrics and Gynecology 110(4) : 522'-533; June 15, 119711. (4) BULAY, 0. Mi.,,wA'r°rENSERG; L,,V4?., Carcinogenic',effect's of subcutaneous administration of benzo (a) pyrene during pregnancy on the proggny., Proceedings of the Society for' Experimental: Biology and Medicine 135 (1) : 84L86, October 1970: (5) Bv'rtER,, N'. R., Ati.BBxzv[AN,, E. D. (Editors). Perinatal Problems. The Second' Report of the 1958'British Perinatal Mortality Survey. London, E, andi S. Livingstone Limit'ed;,1969. 395 pp. (6) COMSTOCK, G. W., LuxDrN, F. E., JR, Parental smoking and perinatal mortality., Americani Journal of' Obstet'rics and Gynecology 98(5) :, 708-718, July 11, 1967: 89'

(7) CoMSTOCK; G~ W., SHAH„ F. K.,, MEYER, M. B,, ABBEY, H. Low birth weight and neonatal mortality rate related, to maternal smoking and socioeconomic status. American Journall oflObstetrics and Gynecology 111(1) : 53-59; September 11,,1971., (8) FEDRICK', J., ALBERMAN,, E. D., GbLDSTEIN',, H. Possible teratogenic ef- fect of cigarette,smoking: Nattrre 231:, 529L530; June 25, 1971. (9) GoLDSTEIN, H. Factors influencing the height of seveni year old ehildren. -results from the National Child Development Study. Human Biol- ogy 43: 92-111, February 1971. (10) GouJAItD, J., ETIENNE, C.,, EvRARD, F. Caract'eristiqpes materneli'es et poids de naissance. (Maternall characteristics and birth weight.), R'evue dii Praticien 19 (28, Supplement):: 54, 59-62, 65, November D, 1969. (11) JUCHAU, M. R. Human placental hydroxylatian of 3,4-benzpyrene dur- ing earliy gestation and at term. Toxicology and Applied Pharmacology 18 (3) : 665-675„ March: 1971. (12) KELLY, M.,, RAY, F: H. Microcirculatory response of' fetal mice to ma- ternal nicotine. (Abstract'.) Clinical Research 19(i2):: 322, April 1971. (13)! KULLANDER; S.,, Kai.LENS B. A prospective study of smoking, and: preg- nancy. Aetai Obstetricial et Gynecologica Scandinavica 50:(1) :, 82-94, 1971. (14): MACMAHON4 B., ALPERT, M., SALBER„ E. J. Infant weight and parental smoking, habits. Americani Journal of Epidemiology 82(i3) : 247-261, November 1965. (15) MURPHY, J. Fl., MULCAHY, R. The effect of age, parity, and cigaretite smoking on baby weight. American Journal of Obstetrics and Gyne- cology 111('1') : 22-25, September 1, 1971. (16) NEUTEL, C. I., BueK, C. Eff'ect of smoking during pregpancy on the risk of' cancer in children. Jburnal of the Nationall Cancer Institute 47 (11) :. 59-63, July 1971. (17) PALMGREN, B., WALLANDER, B., CigarettriDkning och, abort. Konsekutiv prospektiv undersokning av 4'3ll2lgraviditeter. (Cigarette smoking and abortion. Consecutive prospective study of 4312 pregnancies.)' Lakarrtidningen 60(22) : 2611-2616, 1971. (18) PETTEBSSON, F. Medicinska skadeverkningar av rokning. Rokning, och, gynekologisk-obstetriska tillstand. (Harmful clinical effects of' smok,- ing. Smoking and gynecological-obstetrical conditlion.), Social-Medf;- cinsk Tidskrift 2(Special No.) : 78-82, February 1971.. (19) RUSSELL, C; S., TAYLOR, R'., LAw, C. E. Smoking,in pregnancy,,maternal bloodl pressure,, pregnancy outcome, baby weight andl growth, and other related factors. A prospective study. British Journall of Pre- ventive and Social Medicine 22'(3) : 119-126,, July 1968. (20), SIEBER,, S. M.,, FABRO;, S. Identification of drugs in the preimplantationn blastocyst and in the plasma, uterine secretion and urine of the preg- nantxabbit. Journal of Pharmacology and Experimental TherapeuticsI 1176 (1) : 65'-75, 1971. (21)~ STALHANDSKE, T:,, SLtYNINA, P., T.XAI1vE; H., HAZ4ISSQIN,, E,, SCHMITiERLOW, C., G. Metabolism in vitro of'14C-nicatine in livers of foetal, newbarn and young mice. Acta Pharmacologica et Toxicologica 27(5), : 363- 380, 1959. (22)! TAYLOR, W. F. The probability of' fetal death. INI: Fraser, F. C., McKusick; V. A. (Editors). Congenital Malformations. Proceedfngss of the Thirdl International Conference, The Hague, The Netherlands, September 7~13; 1'969. New York, Excerpta Medica, August 1970. pp. 307-320. 90

(23) U:S. PUBLIC HEALTH SERVICE. The Health Consequences of' Smoking. A Report of'' the Surgeon General: 1971. Washington, U.S.Departi- ment of' Health, Education, and Welfare, DHEW Publication 1rlo, (HSM) 71-7513, 1971. 458 pp. (24)~ YEftUsaALM~~„ J. Mothers'' cigarette smoking and survival of infant. American Journal of' Obstetrics and Gynecology 88(4) : 5q5-518; February 1151 1964. (25) YkRVSfrAr.MY, J. The rel'ationship of parents' cigarette smoking to out- come of pregnancy-implications as to the problem of inferring causa- tion from observed associations. American, Journal of' Epidemiology 93'(6)1:, 443-456, June 1971., f 91'

CHAPTER 6 Gastrointestinal Disorders ,j

Contents Page Highlights of Current Gastrointestinal' Information ....... 98 R'eferences. .............................................. 98

c c~.: ~ ca ~. . ;•, ct~ Ma ~

GASTROINTESTINAL DISORDERS The 1971 report; "The Health Consequences of' Smoking" (4), summarized the reldtionsh2p between smoking and peptic ulcer as follows : Cigarette smoking, males have~ an increased prevalence of' peptic ulcer disease andl a.a greater peptic ulcer mortality ratio. These relationships are stronger for gastric ulcer than for duodenall uleer. Smoking appears to reduce the effectiveness off standard peptic ulcer treatment and to~slow the rate of ulcer healing. Studies of the effect of smoking on gastric secretion in patients with! pept'ic uleer andl normall controls have produced conflicting re- port& (1r).Recently. Wilkinson and Johnston (5) reported, a sig- nificantinhibitioni of'pentagastrin-stimulated gastric acid secretion after cigarette: smoking, by normal volunteers, while Debas, et al. (Z') found no significant overall change. Wilkinson and Johnston also studied patients with gastric and duodenal ulcers in whom a sig- nificant inhibition of pentagastrin~-stiBnulated gastric secretion was observed after the patients smoked one or two cigarettes over a period of 10 to 15 minutes. A study by Konturek, et all. (13) suggests that alterations in pancreatic and biliary secretion may be responsible for the relation shipi between smoking and peptic ulcer.. Nicotine was infused in mongrel dogs in doses corresponding to amounts absorbedl from smoking upito~four cigarettes, in, one hour. In the pancreas, niicotineinhibited the secretin stirnulated secretion of both, fluid andl bi- carbonate, and the degree of inhibition was d'ose-related. Spontane- ous biliary secretioni of'bicarbonate was also depressed; by the drug. Niicotine had no: effect on gastric secretion of acid~ gastric mucosal blood flow, orthe mucosall barrier to~hydrogen or sodiumions: Thi& inhibition, of pancreatic andl hepatic bicarbonate secretion may de- prive the duodenum of sufficient alkalfne secretion to neutralize gas- tri,c acidity andl may be one biomechanism liinking, cigarette smoking and peptic ulcer.. D!ennish and Castell (2) noted the clinical', association between cigarette smoking; and heartburm To investigate the biomechanism of'this relationship, Iovwer=esophageal sphincter pressure determi- nations were made before and after smoking in, six normal male volunteers. Alll of the volunteers were cigarette smokers. In each 97'

subj ect after the onset of' cigarette smoking, there : was a rapid de- crease ini lower-esophageal sphincter pressure from the basal level. This diminution in sphincter pressure persisted until smoking, was stopped, at which time the pressure returned rapidly toward nor= rnaI. Mean basal pressure was 19.6 ± 2.1 (± 1 S.E,) mmHg. and mean pressure, during, smoking was 11.4 ± 2'.2~ mmI7ig: The differ- ence between these pressures is statistically significant (P' < .0'01)' No changes were noted when, volunteers puffed on unlit cigarettes. Variable responses were noted when volunteers smoked cigars andl pipes: The investigators concluded that cigarette smoking decreases the effectiveness of the 1'ower-esophageal sphincter as a barrier against gastroesophageal reflux. HIGHLIGHTS OF CURRENT GASTROINTESTINAL INFORMATION In addition to the summary staternent cited at the beginning, of this section, the following; observations have been made: 1. A possible link between cigarette smoking and peptic ulcer has been demonstrated in dogs ini which nicotinewas, found to in- hibit pancreatic and hepatic bicarbonate secretiom This could lead to peptic disease by: depriving the duodenum of suf= fficient alkaline secretion to neutralize gastric acidity.2'. An investigation in human volunteers has suggested that cigarette smoking decreases the effectiveness of the lower- esophageal sphincter as a barrier againstgastroesophageal' reflux. GAS'T1'ROIIxTTESTINAL, DISORDERS REFERENCES (1) 1 DESas,, H. T.,, CaHEN„ M: 1VI., HouUBtTSxx, I. B,, HartRISON, R. C. Effect of cigarette smoking, on human gastric secretory responses. Jburnall of the Britishi Society of' Gastroenterolbgy 12: 93-96, 1971. (2): DENNnsH;, G. W., CASTEUL, D. 0. Inhibitory effect of smoking on the lower esophageal, sphincter. New England Journall of Medicine 284(20): 1136-1137, May 20, 1971. (3) KONTUREK, S. J., SOLqMqN, T. E:,, MCCREIGHT, W. G., JOHNSON, L:, R., JACOSSONS E. D: Effects of nicotine on gastrointestinal secretions. Gast'roenterolbgy 60 ( 6): 1'098-1105y June 1971. (4), U.S. PUBLrc!HEALTH SERVICE. The Health Cbnseauences, of Smoking: A Report of the Slirgeon General: 1971. , Washington; U.S. Depart- ment of' Health, Ediication, and Welfare, DHEW Publication No. (HSM) 71-7513, 1971. 458 pp. (5)' WtLKtNSON, A. R., JOHNSTON, D. Inhibitory effect of cigarette smoking on~ gastric secretion stimulated by pentagastrin in man. Lancet 2'(7725'),:,628r632,, September 18, 119711. Q. 98' ~ ~ .., ~'. ~'. _ 1 W.

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