Tobacco Documents Online

ii Contents Page Introduction--------------------------------------------- 1711 Tl1ePtevalence of Pipe, C'igar„ and C'igaretteZTsage---------- 173~ The Definition and Processing of Cigars, Cigarettes,, and Pipe Tobaccos--------------------------------------------- 175 C'hemicai Analysis of'Cigar Sinoke------------------------- 177 \Iortality Oreralt Morta,lity=------------------------------------ 179 Mortality and Dose-Response Relationships. Amount Smoked-------------------------------- 180' Dn.lialation-------------------------------------- 183 Specific Causes of Mortalily--------------------------- 189 Cancer----------------------------------------- 189 Cancer of the Lip------------------------------- 190, Oral Cancer------------------------------------ 191. Cancer of' the Larvnx---------------------------- 193' Cancer of' the Esophagus------------------------- 1'97 Lung Cancer------------------------------------ 203 Tumorigeniic Act'ivity---------------------------- 210 Experimentlal Studiies---------------------------- 210 Cardiovascular Disease& -------------------------- 215 Chronic Obstructive Pulmonary D'iisease~~ (COPD) - - - - 216, Gastrointestinal D!isorders------------------------ 2M Little Cigars-------------------------------------------- 2'22' Conclusions--------------------------------------------- 229. References---------------------------------------------- 230. List ofFiguires, Figure L-1'nhal~tion among pipe smokers by age----------- 184 Figure 2.-Inhalatt'ion among cigar smokers by agE-Ham- mond------------------------------------------------ 1'85 Figure 3.-Depth of inhalation among, cigarette smokers by age-Hammond--------------------------------------- 185 Figure 4.-Percent distribution ofl 130 brands of cigarettes and. 25' brands of littlle cigars by tar content------------------ 22'5 167 O ~ Ca~ ~ CJl'

Page Figure~ 5'.-Percent~ distribution of' 130~ brands~~ of' cigarettes and 25brands of little cigars by nicotine content______________ 226'. LI isU of Tables Tab1ei.-Percent distribut'ion ofU.S'., males~aged 21 and older by type of tobacco usedl for the years 1964, 1966, and 197'0-_ 173 Table 2.-Percent distribution of U.S. males by type,of'tobacco used and agefor 1970---------------------------------- 174' Table 3.. Percent distribution~ of' British~ males aged 25 and older by type of tobacco used for the years 1965, 1968, and 1977i'------------------------------------------------- 174 Table 4.-Amounts of' several components of' 1 gram of' par- ticulate material frorn~ mainstream smoke of tobacco prod- ucts ------------------------------------------------- 177 Table 5.-A comparison of sev.eral chemical compounds found in the mainstream smoke of cigars, pipes, and ci'garettes-_-_ 178 Table 6'. Mortality ratlios for totall deaths by type of'smoking, (males only)------------------------------------------ 180 Table 7.-Mortalit'yratiosf'or tlotaldeathsofcigar andl pipe smokers byy amount smoked-Hammond and Horn-------- 181 Table 8.-Mortality ratios for total deaths of cigar and pipe smokers by amount smoked'-Best----------------------- 181 Table 9. M'ortality ratios for totall deaths: of ci$ar, and pipe smokers by age and amounti smoked-li:ahn-------------- 1182 Table 1Q.-Mlortality ratios f'or total deaths of cigar and pipe: smokers by amount smoked-Harnmond!----------------- 182' Table11.-The: extent ofinhalingpipes,c'igars; and' cigarettesby British males aged 16' and over in~ 1968 andi 1971 ------- 186 Table 12.-Inhalation among cigar, pipe, and cigarette smokers by age-D'olll and Hill---------------------------------- 1W Table 13.-Mortality ratios for total deaths of cigar and pipe smokers~by age and inhalation-Hammond--------------- 187 Table 114.-Percentage of British male cigar smokers who re- ported inhaling a lot or a fair amount by type of product smoked---------------------------------------------- 187 Ti able 15.-P'ercentage of individuals reporting, inhalation of "almost every pufF" of tobacco smoke by current and pre- vioustobaccolusage and type of'tlobacco usedi------------- 188' Table 16.-Percentage of British males who reported inhaling a lot or fair amount of cigar smoke: by current andi previous tobacco usage and type of tobacco previously smoked (1968)----------------------------------------------- 188 168

~age !'26 73'. 74 f7 Page Table 17.-Extent of' reported inhalation of' cigar smoke by British male cigar smokers who were ex-cigarette smokers in, 11968, analyzed by extent,of reported inhalation of cigarettiee smoke.ehenpreviouslysmokingcigarettes----------------- 189 Table 18'.-Niortality ratios for total cancer deaths in cigar and' pipe smokers. A summary of prospective epidemiologicall studies----------------------------------------------- 189 Table 19. Relative risk of lip cancer for men, comparing cigar, pipe, and cigarette smokers with nonsmokers. A summary of retrospectYvestudies----------------------------------- 192 Table 20.-Mortality ratios for oral cancer in cigar and pipe smokers. A suQnmaryof'prospective:epidemiol,ogical'studies-- T9~3Table 2I1.-Ro1'ativerisk of' oral cancer formen„ comparing cigar, pipe, and cigarette smokers wath~ nonsmokers. A sum- mary of retrospective studies--------------------------- 194 Table 22.-Mortality ratios for cancer of' the larynx in cigar and pipe smokers. A summary of'prospective epidemiological studies----------------------------------------------- 196 Table 23.-Relative risk of cancer of the larynx for men, com- paring cigar, pipe, and cigarette smokers with nonsmokers. A summary of retrospective studies---------------------- 198 Table 24.-Mortality ratios for cancer of the esophagus in cigar and pipe smokers: A summary of prospective epidemio- logicall studies----------------------------------------- 200 Table 25.-Relative risk of cancer of' the esophagus for mens comparing cigar, pipe, and cigarette smokers with non- smokers. A summary of'retrospectlive studies--------------- 201 Table 26.-Mortality ratios for lung, cancer deaths in male cigar and pipe smokers. A summary of prospective studiies---- 204 Table 27:-Lung cancer death rates for cigar and pipe smokers by amount smoked-IDoll and Hill---------------------- 204' Table 28.-Lung, cancer mortality rat'ios for cigar and pipe smokers by amount smoked-Rahn---------------------- 205 Table 29.-Relative risk of lung, cancer for men, comparing cigar, pipe, andl cigarette smokers with nonsmokers. A summary of retrospective studiies------------------------ 206 Table 30.-Changes in bronchial epi'theliumi of male cigar, pipe,, and cigarette smokers as compared to nonsmokers---_ 209 Table 31_-Tumorigenic activity of' cigar, pipe, and cigarette smoke condensates in skin painting experiments on animals-_ 213 Table 32.-Mortality ratios for cardiovascular deaths in male cigar and pipe smokers. A summary of prospective epi- demiological studies----------------------------------- 2116 169 I 0 ® ® 0 0 I t

Page Table 33.-Mortality ratios for chronic obsttlruetive pulmonary deathsin m~a1ecigar and pilpesmokers. Asu.mmary of pros- pective epidemiolbgical stludies-------------------------- 219 Table 34.-Prevalence of respiratory symptoms andi illness by type of smoking--------------------------------------- 220 Table 35. Pulmonary function val'ues for cigar and pipe smokers as compared to nonsmokers--------------------- 221 Table 36'. Mbrtalirt,y ratios for peptic ulcer disease in male cigar and pipe smokers. Summary of prospective studies--- 222 Table 37.-Shipment of small andl large cigars destined for domestic consumption (1970; 1971, 1972)----------------- 227' Table 38,-Selected compounds in mainstream smoke-------- 228 Table 39.-The pH of the mainstream smoke of selected tobacco productas-------------------------------------- 228, 170

Intiroductiiorr r22 i'2!7 ~28. I28 This~ eha.pter, is a review of' the epidemiological, pathological, and esperimental data: on the health conseqpences of smoking cigars! and'~ I)ipes, alone, together, and in various combinations with cigarettes. Previous reviews on the health consequences of'~ smoking have dealt primarilyy with cigarette smoking. Although some of the material on pipes:and cigars presented in this chapter has been, presented in previ- ous reports of'the Surgeon General, this is the first attempt to summa- rize what isInown about the health effects,ofpipe and, cigarsmoking:, Since the use of pipes and cigars is limited almost exclusively to men in the: United States; only data on, men are included in this review.. The influence of pipe and cig~r smoking on health~ is determined byexaminiRrgtheoverall and specific, mortalityandi morbidiityeg-perienced by users of these forms of tobacco compared to: nonsmokers. Epidemilogical evidence suggests that individuals who limit their smoking to only pipes or cigars have overall mortality rates that are slightly higher than nonsmokers. For certain specific causes of deathyhowever„ pipe andl cigar smokers experience mortality rates that are as great as or, exceed those e$perienced! by cigarette smokers. Thiss analysis becomes more complea when combinations of smoking forms ar~e, examinedL Theoveral2 rnortalityrates ofl thosew1v) smoke pipes, cigars,, or both in combination with cigarettes appear to be inter- mediate between the high mortality rates of' cigarette smokers and' the lower rates of those who smoke only pipes or cigars. This might seem to suggest that smoking pipes or cigars in combination with ciga- rettes diminishes the harmful eff'ects of cigarette smoking. However, an analyTsis of mortality associated vr ith smoking combinations of ciga- rettes, pipes, and cigars should be standardi'zedl for the level of con, sumption of each of' the prodhzcts smoked in terms' of the amount smoked, duration of smoking, and the depth and degree of inhalation. f' or example„cigar smokers who also smoke a pack of cigarettes a day might be egpectedito have mortality rates somewhat higher than those who smoke only cigaret'tiesat the level of apack a d'ay„assumingthat, both groups smoke their cigarettes in the same way. Mixed smokers', who inhale pipe or cigar smoke in ai manner similar to the way they smoke cigarettes might bee expected to have: higher mortality rates than mixed smokers who do1 not inhale their cigars and pipes and also 1z1 1

resist inhaling their cigarettes. ~,~nf!ortunately, little of the published material on~ mixed cigarette, pipe, and cigar smoking contains, these types of'analyses or controls:A paradox seems to: exist between the mortality rates of ex-smokers of pipes~and cigars and ex-smokers of cigarett'es. Ex-cigarette smokers experience a relative decline in overall and certain specific causes of mortality following cessation. This decline is important but indirect evidence that cigarette smoking is a ma jor cause of the elevat'ed mor- tality rates experienced by current cigarette : smokers. In contrast to this finding„ several prospective epidem.iological investigationsy Hammond and'H'orn (I0), Best (9)~„Kahn ('50), and H'ammond! (38), have; reported higher death rates for ex-pipe and ex-cigar smokers than for current pipe and cigar smokers.. This phenomenon was ana- lyzedl by Hammond and Garfinkel (3J). The development of ill healthh often results in a cigarette smoker giving up the habit, reducing his daily: tobacco consumption, switching, to pipes or cigars; or choosing a cigarette lbw in tar and nicotline. In many instances, a~ smoking- related disease is the cause of ill health. Thus, the group of ex-smokers includes some people who.are illl from smoking-related diseases, and d'eath; rates anehigh among personsin:ill health.As' a result„ ex-cigarette smokers initially have higher overalll and specific mortality rates than! continuing cigarette smokers, but be- cause of the relative d'ecrease in mortality that occurs in those who quit smoking for reasons other than ill health, andl because of the dwindling number of i11i ex-smokers, a relative: decrease in mortality is observed (within a few years) following cessation of' cigarette smoking. The beneficial effects of cessation «ouldi be obvious sooner were it not for the high mortality rates of those who quit smoking for reasons of illness. A similar principle operates for es-pipe and ex- cigar smokers, but because of't!he lower initial risk of smoking these forms! and thereforethe:smaller margin, of benefi't' following cessationythe effect producedl by the ill ex-smokers creates a larger and more persistent impact on the mortality rates than is seen in cigarette smoking. For the above reasons a bias is introduced into the mortality rates of current smokers and!es-smokers of pipes and cigars,,so that a more accurate pi'cture of' mortality might be obtained' by combining the ex-smokers with tlie current smokers and looking, at the: resultant mortality experience. Because of' a lack of data that would allow a precise analysis of mortality among ex-pipe and' ex-cigar smokers, a detailed analysis of'these groups could not be undertaken in this review. For each specific cause of' death, tables have been prepared which summarize the mortality and relative risk ratios reported in the major t7z

ters Cers ;of ~ect lor- ,' to Ins, ~eIS ha- Lth his Xlg tg- nd kdd le- ho ke. by te Br 19 K- tI, re ~e, Ss ,e le lt f'. prospecti~--e and retrospective studies which contained' informationn about pipe and cigar smokers. The smoking categories used include: cigar only, pipe only, total pipe and cigar, cigarette only, and mixed. The total pipe and cigar category includes: those who smoke pipes only, cigars only;, and~ pipes and cigars. The mixed category includes : those who smoke cigarettes and cigars; cigarettes and pipes; and cigarettes; pipes, and cigars. 'Mortality and relative risk ratios were calculated relative to nonsmokers. The Prevalence of Pipe,, Cigar, and Cigarette Usage: The prevalence of pipe„ cigar, and cigarette smoking in the United States was estimated by the National Clearinghouse for Smoking and Health from~ population surveys conducted in 19641, 1966;,and 1970 (98; 99; 100). In each survey, about 2,500 intervieavs were conducted on a national probabilitysamp16 stratified bytyype of populationandl beographic area. The use of'these products among adult's aged' 21 and older is summarized in tables 1 and 2: The prevalence of pipe, cigar, and cigarette smoking in Great Britain for the years 1965, 1968i and 1971 is presented in tablu :;: TABLE L.-F~ercen;t distr~~ib'ution of ~TT.S::7>za,le smoke~rs~~ aged~ 21 andolder~ by type of tobacco used' for the years 1964, 1966„ and 1970 Forms used 1964 1968 1970 (percent), (percent) (percent) 1. Cigar only----------------------------- 2: Pipe only ------------------------------ 3'. Pipe and cigar-------------------------- 4. Cigarette only -------------------------- 5.~ Cigarette and cigar---------------------- 6: 8 1.7 3,9 28 6 11.3 ' 5.5 3.0 4. 9' 31.,2 9.9 5: 6 3: 6. 4.4 25. 9 6,6 6. 7. 8. Cigarette: and pipe:.--------------------- Cgarette; pipe, and cigar---------------- Nonsmoker-----------------------,------ 5j 3 7: 7 3417 4: 9: 61 3! 34. 3 5. 3 4 6 4410 Total------------------------------ 100.0 10010 100'.,0 Total pipe users; (2+ 3+6-}-7)--------------- Total cigar users (1+3'-{-5+7)-------------- Total' cigarette users (4-}-5+6-F7)----------- 18: 7 29. 9 52: T 1'9:, 2' 26. 7 52.41 17. 9 21. 2' 42: 3' Source: U.S. Department ot Healthi Education, and Welfare (98, 99,10n);. 173:

TABLE 2.-P'ercent dzstribution of U.S. male smokers by type of tobac= co used and' age for 1•970' Forms used' 1. Cigar only----------------- 2. Pipe only------------------ 3. Pipe and cigar-------------- 4. Cigarette,only-------------- 5. Cigarette:and'cigar---------- 6. Cigarette and pipe---------- 7. Cigarette;, pipe,, and' cigar---- E', Nonsmoker----------------- Tota1------------------ Number of persons in sample--- TataP pipe users--------------- Total cigar users-------------- Total cigarette users---------- Age groups 21to34 38to:44 45'to54, 55to64 65to75' + 3,7 6' 5 4.7 6.7 9.3 4 3' 3. 5 3.0 ' 3. 2 3.6 '. 3. 8 3.3 5. 2' 414 6'. 9: 28.8 29:0 27. 1 24:3' 13:61 6.8 : 10.4 5.5 5: 2' 41 2' 6.6 4.4 5.6 4! 0~ 3.8 . 5: 8 4.8 5.0 4. 0 1.4 40:2 38. 1 43:9 48:,2 57.2 100.0 100.0 100L 0 1M 0 100.10 1i, 0w 528 523 405 388 20. 5' 16. 01 18.8 15. 6' 15. 7 20. 1 25.01 20.4 20. 3' 21!. 8' 48. 1 48.6 43.3 37.5 ' 210 Source: M S. Department of'Health, Education, and Welfare (1A0). 11'AS1,E. 3,-Percent' distribution of British male smokers aged 25 and older by type of tobacco used for the years 1965, 1968, and 1971. Formsused: 1. Cigars only'----------------------------- 2. Pipe only------------------------------ 3. Cigarettes on1y----,--------------------- 4. Cigarettes and pipe~--------------------- 5. MixedIsmokers------------------------- 6. Nonsmokers'---------------------------- Total'---------------------------- Number of' persons in sample--------------- Total pipe users--------------------------- Total cigar------------------------------- Total cigarette~-------------------------,--- Source: Todd, G. F: (B!,). 1' 74 1965 1968 1971, 1.9 21 8 3.3 ' 5. 1 5.6 ' 5. 9'. 46.8 ' 45. 7' 40.8 '. 8: 0 7T 0 6: 1. 7. & 9. 1 8.4 30. 7' 29. 9' 35.4 100:0 100.0 100.0 3)576 3, 566' 3,594 13.9 14.3 13, 3 9.0 11.7 ' 11. 3 67,6 67.6 61. 6

The Definition and Processing of Cigars,, Cigarettes, and Pipe Tobaccos CigaretGes A. 3' B. 6 3. 6' L 2 3. 8 1.4 7. 2 10; ~ 388 The U.S+ Government has defined tobacco products for tax pur- poses. Cigarettes are definedl as "(1) Any roll of' tobacco wrapped in paper or in any substance not containing tobaccot and (12) any roll of tobacco wrapped in any substance containing tobacco which, because of its appearance, the type of tobacco used in the filler„or, its packaging and labeling, is likely to be offered to„ or purchased by, consumers as a cigarette described in subparagraph Cigarettes are further classified by size, but virtually all cigarettes sold in the United States are "`small ci'garettes"' whichl by definition weigh "not more~ than 3' pounds per thousand"' which is not more thani 1.361 grams per cigarette (',96). American brands of cigarettes contain blends of different grades of' Virginia, Burley, Maryland, and' oriental tobaccos. Several varieties of cigarette tobaccos are flue-cured. Ifn this process, tobacco leaves. are curedl in closed barns where the temperature is progressively raised over a period of several days. This results in "'color setting," fixing, and dry~-ing, of the leaf. The most conspicuous change is the conversionn of starch; into simpler sugars and suppression of oxidative reactions. Flue-cured tobaccos produce an acidic smoke of light aroma: (35,,112);. Cigars r Cigars have been defined' for tax purposes as:: "Any roll of tobacco ,vrapped in leaf tobacco or in any substance containing tobacco, (other than any roll of tobacco which: is a cigarette w ithin the meaning of subparagraph (2) of the definition for cigarette)"' (112). In order to clarify t!he meaning of' "substance containing tobacco" the Treasury d'epartment has stated that, "The wrapper must (1) contain a signi& cant proportion of natural tobacco;, (2) be within the range of colors normally found in natural leaf'tobacco; (3)': have some of the other characteristics, of the tobaccos from which produced;e.g:,nicotine content, pI-I,, taste,, and' aroma;, and (4)1 notbesochangedl in the reconstitution process that it loses a11 the tobaeco: characteristics" (102). Further, "To be: a cigar,thefilder, must besubstantial,'ly of' tobaccos unlike those in ordinary cigarettes and must not have any added flav.ori'ng which would cause the product to have the taste or aroma generallyattributed to cigarettes. The fact that a product dioes 1i75

not resemble a cigarette (suchas~ many large cigars do1 not~)and'has adistinetiv.e cigar taste and aroma is of considerable significance in making this determination" (102)1. Cigars are also classified bysiae, "Smalll cigars"' weigh notl more thani 3 pounds per thousandi and, "large cigars"' weigh more than 3 pounds per thousand. "Large cigars" are further divided intolseven classes for tax purposes based on the retail price intended by the manufacturer for such cigars (96). Cigarsaremad'eof'fi1d'er,, binder, andwrappert'obaccos. 'Mosti' cigar tobaccos are air-cured and then fermentedL Nfore recently; reconsti- tutedl cigar tobaccos have been used as wrapper, binder, or both. Cigars are either hand4ol'led or machine made. Some brands of'smalli cigars aremanufactured' on regular cigarettemakingmac;hines. 'Il'heaging, and fermentation processes used in cigar tobacco production producee chemical catalytic, enzymatic, or bacterial tiransformations as evi- denced by increased temperature, oxygen utlilizationy and carbon dioxide generation within fermenting ciYar tobaccos. ]fni this complex process, up to 20~ percent of'tlied~yweight of'theleaf is lost through decreases in theconcentlrat'ion ofthemostl readil'yfermentablema- terial's such as carbohydrates, proteins, and alkaloids. The flavor and aromaofeigartobaccosare iazi largemeasuretheresul~t'sof 'preciselycontrolled treatment d~uringtheferment'ation process(35; 36, 112). Pipe Tobaccos The definition of pipe tobacco used by the LT.S. Government was repealed in 11966 ' and there is no Federali tax on pipe tobaccos. The mostpopular pipetokiaccos~ are made of Burley; however, many pipe tobaccos are blends of different types of tobacco. A few contain a significant proportion of midrib parts that' are crushed between rollers. "Saucing" material, or casings containing licorice, sweetening agents, sugars, and other flavoring materials are added to improve the flavor, aroma, and smoke taste. These additives modify the characterist!ics of smoke components (112)'.. CancLu sian. B'ecauseof t!heuniquecuringand processing methods used in the production of cigar andl pipe~tobaccos; significant phy.si~cali and chemi- cal differences exist betweeni pipe and cigar tobaccos and thoseusedl i'n »b.

has a ce in, nore an 3 even the igar lsti- ~ars rars r 01ng *e evi- bon ilexx igh ha- ,ndi ~lY~ 'as he pee a tSy Cs cigarettes. The extent to whichi these changes may alter the health consequences of smoking pipes and cigars can best be estimated by an analysis of the potentially harmful chemical constitutents found in the smoke of'these tobaccos; the tumorigenic activity of smoke conden- sates in experimental animals, andi a review ofl the epidem.iological data which has accumulated on the health effects of pipe and cigar smoking.. Cliemi'cal Analysis of C:gar Smoke Only a few studies have i been conducted that compare the chemical constituents of cigar smoke with those found in cigarette smoke. Hoffmann, et al. (43) compared the yields of several chemical com- ronentls, in the, smokefrom ai pl'a7n 85 mm: cigarette,, two types of cigars; and a pipe. The particulate matter, nicotine, benzo(a)pyrene, and phenols were determined quantitatively in the smoke of' these tobacco products: One: cigar tested was a 135'-mmi long„ 7.8-g.,, U.S''.- madie cigar. The other was a handmade Havanai cigar 147 mm. long weighing 8.6 g. The relative content of nicotine in the particulate matter produced by the cigars was similar to that of the cigarette tars. The benzo(a)pyrene and phenol concentrations in the cigar condensate was two to three times greater than in cigarette "tar''" (itable 4). f£uhn, (58) compared the alkaloid and phenol content in conden- sat!esfroman 80-mrn. Bright-blend cigarette sold comrnerciallyinAustria with, that obtained' from 103-mm. cigars. These were tested TABLE 4.-Amounts of se77erall components of Z' g: o f particulate material from mainstt eam smoke : of tobacco products Tobacco product I Standard' 8.5 mm. 8.5' mm. Compound U.S. Havana pipe Cigarette plain U.S. plain UiS. cigar A cigar B tobacco tobacco cigarette cigarette (b) (b) in pipe, in pipe, (a) (b) (b) IrTicotine: (mg.)---------- 46.2' 63'.6' Benzo(a)pyrene (µg.) ____ 3.9 3. 6' Phenol (mg.)_----------- 8.2 6.7 a-Ctesoll (mg.)---------- 1.6 1. 7 m+p-Ciesol (mg.)------- 4.8 3: 8 m-}°p-Ethylphenoli (mg.)-_ 1. 1 1.5 56:1 61.0 65:9! 77:4 6. 0 3.6 L 2 1.3 15.0 7.3 ' 2.9 4. 1 1.9 1.4 .6 .8 '' 5.6 3. 4 1.4 1.9 1L 1 1.3' .7, .7 177 I Smoking conditions: (a) 1 puff' per minute, duration 2'scc., puff volume 35' ml. L (b) 2 puffs~ per: minute, duration12 sec:,.puff volume 35 ml. Source: HoHmann, et al. (.r,.4).

with and -without the use of a~ celhzl'oseacetatefilter. Tli~econcentra-tions of'totall alkaloids andi phenol in the cigar smoke condensate were essentially the same as in the cigarette condlensate, but pyridine values were about 21/2 ti~meshicher in the cigar condensate., Campbell and, Lindsey (T7) measured' the polycyclic hydrocarbons levelsin thesmoke of'asmal'1lpopular-type cigar 8.8'cm8 long, weighing, 1.9 ~ g.Significant quantities of anthracene; pyrene, ft'uoranthene, and benzo(a)pyrene were detected in the unsmoked cigar tobacco, in con~- centrations much greater than: thosee found in Virginia cigarettes butt of the same order as those found in some pipe tobaccos: The smoking process contributed consi:derably: to the hydrocarbon content of the smoke. Table 5 compares the concentrations in the mainstream smoke of'cigarettes; ci'gars;and pipes of fourhyd!rocarbons frequently found in condensates. The authors reported! that the mainstream smoke from a popular brand of small cigar contained the polycyclic aromatic hydrocarbons; acenaplithylene, phenanthrene, anthracene, pyrene, flnoranthene, andl benzo(a) pyrene. Theconcentrationse ofthese hyd~o-carbons in the mainstream smoke were greater than those found in Virginia, cigarette smoke. Osman, et al. (69) analyzed the volatile phenol' content of cigar smoke collected from a 7-g. American-made cigar wit.h: domestic filler.. Afterquantitativeanalysisof'ph:enol', cresols, xylenols,and'meta and para ethyl phenol,, the aurt•horsconcluded that the levelsofthesecom- pound'sweregeneral'1y siiniilar to those reported for ciga:rettesmoke. O'sma:n and Barson (68) also analyzed cigar smoke for benzene, toluene, ethyl benzene, m-, p-;, and o-xylene„ m- and p-ethyltohiene, 1',2,4' triin.ethylbenzene; andi dipentlene, and generally found levels within the.range of't:liose previously reported for cigarette condensates.. In summary, available evidence suggests that cigar smoke contains mani- of the same chemicali constituents, including nicotine and; other alkaloids, phenols, and polycyclic aromatic hydrocarbons as are found TABLE 5.-A comparison of several' cliemical''compounds faund' in the mainstream smoke of cigars, pipes, and cigarettes Compound 1Vlicrograms per 100 g: o('tohiacco consumed Cigars Pipes I ' Ci@arettps Acenaphthylene--------------------------- 1.6 29. 1 5: o: Anthracene------------------------------- 11.9 110. 0 10.9 Pyrene----------------------------------- 17.6 75!5: 12;5 3;4-benzp_vrene---------------------------- 3.4 8. 5 . 9 I This is a light; pipe tobacco. Source: Campbell, 7: M., Lindsey, A. J: (17). 178

lra- ere. ues ion 119 qid ~ Dn* but ~ ~ng :~ the ~ ~ke : nd ' ~ >rn ~ tiie ne, ~o- ; inn iar ~r. nd n* ke. sls . M ns ier id' !he in~ cigarette smoke: Most of these compounds are found in concentra- tions whicli equal or exceed levels found in cigarette "tar.'"' A more compl'ete picture: of the carcinogenic potential of cigar "tars"' is ob- tainedi from experimental data in animals., Mortality Overall MortalitySev.eral large prospective studies have examined the health conse- quences of' various forms of smoking. The results of' these investiga- tions have been reviewed in previous reports of the Surgeon General in~ which the major emphasis has been on cigarette smoking and its effect on overall and specific mortality and morbidity., The following pages present a current review of the health consequences of smoking pipes and cigars. Data~ from the prospective investigations of Dunny et al. (31), Buell,, et a1.(16)1,Hirayama(42),, and W"eir and Dunn (~105), are not cited, because in these studies a separate category for pipe and cigar smokers was not established.. The smoking habits and mortality experience of 187,783 white men between the ages of 50 and 69, who were followed for 44' months were reported by Hammond and Horn (~41) . The overall mortality rates of men who smoked pipes or cigars were slightly higher than the rates of men who never smoked. The overalll mortality rate of cigar smokers was slightly higher than that of pipe smokers. In a study of' 41,00(Y British physicians,, Doll and Hill (28, 27) re- ported the overall mortality of pipe and eigar smokers as being; only 1 percent greater than that among nonsmokers. Best (9),, in a study of 78;000 Canadian veterans, reported overall mortality rates of pipe andd cigar smokers slightly above those of nonsmokers. Kahn (50) exam- ined the death rates and smoking habits, of' more than 293,000: U.S.. veterans~ and Hammond (38) examined the smoking habits of and mortality rates experienced by 440;559 men. In these studies„ pipe smokers experienced mortality rates similar to t.hose of men who never smoked regularly;, whereas cigar smokers had death rates somewhat higher than men who never smokedi regularly. Table 6 summarizes the results of'these five studies., Thus, data from the major prospective epidemiological studies demonstrate that the use of'pipes and cigars results in a small but dlefi,- nite increase in overall mortality. Cigar smokers have somewhat higher death rates than pipe smokers, and mixed smokers who use cigarettes in addition to pipes and cigars appear to experience an inter- mediate levell of mortality that approaches the mortality experience of' cigarette smokers. 495-028,oL--73'-- 13 179

TnBLE 6.-M'orta:l'ity ratios for total deatJis by type of' smoking (males only) Smoking type A uthor„reference Non- smoker Cigar only Pipe only Cigar and pipe Cigarette and cigar Cigarette and pipe Mixed (cigarette and other) Cigarette only Hammond and Horn 1 (4o)---, 1. 00 1. 22' ll 12' 1. 10 1.36 ' 1. 50 1., 43' 1. 68 IDoTl and Hill (2s)--------- 1.001 ---- ---- 1.01 ------ ------- 1. llli 1.28 Best (9)'----_--- 1. 00 1.06 1.05 .98' 1.22' ll 26 1.13 1.54 Kahn (dQ)------ 1. 00 1. li0 1. 07 1. 081 ------ ------- 1.51 1.84 Hammond 2 (3&)--------- 1.00 1.25 1. 19 1.01 ------ ------- 1. 57 1.86 "Only mortality ratios for ages 50 to 69 are presented! = Only mortality ratios for ages 8.5 to 64, are presentedl Mortality and Dbse-Response R'elat'ionsliiPs A consistent association existls between overall mortality and the total dose of smoke a cigarette smoker receives. The methods most frequently used'o to measure dosage of tobacco products are : Amount smoked, degree of inhalat'ion, duration of smoking experience, age at initiation,, and the amount of tar in a given tobacco product. Forr cigarette smokers, the higher the dose as measured by any of tihese parameters, the greater the mortali'ty.The significance of the small'i increase in overall mortality that occurs for the entire group of pipe and cigar smokers can be analyzed by examining the mortality of subgroups defined by si¢niIar measures ~ of dosage as used in the study of cigarette smokers, A3TOUIr fr SMOKED H!ammond and' Horn (40) reported' an increase in the overall mor- tality of pipe and cigar smokers with an increase in, the amount smoked. lndiv iduals who smoked more than four cigars a day or more. than 10 pipefuis a day had deathi rates significantly higher than men who never smoked (P<0.05 for cigar smokers and P'<0.05 for pipe smokers) (t~able 7):. Cigar and pipe users who smoked less than thiss amount experienced an overall mortality similiar to men who never 160'

qales rette iy ..68 .28 54 L 84 186 '. he St rLt re Ir se Ie srnokedl Thestludyof Canadian veterans (9)al'so~conta.ined evidenceof' a dose-response in mortality by amount smokedl for cigar smoker5. No dose-response relationship was observedl among pipe smokers (table. 8). Kahn (50) reported a consistent increase in overall mortality with an increase in the amount smoked for both pipe and cigar smokers (table 9). Hammond (38) found' no consistent relationship bet«een overall mortality and the number, of cigars or pipefuls smokedl (table 10). TABLE 7~.-1Vlortality~ratios~for totat deaths of'cig,ar and~pipc smokers by, am:aunt smoked-Hammond' and Horn. Amount smoked' Number of d@aths Observed Expected 14lortalityratio Nonsmoker----------------------------- 1,664 1,664 1. 00! Cigar only: Total,-----,------,------------------- 653 598' 1.09' 1 to 4 cigars------------------------ 410 400 1. 03' >4 cigars-------------------------- 229 185 1L, 24 Pipe only: Total------------------------------ 609 560' ll 09 1 to 10'pipef'uls---------------------- 391 374' 1L 05 >10 pipefuls--------------,---,------- 204 172' 1'. 19 Source: Hammond, E. G., Horn, D. (40). TABLE 8.-Mortality ratios for tatal' deaths of cigar and pipe' smokers by amount smoked-Best Amount smoked Number of deaths Observed Expected Modality ratio S'. Nonsmolter------------------------- ---------- ---------- Cigar only: Total-------------------------- 90 821 0'7 I 1 to 2' cigars-------------------- 64 56! 05 3 to 10 cigars. ------------------ 23' 19: 40 > 1'0 1 cigars--------------------- 1 1. 59 t Pipe only: Tota1--------------------,------ 570 566.99' 1 to 1o1pipefuls------------------ , 374 370.09 10 to 20'pipefuls---------------- _-, 141 140.84 I >20: pipefuls------------------- 36 35.90 ~ Source: Best„E. W. R. (9). 1. U0 1: , 1'0 1L 14 !' 1.19 ' .63 1.00 1.01 1.00, 1.00,

The above e'vidence'suggests that a dose-response relia.tionship may exist between the number of cigars and pipefuls smoked and overall mortality. FIowe'ver,becauseof'thehigh-mortalit'y rate ofex-sm~oke'rs: . of cigars and pipes, it is difficul't to interpret the data presented with- out out including this group with the continuing smokers. Without data which examines patterns of both daily rate of smoking and inhal'ationn at various age'leve]iS, no firm conclusions can be drawn as to the'nature of this dosage relat'ionship, 'Tl'Anr.E' 9.-Mortality ratios for t'o~tdl~, death,s~ of cigar and pipe smokers by age and' amount smoked=Kahn' Mortality ratio„age. Amountsmoked 58 Qo 84 6S'to 74' Pilbnsmoker-----------'-------------------------- 1.00 1.00 Cigar only: Total-------------------------------------- 1.01 1.08 11 to 4 cigars per day------------------------- .89 ll 00' 5 to 8'cigars per day------------------------- -, 1. 14 1L 23'. >8' cigars per day-----'---------------------- 1.65 ' 1L, 28 Pipe only: Total!-------------------------------------- - 1.08 ' v. 06, 1 to 4 pipefuls per day----------------------- 1. 16 .91 5 to 19 pipefuls per day'---------------------- 1.04 1. 10, }19 pipefuls per day'------------------------ ---------- 1. 18 Source: Kahn, H. A. (5q). TABLE 10.-Mortality ratios for total deaths of' cigdr and pipe smokers by amount smoked`Hammond' Amount smoked Mortality ratlu lwTonsmoker----------------- 1L, 00 Current cigar smokers:. Total-------------------- 1L 09, li to 4 cigars per day------- ll 03 >4 cigars per day--------- ll 18 Source: Hammond,,El. C. (18)'. 1' 82 Amount smoked M'ortalitip, ratio Current pipe smokers: Total-------------------- 1. 04! 1 to 9 pipefuls per day----- 1.08 > 9' pipefuls per'dax------- . 92'

Inhalation ofl tobacco smoke directly exposes the bronchi and the lungs to smoke and results in the absorption of'the soluble constituents of the gas and particulate phases. Without inhalation tobacco smoke only reaches the oral cavity and the upper digestive and respiratory tracts and does not reach the lungs where further direct effects and systemic absorption of various chemical compounds can occur.. Although the smoker has some voluntary control over the inhalation of smoke, the physical and chemical properties of' tobacco smoke to a degree determine its acceptability and "'inhaTability.7D' The ~ condensate of pipe andi cigar smoke is generally found to be alkaline when the pH is measured by suspending a Cambridge filter in COz-free water. Cigarette condensate is slightly acidic as measured by this method. Since alkaline smoke is more irritating to the respira- tory tract, it has been assumed that the more alkaline smoke of pipes and cigars was in part responsible for the lower levels of inhalation reported by pipe and cigar smokers. Brunnemann and Hoffmann (15) have analyzed the pH of whole, mainstream smoke of cigarettes and cigars on a puff-by-puff'basis using a pH electrode suspended in main- stream smoke: Smoke from several U.S. brands of'cigarettes was found to be acidic throughout the entire length of the cigarette. Of' interest was the findang, that cigar smoke also had an acidic pH for the first two-thirds ofl the cigar and became alkaline only ini the last 20, to 40 percent of the puffs f rom the cigar. Available epideniiol'ogical evidence indicates that most cigar smokers do not inhale the smoke and mostt cigarette smokers db. The fact that smoke from the first half' or more of a cigar is acidic, near the range of pH values commonly found in cigarette smoke, and becomes alkaline only toward the end of the cigar might suggest that the pH of the smoke of a tobacco product may not be the only factor thatinfluences inhalation patterns. Per- haps"`tar"' and nicotine levels as well as the concentration of' ok,her"irritating" chemicals also affect the degree to which a tobacco smokee will be inhaled. Nicotine is rapidly absorbed into the blbod stream from the lungss when tobacca smoke is inhaledl The amount of nicotine absorbed frorni the lungs is primarily a function of the nicotine concentration in the smoke and the depth of inhalation. Some nicotine may also be ab- sorbed through the, mucous membranes of' the mouth. This is moree likely to occur under alkaline conditions .chen nicotine is unprotonated (3, 15, 79). This suggests that cigar smokers mayy be able to absorbb some nicotine through the oralcauity without having to inhale, par- ticulkarly during the time that the smoke from the cigar is alkaline. 1ea ,

With the development of' sensitive measures of' serum nicotine levels (48) the extent to which nicotine is absorbed through the membranes of' the mouth in pipe and cigar smokers can be more accurately determinedl, Inhalation patterns of' smokers were determined in severaI of thee large prospective and some of the retrospective epidemiological studies. Inhalation was usually determined' by the administration of a ques- tionnaire that required a subjective evalhiationi of one''s own patterns ofinhalati~on. A1'thoughi the accuracy of t!heseqpestionnaiereshas not been confirmed by an objective measure of inhalationS such as carboxy- hemoglobin or serum nicotine levels, their reliability is supported by mortality data whichdemonstlratehigber, overall andl specific death rat'eswith self-reported increases~ in the depth of inhalation. Doll and Hill (26) andI'-Iammond (3&')presented information on inhalation patterns of pipe; cigar, and cigarette smokers (figs. 1, 2, 3i and table 12). Some 80: to 90 percent of' cigarette smokers reported inhaling, with the majority of' individ'uals inhaling moderately or deeply, whereas most pipe and cigar smokers denied inhaling at all.. Pipe smokers reported slightly more inhalation than cigar smokers., For each type: of' smoking,, less inhalation: was reported' by older smokers: This change may represent less awareness of inhalation, differences in smoking habit's of' successive cohorts of smokers, or it may reflect the: operation of'selectivefactorswhichfavor survival' of noninhalers. The Tobacco Research Council' of the United Kingdom hast since 1957i„periodi'eally reported the use of tobacco products by the British, Figure I.-Inhalation among pipe smokers by age. M'o inhalation Some inhalation Age 40 SOURCE: Hammond„ E: C. (38): 50 60' 70' 80 184

4els lnes !ely the ies. ies- rns not Ky- by ~th on !ed or ull. M ler bn, it ~ !o,f, tce >h. Figure 2.-lhhalation among cigar smokers by age-Hammond. SOURCE: Hammond, E. C. (38). Figure 3.-Depth of inhalation among cigarette smokers by age: HammondL None Slight inhalation Moderate inhalation Deep inhalation AVge 40 SOURCE: Hammond'y E. C. (38)., Recent reports edited by Todd have contained data on the inhalation pattern of cigar, pipe, andi cigarette smokers (92, 93, 94). Table 11'i shows that most cigarette smokers inhale a "lot" of "fair amount" whereas most pipe and cigar smokers donot'inhaTeatalll or "just alittle."' Little change is observed in the inhalatiion patterns of a given product since 1968. Best(9): reported inhalation data among, malie cigarette smoker&by smoking intensity and age group, but did not report the inhalation~ 60' 70 80' 185

pat'tlernsof' pipe andd cigarsmokers, The overall mortality ratesofs current pipe smokers who inhaled at least slightly were reported by Hammond'! (38) as being somewhat higher t'han for men who never smoked regularly. The overalll mortlalityy rates of current cigar smokers who reported inhaling at least slightly were appreciably higher than for men who never smoked regularly (table 13). Available: evidence indicates that cigarette smokers inhale smoke to agreaterdogree than smokers~of cigarsorpipes:Once a smokerhasllearned to inhale eigarettes,,hmRever, there appears to be a tendency to also inhale the smoke of' other tobacco products. For cigars,, this is evidently true whether one smokes both cigarettes and cigars or switches from cigarettes tlocigars (tables 1!4, 15;16). Bi-ossand Tidings (14): examined th:einhal'at'ion patt'ernsofs smokers of' large cigars, cigarettes, and those «•.ho switched from one tobacco product to another (table 15). Nearly 75 percent of those who: were currently smoking only cigarettes reported inhaling "almost every puff" and only 7 percent never inhaled. The opposite was true for per- sons who had always smoked' only cigars among whomi 4 percent re- TA$LE' 11~.-Th,e~ extent of' inhaling pipes;, cigars, d~~nd~~ cigarettes~ 8y, British; males aged 16' and over in 196'8' and 1971 V Tobacco product Amount of inhalation ~ Cigars Pipes Cigarettes ~ 1968 1971 1968 1971 1958 1971 Iilhale a lot------------------------ 23 19 8 8 47 47 C Inhale a f'air amount---------------- 16 19 1'0I 8 31 W Inhale just a lit'tle------------------ 27 27' 24 ' 26' 13' 15 Do not inhale at a11L---------------- 34 35 59 58 9 8 P; Total------------------------ 100~ 100~ 100 100~ 1001 100 Sourae: Todd, Ci. F. (91; 94). TABLE 12.-lniial'ation among cigar, pipe, and' cigdrette smokers by .lr age-Doll and Hill Percentage of [nhalers, age Smoking type. 26'.to.34~. 35to~44 4b~to64 b8~to164~~. &5~.to74: >74~, Cigar and pipe---------------- 12.00 10.00 ' 7. 00, 5:-00 4.00 4.00 Mixed (cigarette and other)----- 74. 00 60. 00 47. 00 36! 00 30. 00 26.00 Cigarette onlx---------------- 90. 00 85: 00' 75. 00 66: 00 58. 00 41.00 Source: Doll, R'., Hill, A. B: (P6)i 186'

ported inhaling almost every puff and 89' percent said they never inhaleclL Cigar smokers who also smoked cigarettes reported inter- niedi'ate levels of inhalation between the cigar only and' cigarette only categories. Inhalation patterns~ weresimilar whet.her~ theindivi'dua1 continued to smoke both products, stopped smoking cigarettes but continued smoking cigars, or stopped smoking cigarettes and switched to cigars. In alll three groups, about 20 percent reportedd inhaling "almost every puff." This suggests that once an indi'vidualP's inhalation patt~ernsare established on cigarettes, hemaybemorelikel:y to inhale cigar smoke if he switches to cigars, or uses both cigars and cigarettes, than the cigar smoker who has not smoked cigarettes. Tad'd! (93) reported similar data for a sample of' smokers in the United Kingdom (table 16). The preti-.allence of! inhaling a"lot"' or "fair amount" of smoke was highest among cigarette smokers who -were currently smoking cigarettes (77percent)and lowest among, current cigar smokers who had previously smoked only cigars or pipes (188 percent). Individuals nho, switched from, cigarettes to cigars maiat- TABLE' 13,-Afortality ratios for total' dedtJts of cigar ¢nd' pipe smokers by age cund intuclat£on-Hdmmond Irlhalation hEortality ratio, age 45' to 84 , 65 ta 84 Nbnsmoker----------------------------------------- 1.00 1.00 Cigar only: Total------------------------------------------ ll 09 .98 No inhalationL -_---------,-----__ ---------------- 1.02 .91 Some inhalatlion--------------------------------- 1.28 1. 37 Pipe only: Total------------------------------------------ 1.04 .95 No inhalation-----,------------------------------ . 98 .87 Some inhalation--------------------------------- 1.21 1. 11 Source: Hammond, E. C:,(d8)., TnBLR 14.-Percentage of' British male cigar smokers who reported'g inhaling a lot or a fair amount by type of' product'smoked Type of product 1968 1971 Number of Percent Number oi Percent'. indiwidua]s individuais Cigars only------------------------- 706 23.0 111 27.0 Cigars and cigarettes----------------- 1, 193 42'. 0 277 44.0 Cigars and pipes--------------------- 596 35.0 109 32.0 Cigars;,cigarettes; and pipes---------- 26 52'.0 15 32.0 Source: Todd, G. F. (99. 9,1). 167

tainedl somewhat higher levels of cigar smoke inhalation than those cigar smokers who had never smoked cigarettes (30' percent). Toddl (93) examined further tlhe relationship between the inlialationn of' cigarette andd cigar smoke. In generaly cigarette smokers who switched to cigars were much less likely to report iiihaling, cigar smoke: than cigarette smoke:;, however, those who in the past reportedd inhaling cigarette smoke a"lot" or "fair amount"'' were much moree likely to report inhaling cigar smoke to the same degree tlian those ex- cigarette smokers who in the past did not inhale the smoke of their cigarettes, (ta}51e 17)~.. TABLE 15.-Percentage of' individuals reporting inlialdtion of "almost every puff" of tobdcco smoke by current and previous tobacco usage and' type of tobacco used' Type,of tobaeco smoked Number Percen- f T inh l d t Confidence limits - Current usage Previous urage ype a e age o patients inhaled: Lower Upper Cigarettes only---- Cigarettes only____ 2; 359 Cigarette__- 74.8 73: 1 76.6 Cigarsionly_______ CiRars onl'y_______ 649, Cigars----- 4. 5 3. 0 6. 0 Cigarettes and cigars. Cigarettes and cigars. 520 _____do__,___ 20: 4 10: 5 28.0 Cigars Cigarettes and cigars. 93I ----- do_____ 118.3 ' 9.0 30.0 None------------ Cigarettes and'. 186 ----- do_-___ 21.5 ' 17.8 24.2 ' cigars. Cigars----------- Cigarettes only---- 64 ----- do----- 117.2 16.0 281 0 Source: Bross, I:,D. J:,,Tidings;,L (14). TA;BLE 16.-Percentage of B'ritish males who reported' inhaling a lot or fdir, amount of cigar smoke : by current' dnd' previous tobacco usage and' type of tobacco previously smoked (1968) Type of'tobacco smolred, Number of individuals Type inhaled Percentage inhaled Current usage Previous usage Cigarett'esonly_-______ Cigarettesonly------ 2,586 Cigarette'-____ 77:7 Cigars only----------- Nonsmoker--------- 306 Cigars_______ 18.0 Cigars only--,---------- Cigarettes only------- 321 -----do------- 30:0 Source: Todd, O. F. (9k). 1186!

i kose li~on vho gar ted ore ~eg- keTr tost and' Fe' iper TABLE 17.-Extent of reported inhalation of' cigar smoke by British male cigar smokers who were ex-cigarette smokers in 1968; analyzed by extent of' reported' inhalation of' cigarette smoke when previously smoking cigarettes Extent of inhaling cigars Extent of inhaling cigarettes Inhale a lot Inhale a littln oriair amount or not at all' Percerel' Percent Inhale a lot or fair amount-----------------,------ 44.0 5.0 Inhale a little or not at all------------------------ 56: 0 95.0 Tota1------------------------------------ 100:0~ 100.0 Sample size------------------------------------- Source: Todd, (]I. F. (9S). 244 56 Speciflc Causes of Mortali'tty Cancer Several prospective epidemiological studies have'n shov'n a signifi- cantly higher overall cancer mortality among pipe and cigar smokers, compared to;the cancer mortality ofl nonsmokers (table 18)'. Pipe and cigar smokers have mu& higher rates of cancer at certain sites than at others. The upper airway and upper dfigestive tracts appear to be the most, likely target organs. The relationship of'pipe and cigar smoking to the develbpment ofl specific cancers i's detailed in the follbwing sections, TABLE 118.-Mortdli.ty ratios for total ' cancer deaths in cigar, and pipee smokers. A sumnzdry of prospective epidemiological'studies Type of smoking, Author~ reference Nonsmoker Cigaronly Eipe only Total pipe and cigar Cigarette only. Hammond'and Horn (!0)-,--- ll 00 1: 34 1. 44! -,--,----- 1.97 Bestl (9) ------------------- 1.00 L 13 1.38 -------- 2.06 Hammond (38) ------------- 1.00 ------- ------- 1! 21 1.76 Kahn (60)----,------,------- 1.00 1.22 ll 25' ll 25' 121 1'89

Cancer of the Lip. Approximately 11,500~ new cases of' cancer of the lip are reported each year. Because of the possibility of early detection and surgical accessibility of'cancers in this area, there aree less than 200~doaths from cancer of't'h:elip each year in the United States. Sotne,ofthe earliest seientific investigations exploring the association betweeni tobacco, use andd disease examinedi the smoking patterns of individuals with cancer of'the lip. Broders (13) in 1920 examined'' the smoking habits ofl patients in a retrospective study of' 526' cases of epithelioma of the lip andi 500 controls.. Of the cancer cases, 59 percent smoked pipes, whereas this was true for only 28 percent of'the control's. No association: was found betR.een cigar or cigarette smoking and cancer of the lip. In a restrospective study of 439' clinic, pat'ient's with cancer of' the lip andl 300, controls conducted in Sweden, Ebenius (32') reported a significant association between pipe smoking and cancer of tlie lip, A total of' 61.8 percent of the lip cancer cases smoked pipes, while only 22.9' percent of' the controls smoked pipes. No association was found between the use of cigarettes, cigars, or chewing tobacco and cancer of the lip. ][ni other retrospective studies, Levin, et al. (60) reviewed a series of' 143' cases of cancer of the: lip, and Sadowsky, et a1: (77)' reviewed 571 cases of cancer of'the lip. lfn both studies, a strong association was floundl between pipe smoking and cancer of the lip. No significant association was found between the use of tobacco in other forms and cancer at this sit'e: l[n, a study of environmental factors in cancer of the upper alimen, tary tract, Wyndier, et al. (113)', found an association between pipe smoking, cigarette smoking, and cancer of'thelip: There were only 15 cases of cancer of the lip in this study:S~taszewski (87)examinedi the smoking habits of 394 men with carcinoma or precancerous lesions of the lips. An associationi wasfoundl between tlh:e, smoking of pipes and cigars and cancer of the lip; but this was only of doubtful significance. A significant associationn was found between the use of'cigaret't'es and cancer of the lip. Keller (51) conducted a study of lip cancers in which he considered a number of factorsincluding, histologic types, survival,, race,occupa-tions„ habits, and associated diseases. A total of 304 patients with primary basal cell or squamous cell carcinoma of the lip and'i 304 controls from the same hospital matched for age and race «-ere con- sidered in this series. A significant association was floundl between smoking in a11 forms~ and'' combiziationsand carcinoma of thelip., Iitl was a1'so found that inereasing: age andi outdbor occupat'i'ons with exposure to~ thesuni wereequadly significant factors in the etiology ofl lip cancer. 190

In summary, it appears that there are several factors involved in the etiology of cancer of the lip. Among the various forms of'tobacco use, pipe smoking either alone or in combination with other forms of' smoking seems to be a cause of cancer of'the: lip. Table 19 summarizes the results of'these retrospective studies. Oral! Cancer The lips, oral cavity, and pharynx are the first tissues exposed to tobacco smoke drawn in through the: mouth. Variations in inhalation during,the smoking,of various.tobacco products result in different pat- terns of distribution of smoke throughout the respiratory tree. How- ever, the oral cavity and adjacent tissues are the sites most consistently exposed to tobacco smoke. For this reason, differences in inhalation should result in less variation, in exposure to tobacco smoke for these sites than for the lower trachea and t.he lung. The inherent carcinogen- icity of pipe, cigar, and cigarette smoke is most reliably compared at those tissue sites where dosage and exposure to, tobacco smoke are most nearly equal. Data from, the epidemiblogical studies suggest that little difference:exists between the smoking of'cigarettes„pipes„or cigars and the risk of developing orallcancer. Hammond and Horn (40) examined the association between smok- ing in, various forms and cancer of'the combinedi sites of lip, mouth,, pharynx, lary.nx,, and esophagus. The mortality ratios were 5.00 for cigar smokers,, 3.50 for pipe smokers; and 5.06 for cigarette smokers comparedto:nonsmokers. All the deaths from cancer of the lip, oral cav- ity, and pharynx reportedl by Doll and Hi1D (26) occurred in smokers.. The death rates from cancer at these sites were 0.04 per 1,000 for pipe and cigar smokers, 0:10 per 1,000 for mixed smokers, and 0.05: per 1,000 for cigarette smokers. A fairly detailed analysis of oral cancer was pre- sented by Kahn (50) who differentiated between cancer of the oral cavity and cancer of the pharynx. The mortality ratios for oral cancers were 1.00 for those who never smoked, 3.89 for all pipe and cigar smokers; and 4.09 for cigarette smokers. A further breakdown of the pipe and cigar smokers demonstrated a mortality ratio of'. 4.11 for cigar smokers, 3.12 for pipe smokers,,and 4!.20 for smokers of pipes and cigars. For cancer of the pharynx, the mortality ratios were 1.00 for those who never smoked,, 3.06' flor all pipe and cigar smokers; andl 12.5 for cigarette smokers. No deatihs oceurredl among those who smoked only cigars: The mortality ratio was 1.98 for pipe smokers and 7.76' for smokers of pipes and cigars. Hammondl (3b')' combined cancers of the lip, oral cavity, and pharynx. The pipe and cigar smokers had a mortality ratio~ of 4.94 and the cigarette smokers a mortality ratio of 9:90 compared to nonsmokers. 1I9'1

64VV941E0 TABLE 19.-Relat,ive risk of lip cancer for men, comparing cigar, pipe, and cigarette smokers with nonsmokers. A summary of retrospective studies Author, reference Broders (13) : Cases----------------------- Controls_____________________ Ebenius (32) : Cases----------------------- Controls____________________ Levin, et al. (60) : Cases----------------------- Controls____________________ Sadowsky, et al, (77) : Cases----------------------- ---- Controls____________________ Wynder, ' et al. (11 3) : Cases----------------------- Controls-------------------- Staszewski (87) : Ca,ses----------------------- Controls_____________________ Keller: (51): Cases----------------------- Controls--------------------- Number Relative risk ratio and percentage of cases and controls by type of smoking Nonsmoker Cigar only Pipe only Total pipe and cigar Cigarette only Miaed Relative risk____________ 1.0 0 0.8 4.3 --------- 0 --------- 537 Percent cases___________ 7 19 41 --------- 1 - 500 Percent controls_________ 4 16 6 --------- 26 --------- IZelative 1.0 .7 4.1 0.5 _______ _________ 439 Percent cases___________ 49 6 41 4 ------- --------- 300 Percent controls_________ 65 12 13 10 Itelative risk____________ 1.0 1.9 2.9 - 1 4 143 Percent cases___________ 15 27 48 -------- - --------- -- _ . - - 45 _________ - --------- 554 Percent controls_________ 22 20 24 --------- 46 --------- Itelative risk_ _ _ _ _ _ _ _ _ _ _ _ 1. 0 1. 1 4. 3 2.6 1.4 0.4 571 - Percent cases___________ 8 2 18 6 44 22 615 Percent controls_________ 13 3 7 4 53 19 Relative risk------------ 0 . 8 1.8 --------- 1.0 2.2 14 Percent eases___________ - 0 7 29 --------- 36 29 115 Percent controls_________ 24 9 16 --------- 36 13 Itelativerisk------------ 1.0 _________ 2.1 2.4 ________- 394 Percentcases------------ 7 _________ 12 73 _________ 912 Percentcontrols_-_______ 13 _______-_ 11 61 __-______ Relativerisk____________ 1.0 1.4 4.0 2.6 301 Percentcases------------ 7 2 6 1 60 6 265 Percentcontrols--------- 17 4 3 0 53 0 I Percentage based on less than 20 patients. Ratios: relative to cigarette smokers. ;.

These studies are summarized in table 20: They demonstrate that <wokers experience a large:andsignifieant risk of developing, cancer uf the oral cavity compared tononsmokeils: This risk seems~tobeabout rhe same for all smokers whether an individual uses a pipe, cigar, or i ~ aret.te.. 1 number of retrospective studies have examined the relationship between smoking in various foims and cancer of'tlte orat cavity. Thee results of these studies are presented in table 21L Some of the variations i n relative risk of'developing, oral cancer observed in the retrospective ~ -tliclies is probablyy dhie to the lack of a uniform definition of oral cancer r 1)v anat'omie,al sit''eand the variaus, means used in sel'ecting, and deff!n-{ in r cases and controls. It appears, however, that a significant risk of t developing oral cancer exists for smokers compared to nonsmokers and this ri'sk is similar for smokers of pipes, cigars, and cigarettes. j Several epidemiological investigations liave demonstrated an asso- ? <<iation between the combined use of alcoholi and tobacco and the ~ de~~elopment of oral ll cancer.X few of these studies (i52, 6°~y6~3, 109)~~ i contain data on pipe and cigar smokers. Heavy smoking andi heavy ~ drinking are associated withi higher rates of oral cancer than are seen { with either habit alone. 1 TAsnE 20.-11'lort¢lity ratios for oral can+cer in cigar and pipe smokers. A summary of prospective epidemiological studies e 0 ® Author;, reference. m ~ ~ Hammond'and Hornl'(40)- Doll and Hii11,2 ' (26,,2'7)--- Hammond ('38)---------- Kahn (b0)',: Oral 4'----------,---,- Pliarynx'------------ Smoking type Non- smoker Cgar only Pipe only Total pipe and cigar Cigarette only Miaed' 1.00 5: 00 3. 50 -------- 5. 06 -_------ 0. 00: -------- ------ 0: 80, 1.00 2: 00 1.00 -------- ------ 4.94 3'9. 90' -------- 1L 00 4.11 3. 12 3,89 4.09 -------- 1.00 -------- 1'.98' 3.06 12. 54 -------- I Combines dataSor oral;,laryna; and esophagas:, 2 Ratios: re]ative to cigarette smokers. 3 Mortality ratios for ages 45 to 64 only are presented. 4'Eacludes pharynx. c 0 Cancer of the Larynx The larynx is situated at the upper endl of the trachea. Because of! its' proximity to the oral cavity, the larynx probably has a similar' exposure to smoke d~ra.vn through the mouth as the buccal cavity and phaaynx. Tobacco smoke that is not inhaled! may stilll reach as far as the larynx and upper trachea. Pipe, and cigar smokers develop cancer of thelitrynx at rates comparable to those of cigarette smokers. These a. 1'93

3?AALt: 21.-Relative risk of oral cancer for men, comparing cigar, pipe, and cigarette smokers uilh nonsmokers. A summary of retrospective studies Author reference Relative risk ratio and percentage of cases and controls by type of smoking Number ------ , Nonsmoker Cigar only Pipe only Total pipe and cigar Cigarette Mixed only n7ills and Porter (65): Relative risk_____________ 1.0 -________ -------- 7.0 4. 1_________ Cases----------------------- -- 124 Percent cases------------ 10 --------- -------- 55 36 --------- Controls-----------. -------- 185 Percent controls---------- 38 --------- -------- 30 32 --------- Sadowsky, et al. (77): Relative risk_____________ 1.0 2.0 4.4 --------- 1.4 2. 1 Cases----------------------- 1, 136 Percent cases____________ 8 4 i8 --------- 42 28 Controls_____________________ 615 Percent controls---------- 13 3 7 --------- 53 23 Schwartz, et al. 1. (&3) : Relative risk------------- 1.0 _ _ _ _ _ _ _ _ _ ---- 1.6 --------- 1.5 --------- Cases----------------------- 332 Percent cases------------ 16 3 --------- 63 --------- Contr-ols-- - - - - - - - - - - - -------- 608 Percentcontrols---------- 23 77 3 --------- 58 -- ------ Wynder, et al. (109): --- - - - Relative risk_____________ 1.0 3.6 6. 1_ --------- 3.0 3 3.3 Cases----------------------- 543 Percent cases------------ 3 20 - 11 --------- 57 8 Controls_____________________ 207 Percentcontrols---------- 10 13 6 --------- 63 8 Wynder, et al. (113): Relative risk_____________ 1.0 1. 7 .9 _________ 1.2 1.4 Cases----------------------- 115 Percentcases------------ 23 13 12 --------- 37 16 Controls_____________________ 115 Percentcontrols---------- 26 9 16 --------- 36 13 I8VV944c0

::,~ , ... Wynder, et al. (116) : Relative risk_____________ - - 1.0 6.0 -------- -------- .P. Case9----------------------- 178 Percent cases---__-_--__- 4 33 -------- -------- ~ Controls--------------------- 220 Percent controls__--_-_-__ 16 22 0 N x Pernu (73): Relative risk_____________ - - 1.0 - -__-_-__ 3.6 -------- I Cases----------------------- 1,400 Percentcases___-___-____ -- 21 ________ -- 10 ________ w Controls_____________________ 713 PercentcontroLs__-____-_- 39 -------- 5 ________ I ~ Staszewski (87): Relative risk_____________ 1.0 -_______ 3.5 Cases----------------------- 383 Percent cases____________ 6 -------- 13 Controls_____________________ 912 Percent controls---------- 17 it Keller (52) : R.elative risk_____________ 1.0 3.1 3.8 2.2 Cases----------------------- --- 408 Percent cases____________ -- 5 7 4 10 Controls_____________________ 408 Percent controls__________ 14 6 3 13 Martinez (62): Relative risk_____________ 1.0 1.7 1.3 ________ Cases----------------------- ---- 170 Percentcases____________ 8 10 1 ________ Controis--------------------- 510 Percent controls__________ 14 10 2 Martinez 1 (63) : Relative risk_____________ 1.0 2.0 2.8 ________ Cases----------------------- 346 Percent cases___-________ 12 10 15 _____ Controls--------------------- 346 Percent controls__________ 22 9 1 F This study comhtnes data for oral cancer and cancer of the esophagus. zeVV94,C0 2.2 59 50 2.9 11 7 3.6 --------- 72 --------- 61 _________ 3.4 ________- 69 --------- 56 __-_---_- 1.5 2.3 39 34 44 25 1.7 2.5 34 34 36 25

rates are several times the rates of nonsmok:ers. The siQnilarity of the mortality ratios of cancer of the larynx f'or smoking in various fonns suggests that the carcinogenic potentials of the smoke from cigars,, pipes, and cigarettlesare quite alike at thissi'te. Several of tlhe~ prospective epidemiological studies include d'at~aan deaths from cancer of the larynx for pipe and cigar smokers as «eldl as forcigaretlt'esmokers.Havnmond and I-1orn (40), combined data for cancer ofl the larynx with cancer of the esophagus and oral cavity. The mortality ratios comparredi to nonsmokers were 5'.00~ for cigar smokers, 3.50~ for pipe smokers, and 5:06' for cigarette smokers, Tlrere were no deaths from carcinoma of' larynx among nonsmokers in tlhe' study of I>1'ri'tish physicians by Doll and Hill! (26:)~ ; however, thedcath rate for cancer of the lary.nx among pipe and'cigar smokers:was 0.10 per1I,000 wh:ilethe deathi rate.f'or cigarette smokers was 0.05' per 1,000. Kahn ('50)reportedmortallityrat'~i'osforcancer of'thelarynx of10:33' for cigar smokers; 9!441 for pipe and cigar smokers, 7.28 for all pipe and cigar categories'combined~ and 9.95 for cigaret!te smokers: No deaths from cancer of the larynx occurred in pipe smokers: 1-I<ammond (38) reported a mortality ratio of 3.37' for all pipe and cigar smokers and a mortality ratio of 6.09 for cigarette smokers in the age category 45 to 64. These studies are summarized in table 22. Several': retrospective studies have examined the smoking habits of patients with cancer of the larynx and appropriately matched controls. The small number of'e pipe and'r cigar smokers ihi each study results in relative ri'sk ratiost that are quite unstable; however, it appears tliatt pipe and cigar smokers experience a risk of' developing, cancer of'thee larynx that is similar ta the risk observed among cigarette smokers (table 18). TABLE 22.-Mbrtality rdtios for cancer of th,e larynx in cigar and pipe smokers. A summary of prospective epidemiological st'ud'2es Author, reference Smoking,type Mixed Non- Cigar only Pipe only Total pipe Cigarette smoker and cigar only. Hammond and Horn 1 (40) ------------------ 1.00 5.00 3.50 -------- 5.06 -------- Doll and'Hill z(26; 27)--_ 0: 00, -------- ------ 2.00 L 00 0.60 Hammond (38)'---------- 1. 00 -------- ------ 3. 37 3 6. 09......... Kahn (50) -_ -,-_ -,------_ _ 1.00 10.33 ' ------ 7.28 9.95 -------- I Combines data for oral, larynx, and esophagus. I Ratios: relative to cigarette smokers. 3: onlymortality ratios, for ages 45 to fr4'are presented. 1'96

the 'ns rs,, oni elll or ty. ;ar ~re in be ,as ler ~of a.ll Jo' 4d its ry ~ df. Is.. in at. lie rs. Wynder, et al. (108, 113) distinguished' between intrinsic and ex- trinsic larynx caneers: For smokers the relative risk of' developing cancer of the intrinsic larynx was similar to the relative risk of lung, cancer whereas the relative risk of dev.eloping extrinsic larynx cancer was more like the relative risk of cancer of theiupper digestive tract. Histologic changes of the larynx in relation to smoking ini various forms were described by Auerbachy et al. (5):. Mi.croscopic sections of'~ the larynx from~ 942 ' subjects were examined flor the presence of atypicali nuclei andi proliferation of' cell rows. Sectionsi were taken from four separate areas of the larynx in eachicase: Among those who smoked cigars and pipes but'nat cigarettes;only I percent had no~ atypical cells and niore than i5i percent of the subjects had lesions with 50 to 69 percent atypical cells. Four of'the cigar and pipe smokers had carcinoma in situ and in one of these four cases earlyy invasion was seen in three of the sections. Of those who never smoked regu- Iarly.,i5 percent had no atypical cells. Tlieci'garand pipesm~okers,had ai similar percentage of cells n it.h atypical! nuclei as cigarette smokers who smoked one to two packs per day,. With respect to the proli£era, tion of cell rows in the basali la}•.er of the true vocal cord; the least proportion of cases with eight or more cell rows was found in men ,,ii never sm~oked,, and the greatest proportion was found in heavy cigarette smokers. Pipe and cigar smokers had a distribution of celll rows that was comparable to that of cigarette smokers who consumed about a pack a day. Several retrospective studies have reported an association between t'.he combined' use of tobacco and alcohol and cancer of the larynx. A study by `Vynder, et al. (108) included some information on pipe and cigar smoking in relation to drinking habits and the develop:nent of cancer of the larynx,, but because of the limitied number of' pipe and cigar smoking subjects this relationship could! not be adequately determined. Cancer of the Esophagus The esophagus is not dfirectly, exposed to tobacco smoke drawn into the niouthi; however, the esophagus does have contact with that portion of tobacco smoke that is condensed on the mucous membranes of the mouth and pharynx and then swallowed. The esophagus i's also ex- posed to a portion of tobaccosmoke, tllatis~deposit,edl in the mucus cleared from tlle lung by the ciliary mechanismior by coughing. Varia- tions in inhalation of~ atobacco, product maynot appreciably alter the~ exposure the esophagus receives from smoke dissolved in mucus and saliva. This suggest.ion receives support from the prospective and retrospective epideneiolopcal studies which demonstrate simillar mor- tality rates for cancer of the esophagus in smokers of'cigars, pipes, andl cigarettes. 197

TABLE 23.-Relative risk of cancer of the larynx for men, comparing cigar, pipe, and cigarette smokers with nonsmokers. A summary of retrospective studies Author, reference Number Relative risk ratio and percentage of cases and controls by type of smoking Nonsmoker Cigar only Pipe only Total pipe and cigar Cigarette only Mixed Schrek, et al. (s1) : Relative risk------------ 1.0 0 1. 1 --------- 2.3 --------- Cases----------------------- 73 Percent cases----------- 14 0 7 --------- 80 --------- Controls--------------------- 522 Percent controls--------- 24 10 11 --------- 59 --------- Sadowsky, et al. (77) : Relative risk------------ 1.0 2.2 2.3 --------- 3.7 4. 1 Cases----------------------- 273 Percent cases----------- 4 2 5 --------- 60 29 Controls--------------------- 615 Percent controls--------- 13 3 7 --------- 53 23 Wynder, et al. (108) : Relative risk------------ 1.0 15.5 27.7 11. 1 24.6 --------- Cases----------------------- 209 Percent cases----------- .5 8 5 1 86 --------- Controls--------------------- 209 Percent controls--------- 11 10 4 2 74 --------- Wynder, et al. (118) : Relative risk------------ 1.0 9.7 4.5 --------- 6.3 6.3 Cases----------------------- 60 Percent cases----------- 5 17 15 --------- 47 17 Controls--------------------- 271 Percent controls --------- 24 9 16 --------- 36 13 Wynder, et al. (116) : Relative risk----------- 1.0 14.5 16.0 --------- 22.0 16.0 Cases----------------------- 142 Percent cases----------- 1 20 1 --------- 62 16 Controls--------------------- 220 Percent controis--------- 16 22 1 --------- 45 16 A f. 9.7 i SSVV94EO

9gVV944C0 _ __ia---- Pernu (73): Relative risk------------ 1.0 ___-___-_ 4.5 --------- 8.7 3.2 Cases----------------------- 546 Percentcases-__--______ 7 __--___-_ 4 ____ ----- 78 4 -- Controls--------------------- 713 Percent controls--------- 39 --------- 5 - ---------. 50 7 Staszewski (87): Relative risk------------ _ 1.0 -_____--_ --- 5.9 50.2_ __-____-- Cases----------------------- --- - 207 Percent casee----------- - -- . 5 _-_______ -- 2 88 --------- _-- Controls--------------------- 912 Percent controls--------- 17 --------- 11 61 _______-_ Svoboda (90): Relative risk------------ 1.0 --------- 2. 6 --------- 10.0 --------- Cases----------------------- 205 Percent cases----------- 3 _ 3 --------- 95 --------- Controls--------------------- 320 Percent controls--------- 22 --------- 7 --------- 71 --------- Stell (&&) : Relative risk------------ 1.0 _____-__- 1. 3 2.4 --______- Cases----------------------- _ -- - 190 Percent cases----------- - --- 11 -_____-__ 8 79 --------- Controls_____________________ 190 Percentcontrols--------- 17 ___--_-__ 10 50 ---------

In the prospective epidemiological studies, cigar,, pipe, and cigarette smokers alll had similar mortality ratios f'rom cancer of the esophagus. Hammond and Horn (4D)' combined the categories of carcinoma of the esophagus, lEarynx, pharynx, oral cavity, and lip and described mortality ratios of 5.00 for cigar srnokers, 3.50' for pipe smokers, andl 5.06 for cigarette smokers. Dolll and Hill (26) reported an esophageal' aancer mortality ratio of 2:0'for pipe and cigar smokers„4.8 for mixedl Smokers, and 1.5' for cigarette smokers. Kahn (50) reported the fol- lowing mortality i atias for smoking in various forms cornpared to non- smokers: cigar only, 5,33; pipe only, 1.99;, pipe and cigar, 4.57; all pipes and cigars combined, 4.05; and cigarettes only, 6.17. The results of these prospect.ive studies are summarized in table 24. Several retrospective investigations have also examined the assoeia, tion~ between smoking in various forms and cancer of the esophagus. These studies have been summarized in table 25. The evidence sug- gests that cigar, pipe, and cigarette smokers develop cancer of the esophagus atrates substantially higher than those seen in nonsmokers, and that little dift'erence exists between these rates observed in smokers of'pipes and cigars and cigarettes. Histologic changes in the esophagus in relation~ to smoking in vari- ous forms were investigated by Auerbach, et all (7), who looked for atypical nuclei, disintegrating nuclei, hyperplasia, and hyperactive esophageal glands. A total ofl 12,598 sections were made from tissues obtained fromi 1,268 subjects. For each of t.he parameters investigated, pipe and cigar smokers demonstrated sigmificantl more abnormal histologic changes than nonsmokers; however, these changes were not as severe or as frequent as those seen in cigarette smokers. Several retrospective studies conducted in the I7nitedl States and other countries have examined the synergistic roles of tAbacco use and heavy alcohol intake on the development of cancer of the esophagus. Four ofl these investigations contain data on pipe and cigar smoking (12, 62, 63: 107). It appears that smoking in any form in combination with heavy drinking results in especially high rates of cancer of the esophagus.. TnsLE~ 24.-Morttclity, ratios for cancer of the esophagus in cigar and pipe smokers: A summary of prospective epidemiological studies Smoking type Author, reference Non- smoker Cigar only Pipe only Tbtal pipe and cigar Cigarette only Mixed HammondlandHbrnJ'(40)_ 1.00 5.00 3! 50 -------- 5.06 --_-_--- IDo11 and Hill (.°C6; ,°L7),__,-_ 1.00, -------- ------ 2.00 1.50 4180 Hammondl (3S)---------- --, 1.00 --------, ------ 3: 97 "4. 17 -,------- Kahn (60)'-------------- 1. 00 5.33 1.99 4.05 6. 17 -------- I Combines data for oral, Jarynx,,and esophagus. 2 Mortality ratio for ages 45'to &Sl 200

o; 1 fI-- y ~• 11 m TABLE 25.-Relative risk of cancer of the esoph,dgus for men, comparing cigar, pipe, and cigarette smokers with nonsmokers. A sumrriary of retrospective studies N Q 8gI.I'V9I'f:0 Relative risk ratio and percentage of cases and controls by type of smoking Author, reference Number - -------- Nonsmoker ------- - Cigar only Pipe only Total pipe and cigar -- Cigarette only Mixed - Sadowsky, et al. (77): Relative risk------------ 1.0 4.8 3.8 5. 1 3.8 3.3 Cases 104 Percentcases - - -- 4 5 8 6 60 18 ----------------------- _-- -- - --- - Controls--------------------- 615 Pereent controls--------- 13 3 7 4 53 19 Wynder, et al. (118): Relative risk------------ 1.0 3. 1 2. 1 --------- 2.6 . 4 Cases 39 Percent cases - -------- 13 15 18 --------- 51 3 ----------------------- --- - - Controls--------------------- 115 Percent controls --------- 24 9 16 --------- 36 13 Pernu (73) : a Relative risk------------ 1.0 --------- 3.0 --------- 2.7 5.9 Cases 202 Percent cases----------- 17 --------- 7 --------- 59 18 ----------------------- ---- Controls--------------------- 713 Percent controls --------- 39 --------- 5 --------- 50 7 Schwartz, et al. (84): Relative risk------------ 1.0 --------- 2.6 --------- 11.7 8.6 Cases----------------------- 249 Percent cases----------- 2 --------- 2 --------- 88 7 Controls--------------------- 249 Percentcontrois--------- 18 --------- 7 --------- 67 7 Wynder and Bross (107): Relative risk------------ 1.0 3.6 9.0 6.0 2.8 3.7 Cases----------------------- 150 Percent cases----------- - 5 19 9 4 51 11 Controls--------------------- 150 Percent controls--------- 15 16 3 2 55 9 ,.

N 0 N TABLE 25-Relative risk of cancer of the esoph,agus for men, comparing cigar, pipe, and cigarette smokers with nonsmokers. A summary of retrospective studies.-.-Continued Author reference Number Bradshaw and Schonland (12): Cases----------------------- 117 Controls--------------------- 366 Martinez ( 62) ; Cases----------------------- 120 Controls--------------------- 360 Martinez ! (63): Cases----------------------- 346 Controls-------------------- 346 Relative risk ratio and percentage of eases and controls by type of smoking Nonsmoker Relative risk------------ 1.0 Percenteases 15 ----------- - Percent controls--------- 32 Relative risk------------ 1.0 Percentcases----------- 8 Percent controls--------- 14 Relative risk------------ 1.0 Percentcases----------- 21 Percent controls--------- 22 Cigar only --------- --------- --------- 2.0 9 8 2.0 10 9 Pipe only - Total pipe -and-cigai Cigarette only Mixed 4._ 8_ -------- 2. 3--------- 41 -------- 63 --------- 18 -------- 58 --------- -------- 1.5 2.2 -------- 31 43 -------- 34 34 2.8 -------- 1. 7 2.5 15 -------- 34 34 1 -------- 36 25 I This study combines data for oral cancer and cancer of the esophagus. ~ r ~ ~ ~ + CT n . F ~ m ~ u Z F' ~ .~ ~ O © .., - g urc - Gr ~ y 4; "'7 Q rp ~ ry U v~ n c~ ~D !Y ~ ^'3 n ~ cfl ,..r r 9 m f8~~9~~:0

Lung Gancer. Abund'ant evidence has accumulated from epidemiological~ experi- »iental, and autopsy studies establishing, that cigarette snn.oking is the major cause of lung cancer. Several prospective epidemiological! studies have demonstrated higher lung cancer mortality ratios for pipe and cigar smokers than for nonsmokers, but the risk of d'eveloping,lung cancer for pipe and cigar smokers is less than for cigarette smokers. Table 26 presents a summary of' these prospective studies.Dose- i esponse relationships such as t'hose that helped demonstrate the nature of'the association between cigarette use and lung cancer could not be as thoroughlystudied for pipe and' cigar smokers because of the rela- tiv ely few smokers in these categories. Although the number of deaths were few,,Doll and Hill (26) reported increased death, rates from lung, cancer for pipe and cigar smokers with increasing tobacco consump- tion (tablE27)..Kahn (50) also demonstrated a dose-response relation- ship for lung cancer by the amount smoked (table 28). A few of the retrospective studies contained enough smokers to allow an examination of dose-response relationships for pi'pe an:d cigar smok- ing and lung cancer (1, 61, 74; 77). An increasedi risk of developing lung cancer was demonstrated with the increased use of pipes and cigars as measured' by amount smoked and inhalation. The retrospec- tive i'nv estigation of Abelin, and Gsell (1) is of particular interest, The smoking habits of 118 male patients with cancer of the hing from a rural' area of Switzerland were compared with those reported in a sur- vey of' all male inhabitants ofl a~ tawn ini the same ree on. About 20~ percent of the population of this: area were regular cigar smokers, the nlost'popular cigar being the Stumpen, asmald S~viss-made machine- manufactured cigar cut at both, ends with an average weight of 4.5 g. Iln this investigation, cigar smokers experienced a risk of developing lung cancer that was similar to the risk of cigarette smokers. A dose- response relationship was demonstrated for inhalation and amount smoked. These data suggest that the heavy smoking of certain cigars may result in a risk of lung cancer that is similar to that experienced by cigarette smokers. Several pathologists have reported histologic changes in the bronchiall epithelium in relation to~smoking in various forms:Knudt- son (57)~ examined the bronchial mucosa ofl 150 lungs removed at au- topsyy and correlated the histologic changes note.dl with the history of smoking, age, occupation, and residence. Specimens obtained from the six cigar, and pipe smokers demonstrated basal cell hyperplasia;; however, there was no squanious or atypicali proliferative metiaplasiaa as is frequently seen in the heavy cigarette smokers. Sanderud (78) examined histologic sections from the bronchiali tree of' 100 male autopsy cases for the presence of' squamous epithelial. 203 1

metaplasia. In this study, 39 percent of the populittioni were non- smokers, 20 percent were pipe smokers,, and 38 percent smoked cig- arettes: A total of 80 percent of the pipe smokers and cigarette smokers diemonstrated squamous metaplasia of'the bronchial.t'ree, whereas only 54 percent of'the nonsmokersl2ad this abnormality. Auerbachy, et al.(6), examined 3~6;340histologiic sect'iionsobtainedfrom 1,522! white adul'tsfbr variousepithelial lesions including: presence or absence of'cil'iated cell§, thicknes&or number of'cell rows, atypical nuclei, and the proportiom of cel2s of' various types. The pathologic findings in the bronchial epit.helium, of pipe and cigar smokers are compared to those found in nonsmokers and cigarette smokers (table 25)!. Pipe and cigar smokers had abnormalities that were'intermediat,e'between thoseof'nonsmokersand cigaret't~esmokers;although cigar smokers had pathologic changes that in some categories approached the changes seen~ in cigarette smokers. TnBLn~ 26~.-Mortality, ratios~~ for' lu~n.g, cancer deatlts ' in male, ~ cigar and'~ pipe smokers: A summary of ' prospective studies Auth fe Type of smoking or, ,re renoe Non- smoker Cigar only Pip' a only Totl;l'pipe and cigar Cigarette Di~iaed' only. Hammond and'Horn (40)- 1. 00, 3,35 ' 8.50 -------- 23, 12 19.71 Doll and Hill (26, 27)--,-- 1. 00' -------- -----,- 6. 14 13.29 7: 43' Best (8)' --------------- 1.00 2.94 4.35 -------- 14.91 -------- Hammond (38) ---------- 1.00 1.85 I 2.24 1.97 9: M 7.39 Kahn (6.q)-------------- 1.00 1. 59! 1.84 1.67 12. 14 -------- TAByE 27.-Lung cancer death rdtes for cigar and pipe smokers by dmount smoked -Doll dnd' Kzll 8inoking type Death rate per 100 Number of deaths 1wTonsmoker-----------------------,---------- 0. 07 3 Cigar, and pipe: I to 14 g. per day----------------------- .42 42 12 15't&24 g. per day---------------------- .45 6 >24 g;,per day------------------------- . 96 3 Cigarette only------------------------------ .96 14'3' 8ource: Doll, R., Hill, A. B: (t6). . 'I?:~, I L'ip( 204

Tns>:;E2'8:-Lung, cancer mortality ratios for cigar and pipe smokers by am ount' sm oked-KaJtn ined ing: o`ss, The igar rette that kers, )riess ted i 9: 71 7.43' 7. 39 xunt 3' 12 6 3 143 Smoking ,type Mortality ratio Number of deaths ti onsmoker--------------------------------- 1. 00, 78' Cigaar smokers: <5: cigars per day'----------------------- ll 14 12' 5 to 8' cigars per day--------------------,- 2.64 11' >8 cigars per day----------------------- 2.07 2 Pipe smokers: <5 pipeful§ per day--------------------- .17' 2~~. 5 to 19 pipefuls per day------------------ 2.20 12 > 1'9' pipefuls per day-------------------- 2.47 3 Cigar and pipe: 8 or less cigars, 19 or less pipefuls-------_- 1.62 ' 18 >8 cigars, >19 pipefuls------------------ 2'. 19 2' Source: Kahn, H.,A. (50).

TABLE 29.-Relative risk of lung cancer for men, comparing cigar, pipe, and_ cigarette smokers ?/I2th nonsmokers. .okers. A sum- mary of retrospective studies Relative risk ratio and percentage of cases and controls by type of smoking Author, reference Number - __- Nonsmoker Cigar only - Pipe_ only Total pipe and cigar Cigarette Mized only Levin, et al. (60) : Relative risk-- - -- - ---------- 1.0 0.7 0.8 --------- 2. 1-__--_-__ --------- Cases----------------------- --- 236 Percent cases- ---------- 15 11 14 --------- 66 --------- Controls_____________________ 481 Percent contro ls--------- 22 23 25 --------- 44 ________- Schrek, et al. (81): Relative risk-- ---------- 1.0 . 6 .7 --------- 1. 7_________ --------- Cases 82 Percent cases 15 4 5 61 ----------------------- - ---------- - --------- __-__-___ --- Controls____________________ 522 Percent contro ls--------- 22 23 11 --------- 59 __-__-_-- Wynder and Graham (111): Relative risk 1.0 5. 1 3 6 - 15.7 -- -- ---------- - - . ______-__ __---__- Cases----------------------- 605 Percent cases- ---------- 1 4 4 --------- 91 --------- Controls-------------------- 780 Percent contro ls--------- 15 8 12 --------- 65 --------- Doll and Hill (25): Relative risk-- ---------- 1.0 -----_ --------- 5. 1--------- 9.6 -______-- --------- Cases----------------------- --- 1,357 Percent cases- - ---------- .5 --------- 4 - --------- 74 --------- Controls--------------------- 1,357 Percent contro ls--------- 5 --------- 7 --------- 69 --------- Koulumies (56) : Relative risk-- ---------- 1.0 - - --------- 9.6 --------- --------- 29.3 --------- Cases----------------------- --- 812 Percent cases- ---------- •6 -- --------- 2 --------- 77 --------- Controls-------------------- 300 Percent eontro ls--------- 18 --------- 6 --------- 76 --------- Sadowsky, et al. (77) : Relative risk-- ---------- 1._ 0 2.4 1._ 4_-_____-_ 3._ 7 5.6 Cases----------------------- 477 Percent cases- ---------- 4 --- 2 3 --------- ------ 57 31 - Controls_____________________ 615 Percent control s--------- 13 3 7 --------- 53 19 I !l..1.•livr r%~k 1.0 4.0 - M7V94C0

0 V ---- --- --- - - - 477 Percent cases Controls 4 615 Percent controls____ 2 -- 13 .1 Wynder and Cornfield (110): Cases ----------------------- Controls _- Controls--------------------- Randig (74): Cases----------------------- Controls_____________________ fi3 133 415 381 Mills and Porter (65): Cases----------------------- 444 Controls_____________________ 430 Mills and Porter (66): Cases----------------------- 484 Controls_____________________ 1,588 Schwartz and Denoix (82); Cases----------------------- 430 Controls --------------------- 430 Stocks (89): Cases----------------------- 2,101 _ _--- Controls--------------------- 5,960 Lombard and Snegireff (61): Cases----------------------- 500 Controls_____________________ 1,839 Pernu (7g): Cases----------------------- 1,477 -- Controls--------------------- 713 Relative risk____________ -- Percentcases___________ Percent controls_________ Relative risk_ _ _ _ _ _ _ _ _ _ _ _ _---- Percentcases___________ Percent controls_________ Relative risk____________ - Percent cases___________ Percent controls_________ Relative risk_ _ _ _ _ _ _ _ _ _ _ _ - Percent cases___________ Percent controls_________ Relative risk____________ Percent cases___________ Percent controls_________ Relative risk____________ Percent eases___________ Percent controls_ _ _ _ _ _ _ _ _ Relative risk_ _ _ _ _ _ _ _ _ _ _ _ Percent cases___________ Percent controls_ - _ _ _ _ _ _ _ Reiative risk_ _ _ _ _ _ _ _ _ _ _ _ - - Perc-ent cases___________ Percent controls_________ 3 ------- 57 31 7 --------- 53 19 1.0 2.5 4.0 _________ 4 13 6 ___-_-__- 21 27 8 _________ 1.0 5.3 5.0 -_-__-_-- 1 21 11 __________ 6 19 11 ___ __ 1.0 --------- -------- 7 --------- -------- -- 31 --------- -------- 1.0 --------- -------- 8 --------- -------- --- 28 --------- -------- 1. 0 --------- 1 11 1.0 --------- 2 --------- 9 --------- 8.5 --------- 77 ___- 45 --------- 5. 0 --------- 67 --------- 64 --------- 6.0 5.4 _________ 37 55 --------- 26 43 2. 8 4. _5 _________ 13 78 --------- 16 57 _________ 4. 7 --------- 13.5 --------- --- 6 --------- 96 --------- 14 --------- 78 --------- 3. 1 --------- 5.0 --------- ---- - - - Q --------- 89 --------- 13 --------- 78 --------- 1.0 --------- -------- 2 --------- -------- --- 10 --------- -------- 1.7 8.1 _________ 4 95 _____ 15 75 _________ 1.0 --------- 4.2 --------- 9.2 11. 1 7 4 --------- 77 13 -- - 39 --------- 5 --------- 50 7 '-~..~-.....~..-..«: '3 : MME0

S6VV9LCQ TABLE 29.-Relative risk of lung cancer for men, comparing cigar, pipe, and cigarette smokers with nonsmokers. A sum- mary of retrospective studies-Continued Author, reference Number Relative risk ratio and percentage of cases and controls by type of smoking Nonsmoker Cigar only ~ --- -- - Pipe only ~ Total pipe and ctgar Cigarette only Mixed Wieken (106): Relative risk------------ 1.0 --------- - -------- 2.2 4.3 4.2 Cases 803 Percent cases 4 10 78 7 ------------------------- ------- ----------- --------- -------- Controls----------------------- 803 Percent controls--------- 14 --------- -------- 16 64 6 Abelin and Gsell (1) : Relative risk------------ 1.0 30.7 21.8 39.9 31.0 24.7 Cases 118 __ Percent cases 2 28 7 58 25 24 ------------------------- ---- -- ----------- Controls----------------------- 524 Percent eontrols--------- 35 19 6 31 17 10 Wynder, et al. (115) : Relative risk------------ - - 1.0 --------- -------- 2.0 12.4 --------- --- Cases------------------------- 210 -- Percent cases ----------- 3 --------- -------- 5 92 ---- Controls----------------------- 420 Percent controis--------- 21 --------- -------- 15 47 ,.

TABLE 30.-Changes in bronchial epithelium of male cigar, pipe, and cigarette smokers as compared to no71smoker$ N O Group Number of subjects Percent sections Sections with with epltheliai epitheliuum- lesions Percent 3 plus cell rows with cilia Percent atypical cells present Total sections Percent hyperplasfe and goblet cells in glands ~ 1st set (none vs. pipe vs. cigarette-_matched on 1:1 basis) : i+Tonsmoker---------------------------- - - - 20 985 21.7 11.2 2.6 1,031 10.3 Pipe only ------------------------------ 20 924 65.5 38. 1 37.0 979 35.9 Cigarette only------------------------- 20 914 96.8 88.6 95.2 982 72.1 2d set (none vs. pipe vs. cigarette-matched on frequency basis) : Nonsmoker---------------------------- 25 1,246 22.9 13.4 . 7 1,277 11.5 Pipe only---------.---------.------------ - 25 1,164 68.7 38.7 38.2 1,247 37.9 Cigarette only------------------------- 25 1,126 96.3 88.7 99.5 1,237 75.5 3d set (none vs. cigar vs. cigarette) : Nonsmoker---------------------------- _ _ - 35 1,706 27.4 12.7 . 8 1,748 15.3 Cigar only-------.---------.------------- 35 1,733 90.8 40.0 73.6 1,828 52.5 Cigarette only------------------------- 35 1,526 99.0 92.7 97.8 1,693 80.2 Source: Auerbach et al. (6). - ~=~:;',t ^ .- __ . __~---_ 96VV94c0

Tiimorigenic Activity The tumorigenic activity of tobacco smoke can be modi,fi'ed ia1~ both a quant'itat.iveand' qualitati'vesense. Physical or chemical changesimtobacco that result in a reduction of' total particulate matter upon combusion of a given quantity of tobacco may result in a reductionn of carcinogenic potential. Suchi factors as tobacco selection, treatment, blendi~ng;cut, and' addit.ivesmay quantit'ativelyaltertar~ production.. Wrapper porosity and filtration, may also affect tar production. Quantitative changEs in the tumorigenic activity of tobacco tar on a gram-for-gram basis can be producedl by the selection and treatmentt of'tobacco,,the use of additives or tobacco sfieets; or adjustments in the cut and packing,density.C'ombustion temperature can also produce quantlitative changes in the particulate matter of tobacco smoke. Although high-temperature burning producesIess particulate matter in the smoke, i't appearsthat tumorigenic components occur in higher concentration when tobacco is pyrolizedi at'tlemperat'uresliigher than 70p° centigrad'e(;34). Cigars, pipes, and cigarettes are similar in that they are smoked orallyy and have a common site of introduction to the body. The tissues of the mouth,, larynx, pharynx, andl esophagus appear to receive ap- proximately equal exposure to the smoke of these products: Inlialationn causes smoke to be dlrawn deeply into the lungs and also allows for systemiic absorption of' certain constlituent:sof tobacco: smoke which then can be carried further to other organs. Pipe tobacco and cigars vary from cigarettes in a number of charac- teristics that can produce both quantitative and qualitative changes i'n the total particulate matter produced by their combustion. Experi- mental evidence suggests that althoughthere is some difference in the amount and quality of tar prodiucedl by cigars, this cannot account for the reduced mortality observed'' i'n cigar smokers compared to cigarettee smokers.. Experimental Studies Several experimental, investigations have been conducted to examine the relative tumorigenic activity of tobacco smok- condensates obtained from cigarettes, cigars, and pipes.llTost of these studies were standard- ized in aniattempt to make tlie results of the cigar andlpilpe experiments more directly comparable with the cigarette data and most used the shaved skin of mice for the applieation of tar. Tars from cigars, pipes,and cigarettes were usually applied on an equal weight basis so that qualitative differences in the tars could: be determined. In sev.eral ex- periments„the nicotine «-asextracted from the pipe and cigar conden- sates inani attempt to reduce the acute toxic effects that resulted inn animals, from the high concentrations of' nicotine frequently fonnd in these.prodnct'se zio.

Aha %s inn ipon ;tion aent, tion.. x on nent ithe hs in. ;ture that co is )ked 6ues ap_ t:iion i for hich irac - % in ,)eri- tkle for rette nine i'nedl ard- ents rithe lpesi that eg- len- i in I in Wynder and' Wright (117) examined the differences in tumorigenic activity ~ of~~ pipe and cigarette condiensates. Tars~ were~ obtained by ~ the~ smoking of a popular brand of king-size cigarettes and the same ciga- rette tobacco smoked in 12 standard-grade briar bowl pipes. Both the cigar.ettes~ and pipes~were~ puffed three~ times a minute~ with a,2'-secondd puff! and a35-ml. volmne. Both the~ cigarettes~~ andl pi'pes~attained similar masilnum combustion zone temperatures; however, the use of cigarette tobacco in the pipe resulted in a combustion chamber temperature that averaged~ about 150~°'centigrade~ higller~than temperatures, achieved when pipe tobacco was uscdL Chemical fractionation was accomplished and equal concentrations of the neutral fraction were applied i'n threee weekly applications to~ the~ shaved skin of~ CW1F, and Swiss mice. The~ results~indicate,that neutral tar obtainedif'rom, cigarette~tobacco~ smoked, in piipes, is more activ~e~tl7an that obtained in the~usual manner from~ cigarettes. About twice as many-. cancers.vere obtained in both the CAFl and the~ Swiss~mice,~ and t'he~ latent period was~~ about~2 months shorter.. Extending these data, Croninger, et~a]. (20)~ examined the~ biologic: activity~ ofl tars obtained from, cigars,~ pipes, and cigarettes., Each form . of tobacco was~~slnoked as~it was~rmnu~factured in a manner tolsimulateI 11nm~ani smoking or to~ maintain tobacco combustion. The whole~ta.r was~ applied in, dilutions of one-to-one~ andl one~-to-two~ with acetone~ to~ th~e~ shav ed backs of female CAF;, andl female Swiss mice using three .~l~hlications~each~ ~~ eek~for the life-span span of'the~ animal. The ni eotine~~ ~ti ~as~ extracted from~ the~~ pipe and cigar~ condensates~~ to~ reduceI the acute toxicity of~the solutions. The Swiss mice,,pipe~„cigar, andci~garette~tars produced both benign and m~alignant tuinors: The incidence irates~~ of' maligfil~Uat tumors given as:percent''~s z~ ere~: 44„411, and 37; respectively~. These resnlts suggested a somewhat higher degree of carcinogenic activity ~ for cigar and pipe ~ t~a rs thani for cigarette tlair: Similar~ results were~ reported by Kensler (53): who~applied conden- sates obtained from cigars ancL cigare:ttes, tl the shaved skin of~ mice: The incidence of papillomas produced by cigar smokee concentrate was no~~ different from~ that of~ theI cigarette~ smoke~ condensate. Similarliy;~ there~ «-as~~no~ difference between cigar and cigarette~smoke~condensates when caT•ci~noma~ inci~dences~were connpared.. Homburger„et a~~lL (.1.:.~)~, prepared tars~from cigar,,pipe,,and cigarette toiaecos~ that were smoked in the fQrm of cigarettes. ]fni this~ way„ all tobaccos were smoked~~ in an identicall manner~and uniform combustion temperatures~ «ere~ achieved.~ Recause~~ of this stlanelardivation,~ diff~er-~ ences~ in tumor~ yield could be attributed to~ tobacco blend~ and not the~ manner in which the~ tars~ were, prepared. The~ whole tars were diluted one-to-one «ith, acetone and applied! to the shavecl, skin of~ CAF, mice three~ tiines a.i•eek for the lifespan of~ the test animal. Skin, cancers~ were~~ produced more quiekly.~ with pipe: andl cigar smol:e condensates than~ with cigarette smake~ condellsat'es. This~suggests~that~the~ smoking~ 495-028 0-73-15' 2' 1 1' t' I a, i ; r I

of' pipe andi cigar tobaccos in the form of' cigarettes does not alter the condensates to any significantdlegree. Davies and Day (22) prepared tars from small cigars especially manuf'actured from a composite blend of cigar tobacco representing, small cigar brands smoked in the United Kingdom,, cigarettes espe- cially manufactured from the same tobacco used for the cigars de- scribed above, and plaini cigarettes especially manufactured from a cpmpositle~ blend of ' flue-cured tobacco representing the major plain cigarette brands smoked in, the United Kingdom. The whole tar was diluted to four concentration levels and applied to the shaved backs of' female albino mice for their lifespan using four dosing, regimens. A statistically significant increase in mouse skin carcinogenicity was shown with the cigar smoke condensate compared with the tars obtained from eitherflue-cured~ or cigar tobaccociga:rettes. Theseresults are consistent with those of'' the: previously reportedd investigations. The effect of curing on carcinogenicity was examinedl by R'oe„ et al. (76)~. Bright tobacco grown in Mexico was either flue-cured or air- cured and bulk fermented. Both flue-curedand air-cured tobaccos were made into cigarettes standardized for draw resistance and were smokedd u~nder similar, condi'tions. Condensates from thesecigarettes, werea:p- plied to mouse skin three times each week in an, acetone solut'.ion. The development of'skin, tumors«-as, higher in mice treated with! the flue- cured condensate than in mice treated with the air-cured condensate (P'<O:Q1'1). The dilff.erence may have been due to the use of equal weights of condensate rather than the use of extracts from an equall number of cigarettes. Theaiir-cured cigarettes~ produced a, greater weight of' condensa;tethani didi t!he~ flue-cured cigarettes. A chemical analysi'sof the two tobaccos and two condensates revealed only sma111 differences in composition. Evidently air curing of Bright tobacco in the methodl usedl is nott associated' with a loss of reducing sugars. A more detailed analysis of these experimental studies is~ presentedl initable 31. These experimental data suggest that cigRr and pipe tobacco con- densates,havea carcinogenic potential that is comparabletocigarettecondensates.Thisissiihport~ed byhuman, epidt;miologiical data for thosesitesexposedequallyt'o tli:esmoke of cigars, pi~pes, and cigarettes.The partially alkaline smoke derivedl fromi pipes and cigars is gen- erally nott inhaled,, and as a result there appears to~ be a lower level ofexposureof the lungs and other systems totlie harmful properties of pipe and cigar smoke tha,n, occurs u•ithcigarette smok~iiig.ftis~ antic~-ipatled that 1nodificationsin pipetobaccolor cigarswhich would result in al product that was more readily inhalablewould eventually result in elevated mortality fromicaneeraf the liuig,, bronchitis,an:d emphy- sema, arterioscleroticcardi,ovascu~lar diseases, and the other condi~tions which have been clearly associated with cigarette smoking. 212'

[II -- - ~-~ ~ ~"'~_ .. n ~ .~ .,~ ... ..... _ _~. .-__--- '1- iC 0 -~ R' [~n ~ U~1 ~ ~ ~ ~ ~ ~ ~ ~ @ s TASLE 3 1.- Tumorigenic acti7lity of cigar, pipe, and cigarette smoke condensates in skin painting experiments on animals (Key: A=Method. B=Frequency. C=Duration. D=Material.) Percent Author, reference Animal Activity Treatment Number Papillomas Carcinomas Wynder and Wright CAFI and Swiss mice. A. Painting shaved skin. B. 3 times a week. CAF1: Pipe (cigarette tobacco)___-_- 30 60 20 (117). -- - C. Lifespan_ (24 months). --- Cigarette------------------- 30 30 3 D. Neutral fractiop tar from cigarettes and cigarette Swiss: Pipe (cigarette tobacco)___-__ 30 63 50 tobacco smoked in pipes. Cigarette------------------- 30 63 33 Croninger, et Female Swiss A. Painting shaved skin. Cigar, nicotine free (1:1) ------- 46 65 41 al. (20). mice. B. 3 times a week. Pipe, nicotine free (1:1)-------- 45 71 44 C. Lifespan. Cigar (1:2)___________________ 78 33 18 D. Whole tar diluted in Pipe, nicotine free (1:2)-------- 89 30 16 acetone. Cigarette (1:1)---------------- 86 47 37 Acetone controls______________ 23 0 0 Kensler (6$)__-_ Swiss mice______ A. Painting shaved skin. Cigar tar (J) 100 mg. per week__ 100 42 41 B. 3 times a week. Cigarette tar (G) 100 mg. per 100 40 28 C. Lifespan. week. D. Whole tar diluted in Cigarette tar (E) 100 mg. per - 100 34 34 acetone. week. OOSV9,GCp N Y t .

N A I03 V 9& f;0 TABLE 31.-Tu7no7"igenic activity of cigar, pipe, and cigarette smoke condensates in skin painting experiments on animals-Continued (Key: A=Method. B=_h'requency. C=lluration. L)=Material.] Author, reference Animal Activity Homburger, et CAF, mice------ A. Painting shaved skin. - al. (45). B. 2 to 3 times a week. C. Lifespan (2 years). 1?. Whole tar diluted 50 per- cent in acetone. Davies and Female albino A. Painting shaved skin. Day (22). mice. B. Varied. C. 116 weeks. D. Whole tar in 150 mg. - acetone. Roe, et al. Female Swiss A. Painting shaved skin. (76). mice. B. 3 times a week. C. Lifespan. D. Whole tar diluted in acetone. Treatment Number Percent Papillomas Carcinomas Cigar tobacco cigarettes t 65 mg. 100 37.5 19 per week. Pipe tobacco cigarettes t 64_ ing. 100 23 20 per week. Cigarettes' 62 nig. per week---- 100 15 23 Acetone controls-------------- 100 0 0 Cigars, small 83 mm. long 150 144 44 27 per week. Cigar tobacco cigarettes 150 72 32 14 per week. Cigarettes 150 per week-------- 144 28 13 Flue-cured Bright tobacco 180 400 52 30 - mg. per week, Air-cured Bright tobacco 180 400 68 23 mg. per week. Acetone controls 0.75 cc. per 400 1. 3 0.5 week. I Cigar, pipe, and cigarette tobacco smoked as cigarettes ut similar combustion temperatures. 1. 1

(.riAl¢DIovAscUI-1R DT6FZA:sE,4' r* The majority of deaths in the United St'ates each year are due to cardiovascular diseases. Cigarette smoking has been identified as a major risk factor for the development of coronary heart disease (~CH!D). However, pipe and cigar smokers experience only a small increase in mortality from, coronary heart disease above the rates of nonsmokers. Cigarette smokers have higher death rates from cerebro- vascular disease thannonsmokers, whereas pipe and cigar smokers have cerebrovascular death rates that are only sligkrtly above the rates of nonsmokers. Table 32 summarizes the major pr.ospective epidemiologi- OroupStudy of coronary heart disease, reportedl an incidence of coro- nary heart disease in men aged 50 to 59 whowere pipe and cigar smok- ers that `vas intermediate between the rates seen in cigarette smokers and nonsmokers. No ~increase in incidence of coronary heart disease was seen among the pipe and'. cigar smokers in the younger age groups. Shapiro, et al. (85), in a study of the: health insurance plan (HIP') population, reported incid'ence rates for myocardsal' infaretion, angina pectoris, and possibleMI, in pipe and cigar smokers that were similar cal investigations that eramined the association of smoking in various forms and total cardiovascular diseases, coronary heart disease, and cerebrovasculardisease: Doll and, Hill. (28), Best (9), and Kahn (50)~, examined dose-responserelat'ionshipsfor pipe and cigar smokers andG reported a slight increase in mortality from, coronary heart disease with an increase in the number ofcigars or pipefuls smoked. Other prospective epidemiological studies have also egamined the relationship of smoking in various forms to coronary heart disease and related risk factors: Jenkins, et al. (49) in the Western Collaborative tio the incidence rates seen in cigarette smokers. These rates were con- siderably higher than those of nonsmokers. Data from the pooling project (47) suggested that the incidence of CHD deaths, sudden death, and the first major coronary event in pipe and cigar smokers was intermediate between the incidence experienced by cigarette smok- ers and nonsmokers. In contrast to these stud'ies; Doyle„ et al. (30) reported no increase in CHD deaths; myocardial' infarction„or angina~ pectoris in pipe and cigar smokers over the rates of nonsmokers in the Framingharn study. The retrospective studies of Mills and Porter (64), Villiger and Heyden-Stucky: (104), Schimmler, et al. (80):, and Hood,, et al. (!46:)~ contained' data suggesting that pipe and cigar smokers experience mortality rates from coronary heart disease that are essentially similar to those esper.ienced by cigarette smokers. The retrospective study of Spain and Nathan (86) reported lower ratesofcoronaryheart dis- ease in all smoking categories than were: found in nonsrnokers,Van Buchem (103), and Dawber, et al. (23): examined serum choles- terol levels, in groups of individuals classified accord'hng to, sm,oking I 4

habits., In theset'wostudies; pipe and cigar smokershad serumclioles, terol let-els that were nearlly irlentiical with the levels found in nonsmokers. Tibblin (91) and Dawber,,et al. (23)1 investigated tllie~effect'of'smok- ing on blood pressure. The proportion of smokers d'ecreased in groups with higher blood pressures, although this was not as dramatic for pipe and cigar smokers as it .vas'for cigarette smokers: IIn an experimental study using anesthetized dogs, Kershbaum and Bellet (54, 55): examined the effect's of inhaledl and noninhaled ciga- rette; cigar, and& pipe smoke on serum free fattyy acid levels and urinary catecholamine and nicotine eieretiom In this study, inhalation of to- bacco smoke from all these sources resulted in similar increases in serum free fatty acids and in catecholamine and nicotine excretion. TABLE 32. 1l2ortad2ty, ratios for cardiavascular d'edths in: male cigar and ' pipe smokers, A summary, of prospective epidemiological st'udies Author, reference Category Type of'smoking Non- Cigar smoker only Pipe only Total Clga- pipe,and rette only 14fYaed cigar Hammond and Cardiovascular 1. W 1.26 1.07 ' ------ 1.57 _____- Horn, (40). total. Coronary----------- 1.00 1.28 ' 1.03 ' ------ 1.,70' _-__-_. Cerebrovascular-_ _ _ _ 1.00 1.31 1.23 ' _ - _- - _ 1.30 _ _ _ _ _ _ Dol'Landi Hill' Cardiovascular 1.00 ----- ------ 0.99 1.26 1.13' (26, 27). total. Coronary----------- L 00 ----- ------ .941 1.23 ' 1. 18 Cerebrovascular-_--_ 1.00 ----- ------ .95 1. 13 .97 Best (9) -------- Cardiovascular 1.00 1. 14' .95 ------ 1. 52 __-_-_ total. Coronary----------- 1'.00 .99 1.00 ------ 1.60 -_--__ Hammond ~ Cerebrovascular_-_-_ Cardiovascular 1.00 11 ' 28 1. 00 ----- .85 ------ ------ .88 U. 06 ll 90 _--___ (38). total; Coronary.----------- 1. 00 1.35 11. 19 ------ 1'.84 1.58 Cerebrovascular__--_ 1.00 ----- ------ 1.09 1'.41 1.40' Kahn (50)------ Cardiovascular 1.00 1. 05 1'. 06 1! 05' ll 75 ____-- tot!al. Coronary----------- 1. 00, 1.04 11. 08 IL 05 ll 74 -___-_ Cerebrovascular~___-- 1. 00 1.08 11. 09 1L 06 L 52' __---_, I Mf ortality. rat i.os ~{or ages~ 5'b to 64~4 only, are,. presented . CHRONIC OFBS"rRi;('TIi\'E PUL3fON:1RY DISE.aSE ((iO!PD)'. Chronic bronehiti~s~and pulmonary emphysema account for most of the, morbidity: and~, mortality from chronic respiratory disease in~ the~ L7nit~~ed titates. Ciga~rette snookers~ have~ higher deat1l, rates fi•om~ thesc~ ;i 216. O ~ ~ ~ ~ ~ 0 ~

diseases and have more pulmonary symptloms and impaired pul- monary function than nonsmokers. Cigarette smokers also have more frequent and more severe respiratory infections than nonsmokers. The relationship between smoking, pipes andi cigars and these diseases is summarized in tliis chapter. The major prospective epidlemio3ogical studies are summarized in table 33, In a retrospective studly of' 1,189! males, andl matched controls in Northern Ineland,Wicken (106.)~ investigated smoking in various forms~and mortality from bronchitis. Th~erelativerisk ratios com- pared to nonsmokers for mortality f'rom, chronic bronchitis were 1.98for all smokers. 1.55 for pipe and eigar smokers, 2.25 for cigarette smokers, and 1.49 for mixed smokers. Nroma review of these prospective and retrospective studies, it from appears~~ that pipe andl cigar~ srnokers ex'perience~ mortalit~y~ rates~~ , a - 11 1,.. ,.1,;4: 111 ll. tih,,+T, ,~h fli. ML.,. .,E., r.Fl I 11 .< .......... .... „LLZ.,,~~~...,u ..,..u .. ,.,~,.~~ .,. .., ...~ ....~., .,~ ...,.. I . I smok,ers~., Although, these mo~ra~lrity.~ rates~ approach those of' ci'gare,tte~~ smokers, in most iiist~ances~ they are~ intermediate between the rat'es~ of cigarette smokers and nonsmokers. i d Pipe and cigar smokers have significantly more respiratorysymp- r toms andl illnesses! than nonsmokers. Those, studieswh,ich contain data on pipe and cigar smoking as relatedl torespir•atorysymptomsaresummarized in table :34. Only a few studies have examined pulmonary function in pipe and cigar smokers. There appearsta be little ditFerence in pubuonary func- tion~ values for pipe and cigar smokers as compared to nonsmokers 0 t bll 5 e a ). ( s ~ ~7 + Naeye (67) conducted an autopsy study on 322 Appalachian coal' ~ workers who were classified according to the type of coal mined and tobaccousage: Eznphysemawas slightly greaterin cigarettesmokers, as were anatomic evidences of chronic bronchitis and bronchiolitis. '1L' hose chan es found in l e and cr ar smokers were intermediate g p p g I ~ between those of cigarette smoking, miners and nonsmoking msners. 5gChanges in~ pulmonary histology in relatiorr to smoking habitsandl i b ib l d b A h l i l age wereexani uer ros s; a arrupturer ne y ac et a (8) veo ~,.i. r thickening of the wallsofslmlll arteries, and thic.keningof the walls of the pulmonarti-aiteriol'es were found tobehighly relatedl to thee smoking habits of'the 1,340 male subjects examined. The 91 pipe and cigar smokers over the age of 60 were found to have somewhat more alveolar rupture thani the men of the same age distribution who ~ never smoked regularly. However, pipe and cigar.srnokersas a, groulihael far less rupture than cigarette smokers. The same relations as described above were found for fibrosis, thickening of the walls of the arterioles if and small arteries,~ and pa,dl~ik~e attachments to the alveolar septums. ~e Tobacco~ snioke, has~ beeii shown experimentally ~ to Ilave~ a ci'liostatic e~ffect on t'he~ respirat'oryy epithelium. Tlle~ interval between pulls, the~ 2117

amount of volatile and particulate compounds in the smoke, andi the exposure volume have been shown to infl'uence the toxic effect of' tobacco smoke. Dalhamn andl Rylander (2Z ) exposed the upper trachea of anesthetized cats to the smoke of' cigarettes and cigars, observing the effect on ciliary activity through an incident-light microscope. A chemicall analysis of the gas and particulate phases revealedl that the cigar smoke was more alkaline and,, in general, contained higher concentrations of isoprene, aeetone, acetonitrile, toluene, and totall partiiculatematter comparedl tocigarettiesmoke. Tiheaverage number of's puffs required to arrest ciliary activity was found to be 73' for the cigarette smoke and 1114 for the cig ar smoke. The difference is statisti cally. significant (P C0.01). Of the two smokes,,the smoke 'with the highest concentration ofI volztilecompounds was found to be! t ~eleast ciliostatic. This suggests that the degree of ciliotoxicity ofi a, smoke is not necessarily correlated to the level of'one or several of the substances found in the smoke. Passey, et al. (70,71;, 7'M') studied the effect of smoke from flue-cured cigarette tobacco cigarettes and air-cured cigar tobacco cigarettes on the respiratory system of rats: In two separate but similar experi-ments, a total of 48 animals were expo d to. E:nglish cigarette tobacco smoke, IBwereexposed to air-cured cigar tobacco~ smoke, and 12~ were exposed toan air-cured B'unley.tobacco smoke. The rats in groups were exposed to the specific smoke in a snmoke-fillled cabi'net,, Animals ex- posed tolhe smokefromair-cured tlobaccosremained liealthythrough- out the experiments, even at high levels of smoke exposure. The three deathsthat, occurred within, this group were from nonrespiratory causes.Isr kiothiex.periments;the rats exposed t~ocigarettetobacco smoke began todie.rithin 1 or 2 months, and ineach.experiinentmostoftheani'mals died within a,week or two of the first deaths. At autopsythey rats exposed to, flkte-cured tobacco smoke on, gross examination were found tohav.egreatly enlarged lhingsy t'hetrachea wasoft~en full of mucus,and there was evidence of pneumonia. On microscopic examina, tion it, was found thatt the trachea and bronchi contained' purulent celltdarexudiites, evidence of metapl'astic changes;an absence of cilia,, and goblet cell hpyerplasia. Typically; the causeof' death wasalobaror bronchopneumonia. The author concl!uded that, "the smokes of'flue- cured t;obaccosaremore: dangerous to man and to animals than those of'air-cured tobaccosi"' 218

I Unfortunately.; few details were published concerning the method used to expose the animals to the different types of smoke. The fre- quency and duration of exposure were not speciffedy and the extent of actual inhalation of smoke by the different groups of rats was either not determined or not reported. It is also difficultto determine the effect of smoke exposure on the frequency andl severity of respiratory infections when animals are expo5edlto smoke in groups where common exposure occurs. The rat strain used was not identified, but it was noted that animals appeared to suffer from an endemic rat bron- chiectasis. It is not known to what extent epidemics of respiratory infections occurred among these animals. Because of'these difficulties, no firm eoncTusion can be drawn concerning the effect of' smoking flkle- cured or air-cured tobaccos on the incidence of respiratory infections in~ rat's. TABLE 33:-Mortdlity ratios for chronic ob'structive pul'mondry dcatli.s in male cigar dnd pipe smokers. A' summary o`f prospective epidemia logical studies c Type of smoking', Author, reference Categnrry Non- Cigar Pipo Total Cigg- f smoker only only pipe and'rette only Mixed cigar Hammond and COPD total-------- 1.00 1.29 1.77 ----- 2.85 ------ Hbrn (40). Emphysema-------- ---- ----- ----- ----- ------------ Bronchitis---------- ---- ----- ----- ----- ------------ Doll' and Hill, COPD total,-------- ---- ---,-- ----- ----- ------------. (2E, 2'7). Emphysema-------- ---- ----- ----- ----- ------------ Bronchitis---------- 1'.,00 ----- -----, 4.00 7.00 , 6.67 Best (9) -------- COPD totall-------- ---- ----- ----- ----- ------------ Etnphysema. ------- 1L 00 3. 33 . 75 ----- 5.85 ' ------ Btonchit'is---------- 1L 00 3. 57, 2. 11 ----- U 42 Hammond (3b')-- COPD' total-------- ---- ----- ----- ----- ------------ Emphysema,-------- 1.00 ----- -,---,- 1L 37 1 6: 55 -----_ Bronchitis---------- ---- ----- ----- ----- 1 ------------ Kahn (60)------ COPD' total-------- L 00 . 79 2'. 36 .99 99 10.08 08 -----_ Emphysema---_---- 1. 00 11. 24 2. 13 1. 311 14 17 ------. Bronchitis. --------- 1.00 1,.,17 1.28 1.17 4.49 ---,-_-, I Only mortality ratios for ages 55 to 64 are presented. 495'-628 0-73-16 149 ~ ~ ~ ~ ~. ~ ~

TnBL>r 3!4.-P~revalenae of respiratory symptoms ¢ndillness by type of smoking Percent prevalence Author, reference Number and' type oi' Illnesss population 1+1an. Total Ciga• smoker pipe and, rette 1Wfiied cigar only Boake (10)___ Parents of 59 Cough____________ 32' 32' 48: ______. families. Sputum 24 15 20' ______ production. Chest il'lness______ 5 4 5______ Edwards, et 1,737 male Chronic bronchiti& , 17 119' 31 14 al. (38). outpatients. Ashford, et 4,014 male Bronchitis________ 10 1 35 211 37 al. (4). workers in 3 Pneumoconiosis____ 11 t 34 14 2' Scottish collieries., Bower (11')__- 95 male bank Cough------------ 0'' 0: 29' ______ employees: Sputum 8 15 33 ______ production. Wheeze----------- 8' 31 33 ______ Chesti illness------ 15 54 40, ---__- (California). Chest illness 7 6 11 ______ (New York). Chest illness 91 10 12' (California). lInfllienza 28' 24 31 __ _ _ _ _ California. York). patients in Influenza (New 11 21 24 - andl 315 male (C'alifornia).. Wynder, etal. 315 male paL Cough (New 14 33 56 51 (114)L tients in York). New York Cough 22 30 67 66I Densen, et al. 5,287 male Persistent cough_ _ 7 111 25 -_____ (24). postal and Persistent 1'1 16 26, ______, 7;213'male sputumm transit production. workers in Dyspnea.--------- 16' 19, 26' ______ Nlew York Wheeze----------- 14' 21 32'------ City. Chest illness______ 13' 16 18 -_____ Cederlof, et 4,379twinpairs; Cough----------- 4 : 7 17 al ('18). all i.ilS! Ptolonged cough_-_ 2: 4 11 -__,-__ veterans. Bronchitis____-___ 2 3 10 ______ Rimington 411,729 male Chronic bronchitis_ 5. (76), volunteers: 220 1 9 17 __

! TABLE 34.-Preralence of respiratory symptoms and il'lness by type of' smoking-Continued A th f nd t f' b N IDn Percent prevalence r or, re erence u tun er, a ype o population ess Non- Total smoker pipe and cigar Ctgs- rette Mized'd onlp. Comstock, et 670 male tele- Persistent cough_ _ 10 16 41 ______ aii (1'9). phone Persistent 13 20 42' ______ emplbyees~. sputum. Dyspnea_________ 33 39 44'-_____ Chest illness in 14! 18 20 ______ Lef coe and! 310 ma.1e phy- past 3 years. Chronic respirar 9 18 44 ______ Wonnacott (69). sicians in London,, tory disease. Chronickironchitis- 1 12 34 -_____ Ontario: Obstructive hung 1 3 4______ disease. Asthma---------- 7' 3 6 ------ Rhonchi'---------- 0 3' 9'--_-_,_ I 'Figures for pipe only!:. TnBLE 35:-Pulrnondry function a,ulues for cigar and pipe smokers ass comparedto nonsmokers Type of'smoking, Author, reference Number and type of'population Function Pdon. smoker Total pipe and cigar Cigarette only Mixed Ashford, et 4,014 male FEVi.ol _,--___, 3. 39 1 2. 59 3.14 2.62 - I all (J+), ol'demith, workers in~ 3 Scottish collieries., 3,311 active uffmeter---- 13.63 99.26 26 03.44 _-_ __ etall (37). or retired FEVI.o------- 2:99 2.80 2:91 ____,__ longshore- TVC--------- 3. 87 3.68 3.88 ! _--_,__ Comstoek,, men. 670 male FEVi„o------- 3. 12' 3.26 ', 2.82 ____, et al. (19). Lefcoe and! telephone employees. 310 male FEVI,o------- 3.39 3'. 17 3.11 _-__-_ i; Wonnacott physicians MM'F~R liters 4.09 4! 17 3.64 -__-__ ~; F- (69). in London, per second. Ontario. /' I Figures for pipe only, v t 221'

GASDROI'NTESTIN A:L DISORDERS Cigarette smokers have an increasedl prevalence ofpept'ic ulcer d'iseaseandl agreater' peptic ulcer mortality rat'iothan is: . found! in~ nonsmokers. These relationships are: stronger for gastric ulcer than. for duodenal ulcer.Cigarett.e smoking appears to reducee the effective- ness of standardl peptic ulcer treatment regimens and slows therate of' ulicer healing. Cigar and pipe smokers experience higher deathh rates from peptic ulcer disease than nonsmokers. These rates are higher for gastric ulcers than for dluodlenal ulcers butl are some«-hat, less than those: rates experienced by cigarette' smokers. Table 31 presents the mortality ratios f'or'ulcer disease'in.cigar and pipe smokers as reported inthe~prospectiue epidemiol'og ic'al studies.Retrospectiveorcross-sectionall studies by T>rowell (95), Allibonea'nd Flint (2),, Doll, et al. (29), and Ed.rards, et al. (33) containn data on ulcer di'seasein pipesmokersaswelD as:cigarette smokers: hToassociation was found between pipe smoking and ulcer disease in these investi~gations., TABLE 36. 1Y2artality ratios for peptic ulcer disease in male cigar and' pipe smohers: Summary, of prospectiue studies Type~e of'smoking. Aluthor~ reference Illness Non- Cigar smoker only' Pipe only Total pipe and cigar C1ga- rette only Miaedl Hammond and Duodenal ulcer------ 1. 00 0. 25 H' ( 0 1.67 ------ 2:16 _-____ orn 4 ). Doll and Hill Gastric ulcer-------- 1.00 ' ------ ----- 4.00 T. 00 5. 30 ('26; 27). Hammond (38)-- Gastriculcer-------- 1.00 ----- ----- 2.04 2.95 ___,--- Duodenal ulcer------ 1.00 ' ------ ----- .92 2.86 -_-,-_- Kahn (60)------ Gastriculcer-------- - 1.,00: 2,' 90: 2. 84 2. 48, 4.13 _-___- Duodcnal ulcer------ 1. 00' 1. 58 1. 59' 1. 39 2.98 -_-,-__. lLittle Cilgars In the, past year, several new brands of' littlle cigars(weighing, 3 pounds or less per 1,000) have appeared on the nationall market. These eigarette-siaed products, are manufactured, packaged, advert'i'sed, and sold in a manner similar to cigarettes. Little cigars enjoy several legal advantages ouercigarettes ~: ~ They have aceess : to ~ tellevision ad'vertising'; they are taxed by the Federal Government andby most States„at much lower ratesthancigarettes„resulting in a significant price advantage; 222'

5e ;d 11 and they do not carry the warning label required on cigarette pack- ages and in cigarette advertising. A market appears to be developing for these products, as there has recent'ly been a sharp increase in the shipment ofl little cigars destined' fordomestic consumption (table 37). It is important to estimate the potential public health impact of' these little cigars. An adequate epidemiological evalaation~ of the ef- fect of little cigar smoking on health could take 10 or 15~ years and is probably an impractical consideration; however, a review of the epide- miological; autopsy, and experimental data concerning the health~ con- seqtzences of cigarette; pipe, and cigar smoking summarizedl in this and previous reports is helpful' in considering the potential impact onn health of smoking little cigars. An amalysisof' the chemical constit-uents suggests that both cigarettes and cigars contain similar com- pounds in similar concentrations. Two exceptions are redhicing sugars; which are not found in quantity in the fermented tobaccos commonly usedl in cigars, and the pH1 of'the inhalpd~ smoke. The pH of the smoke from U.S. commercial' cigarettes is below 6.2 from the first to the last puff; whereas the smoke f'rom, thelastRaif of'a cigar may reach as high as pH 8 to 9. With increasing pH, nicotine is increasingly present in the smoke as the free base. Skin painting experiments in mice indicate that tumor yields with cigar or pipe "tars" are nearly identical with those obtained witheigarettes "tars~''. In addition,, the epidemiologilcall data suggest that depth of' inhalation probably accounts for the fact that cig<lrettesaresomuch more:harmfnl than cigars and pipesi'n con- tributing to the development of lung cancer, coronary heart disease„ and nonneoplastic respiratory disease. For, such, diseases as cancer of the orallcavity, larynx, andlesophagus, «here smoke from cigars, pipes, and cigarettes is available to the target organ at comparable levels, the mortality ratios are very similar for all three forms of tobacco use. Severali factors, including "tar,"nscotine; andl the pH of the smoke,, probably operateto influence inhalation patterns of' smokers. The relative contribution of individual factors to the inhalability of a tobacco product has not been determined. Smoking those brands of little cigars which can be inhaled by a significant portion of the population in a manner similar to the pres- ent use of cigarettes would probably result in an increased risk of de- veloping, those pulmonary and cardiovascuIar diseases which havee been associated with cigarette smoking. On the other handi,, smoking those little cigars which are used like most large cigars whereby the smoke is rarely inhaled «ouldl probably result in lower rates of' those pulm.onary andl cardiovascular diseases than would be found among cigarette smokers. Only a limited analysis is available comparing the chemical' com- pounds found in little cigars, cigarettes, and large cigars. The FTC ana~lyzed thetair and nicotine content of all the little cigars (34) and . cigarettes (97) currently available on the market. Little cigars have 229 9 a

generally a hig)ier~~ "'tar"' and nicotine levell than~ cigarettes, although~ considerable overlap resul'tls in some little cigar brands having, "tlar"' and nicotine llevels comparable to those of some brands of cigarettes (figs:~ 4 and 5)~. Hoffinann andi Wynder (I4) ' recently~ compared th~~ree~~ brands of little cigars with an unfiltered cigaret.te, a filteredl ci'garette, and a, large cigar. They measured' a number of'smoke constituents, in- cluding: "tar,'7 nicotine, carbon monoxide, carbon dioxide, reducing sugars, hydrogen cyanide, acetaldehyde, acrolein; pyridines, phenols,, benz(a)anthracene~,-and benzo(a)'pyrene (table 32). Cigarette A was the Kentucky reference cigarette, cigarette Bwas a popular brand of' filter cigarette. Cigar A was an 85' mm. little cigar, cigar B was an. 85 mm. little cigar, cigar C was a 95 mm~ small cigar, and cigar D was~ a 112 mm. popular brand of' medium sized cigar. The~ srnoke~ pH~ was analyzed pu~~fE~ by puff~ (tabl!e~ 39). Cigaret'tle~~ smoke was found to be acidiie (',pI-I less than 7) for the entire cigarette. The~ smoke from little~ cigarsbecam~e~ alkaline~ only ~ in~ the last~ puff or two, whereas about the, last 40 percent of'thepuffs from the larger cigan~were alkaline. Although the~pHl~of the~tlot~all condensate obtai~ned' from~ cigarettes~ is usually' ~ acidic and the totall cond'ensate~ obtained from cigars is usually alkaline, the above data indicate that smoke pH of tobacco prodkzcts changes during the combustion process. Sinoke from large cigars may be acidic dh'zring the first portion of the smoke and not become~a~lkaline untillthe lastha~lf~of'tili~e~cigar~is: smokedBrunnemann and Hoffmann (15), using the same techniques de- scribed above, examined the effect of'~ 60 leaf' constituents on smoke pH.. For~severallvarieties~of cigarette~tobacco„they~~ found a high correlationn between~ the,total aklaloid and n~~itrogen content a~nd smoke ~ pH. Stalk~~k position~~ also~ affected smoke ~ pH. 'Il'obaceo~ leaves, near tlte~ top~ of' tlie~ plant, which contalin high levels of tar and nicotine, y~ielded a sm~oke~ with a muchihigher~pHf than leav.es~ lo..-err on the~ plant. At pr:esent~ it is~~ not~ known to what extent t~hese~ factors~~ i'nfluence~ the~ p1-lf of the~ smoke of~tobaccos~com~monl'y~used in cigars~or how these kinds of pH~ch~anges intiuence~the~ inhalability of tobacco smoke:. The~ inhalation of'sm~oke, however„appears to be tlte~~ most i~mportantlt factor~ d~etermining~ the, impact a cigar will have on overalll health. Those~ physi~call and chemical charact'~eristics~~ of a tobacco~ product which most influence~ inhalatlion, of tobacco smoke have~ not been accurately~ determined. Nevertheless, it appears likely that the smoke~ of'sorne brands of'cigars mayy be.compatible with inhalation by a sig- nificant: portion of the smoking~ population,~ since~:~~ (a~)~ Little~ cigars~~ have tar and nicotine levels which. in some brands, are similar to the l~evels!~ found in cigaretlt:es,~ and (b' ) the ~ p~H'i . of the~ smoke~~ of~ some~ little~~ cigar brands is acidic for the major portion of the little cigar and becomes alkaline only in tlhe last puff or tv-o:~ 2za!

It is reasonable to conclude that smoking little cigars may result in health effects similar to those associated with smoking cigarettes if little cigars are smoked in amounts and with patterns of inhalationn similar t.o those used, by cigarette smokers, fmr the reasons cited above, and''theseadditiionallreasons~: (a)~Int'hoselit•tleciga.rs for«-hich pre-liminary data are available,, the concentrations of carbon monoxide, hydrogen, cyanide, acetaldeltyde; acrolein,,pyridine, phenol„and poly- cyclic hydrocarbon levels are comparable to those found in cigarettes; (b) cigarette smokers wH.o switch to cigars appear to be more likely to inhale cigar smoke than cigar smokers who have always smoked cigars (14'); and (c) cigarette smokers who switch to little cigars mayy be inclined to use them as they did cigarettes because: of the physical similarities between the: Tittle ciga:rsand' cigarettes,, includsng, their size and shape;, the number in a package, the burning rate, and the tio'ne it takes to smoke them. Figure 4!-Pereent distribution of, 130 brands of oigarettes andl25 brand5 of little cigars by "tar" content. 50 45 1 arettes Little Ci ar 40 35E 30 115 10' 0 , L11L~R Mg „tar" 0 0 0 16.0 8.01 32.0 32:A 0 1 810. 4.0 Cigarettes 0-4! 5-9 10-14 15-19 20-24 25-29 30~34 35-39 40+44! 45-49 Little Cigars 3.1 3'.1' 10.0 46.2 23:1 10.0 319 0.8' 0 01 SOURCE: U.S;.Department,of, Health, Educaition, and'.Welfare (97)and.Federal Trade.Commission (34). 225'.

Figure 5.-Percent distribution of 130'brands of:cigarettes and 25 brands of little cigars by nicotine content. 50 YI VI Cigarettes~ Little cigans F a iw i v ry ~ d ~ ~ ~ ~ p~ 0 N 1[l h O N Ia7' n O' N ~1 O~ ©~ Cjl .+ ~ '. .-r a N~ N~i lei ~i c+7, CT, 0 Ct Q!' QD M te~e Cm ai st cri M v N Ln m p o 0 O: N~. Q0~~. N ~ CG` ~~. Wv SOURCE: U.S. Departmenti of' Health, Education, and Welfare (97) and Federall T.ade Com- mission i(34). 226

TAB1,E 37.-Shipment of' small and large cigars destined' for domestic consumption (1970, 1'971, 1972). Year 1970 1971 1972 Small cigars January---------------- 58; 328; 5'20 85, 753, 780' 123, 477, 550 February--------------- 63, 431, 580 72, 092; 205 179i 817,, 839. March----------------- 85; 881, 860 46, 542, 800' 198; 165, 593. April' ------------------- 101, 613, 500 59,,059, 920, 125; 335, 740 May------------------- 81, 093, 180 93,,237, 473 159;,334, 56.5 June------------------- 82, 471„120' 94, 560, 140, 180; 582; 243. Subtbtal---------- 472, 819; 760 451, 246, 318 966;,713, 530 Ju1l-------------------- 62, 143, 140' 70, 332,' 500 127; 713, 320 August----------------- --, 68, 220, 365 127, 709; 310 670, 936, 869 September-------------- 79, 101,045 95; 027, 340 422, 534, 705 October---------------- 90; 752,880 109, 567, 900 708, 116; 830, November-------------- 64; 290, 600 106, 666, 107 5514 326, 888 December-------------- 63,806,010 123, 809, 553' 485, 587, 014! Subtotal'---------- 4'28, 314, 040 633, 112,,710 2, 966, 215,, 626 Yearly total------- 90!1, 133, 800 1, 084, 359, 028 3, 932, 929;,1i56 Large cigars January ,------ ------- February ------------- ll^larch'- ---------------- April'------------------- h'Iay------------------- June------------------- 581, 742;,001 57,3; 039, 120 534, 565, 488 595, 249;,522 586,810,844 562; 414, 577 629, 977, 375 665,, 998, 099 654, 827, 796 652, 800, 2001 655, 850, 213 554, 242, 048 748, 040„796 670, 064, 933 719;,489; 529 644, 539,,03'i 692,436,529 578, 501, 068 Subtotal---------- 3, 852, 348,,925' 3, 844,,199, 738 3, 604, 040,,506 July------------------- 647, 397, 547 619, 838, 386 520, 873, 339 Augusti----------------- 673,,082, 971' 662,970,148 ,' 682, 333', 630 September-------------- 721,561,449 680, 476, 4'18' 594, 843, 957 October---------------- 797, 601, 253 679, 420;,968' 693, 150, 668' November-------------- 696,526,464 742, 948,,802' 650,746,540 December-------------- 596, 244', 159 516, 879, 415 437, 429„996' Subtotal,---------- 4, 132, 413, 843 3;,902, 534, 137 3;,579, 356„130 Yearlytotal------ _ 8,,084, 762, 7687, 746, 733,,875711183, 396„636 Sdurce: II.S. Department of the Treasury, (101). 227

TABLE 38. -Selected' compounds in' mainstream smoke Smoke eompound "Tar"; milligram per cigarette_ __ Nicotine, milligram per cigarette_ Carhon: monoxide, volume per- CarMon dioxide, volume percentL_ Reducing sugars, percent ofl tobacco weight______________ Hiydrogen, cyanide;, microgram per cigarette_ _ _-----_-__-__ _ Acetaldehydo, microgram per cigarette-------------------- Acrolein, microgram, per cigar- etlte------------------------ Tot'al' pyridines, micrograms per, cigarette-------------------- Phenolj microgram per cigarette__ Benz(a) anthracene, nanogramn per: cigarette_ _-_-______-____ Benzo(a)pyrene, nanogram per cigarette-------------------- Cigarette A Cigarette B Little Little Small (nonfilter) (fllter) clgar A cigar B cigar C 36. 1 20! 3 17'., 4 31. 8 40. & 2.7 L 4 . 6 118 ' 3. 1 4. 6 4. 5 5. 3' 11. 1 7.7 9.4 9~ 6 8. 5 1112 ' 12.7 9:3 7:9 1l5 2.9 17, 536.0 ' 361.0 381.0 697.0 1!, 029: 0 770.01 774.0 630. 0 1, 238! 0 1,150.0 1105.0 71. 0 4!1L 0 54.0 66. 0: 82'.8 27:3 58.0 85:3 80:3' 124.2' 33.0 35:1 63:4 9411 74. 0 31.0 34. 0 25.0 39.0. 47.0 20.0 18: 0 22.0 30., 0 Source: HutImann,, D., Wynder„E. L. (44). TABLE 39.-The:pZd of'the mainstream smoke of setected'tobacco products (Numbers in parentheses indicate number of', last puSa' Average pHi Cigarette A (nonfilter)' Cigarette B (filter) Little cigar A: Little cigar B Small cigar C. Cigar D 3d puff_,____ 6. 19 6. 15 6.44 6.55 6:53' 6:4'7 5th puff---- 6. 14' 6. 12' 6.34 6: 46 6.49 7th puff'---- 6~: 09 6.01 7.03 6, 51 6.56 '. 9th, puff---- 6~: 02 5.83 ' -------- 6' 98' 6.59 . 6.27 13th puff'--- -------- -------- -------- 6.39 18th puff--- -------- -------- -------- 6. 41 23dlpuff---- -------- -------- -------- 6.81 28th puff--- -------- -------- -------- 7:22 33d puff_--_ 7 53 323th puff--- -------- -------- -------- -------- -------- 7.78: Lagtpuff_,__ 5.96(11!) 5:76(1'0) 7.73 (8) 7:25'(1'0'), 7. 11(11) 7:96(43) Source: Hoffmann, D., Wynder„E. L. (44)', 228

Conclusions Pipe and' cigar smokers in the United States as a group: experience overall mortality rates thatare slightly higher than those of'nonsmok- ers, but these rat'es are substantially lower than those of cigarette smokers: This: appears to be due to the fact that the total exposure to smoke that a pipe or cigar smoker receives f'rom! these prodncts is relatively low. The typical cigar smoker smokes fewer than five cigars a day and the typicall pipe smoker smokes less than 20~pipefuls, a day. Most pipe and cigar smokers report that they do not inhale thesmoke. Those~ who do inhale, inhale infrequently and only slightly. As aa result, the harmful effects of' cigar and pipe smoking appear to be largel'ylimited to increased death rates from cancer at those si'teswhi& are exposed to the smoke of these products. Mortality rates from cancer of t!heora~l cavity, intrinsic~andc extrinsic larynx, pharynh,and esophag us are approximately equal in users of cigars, pipes, and ciga- rettes. Inhalation~ is evidently not necessary to expose tliese sites to tobacco smoke. Althougli these are serious forms of cancer, they account for only about 5 percent of the cancer mortality atnongmen.Coronaryg heart disease,, lung cancer,,emphysema, chronic: bronehitis,, cancer of the pancreas, and cancer of the urinary bladder are diseases which are clearly~~associa.ted! with cigarettesmoking,but'fior cigar and pipe smokers death rates from these diseases are not greatly elevatedd above the rates of'nonsmokers. These diseases seem to ~ depend on mod- erate to deep inhalation to bring the smoke into direct contact with the issue at risk or to allow certain constituents, such as carbon mon- oxide; to be systematically absorbed through the lungs ortoaffsct theternporal patterns of absorption of other constituents such asnicotinethat can be absorbed eitherr through the oral mueosa or through the luna . Evidence from countries where smokers t'end to consume more cigars and inhale them to a greater degree than in the L; nited States indicates thatt rates of lung cancer become elevatedl to lev,els approach- ing those of'cigarette smokers. AvailWe data on the chemical constituents of cigar, pipe, and'' cigarette smoke suggest that there are marked similarities in the com, position of these products. Pipe andl cigar smoke, however, tends to be more alkaline than cigarette smoke, and fermented tobaccos com- monly used in pipes and cigars contain lpss reducing sugars than the rapidlyy dried varieties commonly used in cigarettes. Experimental evidence suggests that little difference exists between~ the tumorigenic activities of' tars obtained from cigar or cigarette 229 0

tobaccos. Malignant ski6 tumol:s appear somewhat more rapidly andd in larger numbers in animals whose skin has been painted with cigar tars than in those'animals painted with cigarette tars: One must conclude that some risk exists from smoking cigars and pipes as they are currently used iii the' United States, but for most d'iseasesthis is small' compared to the risk of smoking cigarettes as they are commonly used. Nevertheless, changes in patterns of''usage that wouldbring, about increased exposure either through~ inerease& indi- vidual use of cigars and pipes or increased inhal4ation of pipe andcigar smoke have' the potential of producing risks not unlike those now incurred byeigarette smokers. iV'Iecllanical or, chemicalmodificationsl of pipe tobacco and cigars that «oul'd' result in a smoke more eompat- ible' with inhalation couldl llav.ethi'seffeet. Fiipe an~dl Cigar References (L) 2,.BEnIN, T., GSELL, O, T. Relative risk of' pulmonary cancer in cigar and pipe smokers, Cancer 20(8) : 1288-1296, August:1967: (2) AI.I:ISoN¢, A.,, FLINT, F., J. Bronchitis, aspirin, smoking,, and other factors in the aetiology of peptic ulcer. Lancet 2': 179-182,, July 26, 1958. (~3)AR3fITAGE,. A. K., TURNER;. D. M. AbsOrptil7nn off niCotine'e in cig"arettee and cigar smoke through~ the oral mucosa: Nature 226(5252) : 1231-1232; June 27, 1970. (k.). As'H'.FORD, J..Rs, BRo'wIi, S., DUFFIEZ.D, D. P:,. SM,rDH',, Q.. ~.g,.,, F'AY',. J.. w'. Jl The' relation betweeni smoking habits and physique, respiratory symp- toms, ventilatory function, and radiological pneumoconiosis amongst'~ coall workers at three Seotti'sh collieries, E3ritiqhJoiunal of Preventive and Social, Jiedicine 15: 106-1i17, 1961. (,9), AUERBACII4 O., HASIMaND,, E. C., GARFINKEL, L. Histologic' changes in the larynx in relation to snial:ing7ialiits. Cancer 25(1) :'J2-104,,January 1970: ( 6:). AUERBACH„ Q:,, .caTOUT., A. P., HAJfIMOND,, E. C., GARFINKEL,: L. Changes~ in, bronchial epithelium in relation to sex, age,, residence„ smoking and pneumonia. New Eilgland Journal of' Medicine 267 (3),: 1I11-11J, July 19', 1962. (7) A:UERBACH,. 0., STOUT, A. P., HA4I3iOND;, E. C:,.!irARFINKEL, L. HlstolOgic' changes in esophagus in relation to smok'ing,habits.,A:rchives of Environ- mentlalHealth11(1) : 4-15, July 1965~ (8): AUERaAOH, 0.,. STOUT,. E>L., h.. HAMMOND, I''~u. C':, GARFINKEL, L.. S.mokinghabitsand age in relation to pulmonary changes. Rupture of al'veolarr septums, fibrosis and thickening of'walls of small arteries and arterioles. New England Journal of 3ledici,ne 269:(20) : 1045-1054, Nov. 14, 1963: (9) BEST, E. W. R'. A Canadian Study of Smoking and Health. Ottawa. Depart- ment of'~ Nationali Health and Welfare, 1966; 137 pp. (10) BoAx:E, W. C. A study of illness in a group of Cllevehuid families. XVIII. Tobacco smoking andi respiratlory infections. New Ehgland Journal of Medicine 259(26) :1245-12-19; Dec. 25,1958;(11)~ BotivER, G. RespiratorFsymhtomsandy ventilatory , function in 172adultsemliloyed in a bank. Ameri¢an: Review of Respiratory Di:seases83i: 684-689, 19611. 23q,

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CHAPTER 7 Exercise! Performance I~

Contents Introd!uction-------------------------------------------- Page 241 IVII Studies of Smokers-------------------------------------- 24!1. Studies Comparing Smokers to Nonsmokers: Ath,letic P'erformance--------------------------------- 243 Bicycle Ergometer Performanee------------------------- 244 ,. Tread'mill Performance -------------------------------- 245 Performance in Other Tests of Fitness------------------- Discussion---------------------------------------------- Biomechanisms----------------------------------------- 24'5246'1 246 Summary---------------------------------------------- 247 References--------------------------------------------- 248 .

C'. 4: ~ Q: ~ ~~' N~ ~

Introduction II Although it has long been held by athletes andl coaches that cigarette smoking, is associated with "shortness of wind"' and impaired perform- ance, until recently there has been lit't1E scientific evidence W support this view. In the past few years, a variety of studies have appeared dealing with~ the effect of cigarette smoking on the response of' man to exercise. TI he following is a review of these studies.t1ge; sex, training,, health, weight, and other factors are known to infiuence exercise performance. Because rnostof the investigations were carried, out in healthy,, young male volunteers, the groups were quite comparable with regard to age, sex, andl health; however, weight,, training,, and other factors were often inadequately controlled. Furthermore, problems in study: design and statistical analysis limit the value of several of'these studies.1Vlany forrns of exercise were performed' in t'hese experiments, in- cluding : pedaling ai bicycle ergometer, running on a treadmill, running on a track,, swimming, step climbing, gripping a hand dynamometer, and doing several different exercise activities as part of a battery of tests; Small to maximum amounts of' work were carriedl out in the various studies revewed. Studies of Smokers I Most of the studies of habitual! cigarette smokers followed a similar format with respect to smoking: (a) The subject's refrained f'rom, smoking, for a few hours prior to testing, and (b) two test runs were performed', one without smoking, and one in which smoking imme- diately preceded; the exercise or was incorporated with, the exercise protocol. Several investigators (1,,15, 28) studied the effect of smoking on, maximum grip strength. W,ilTgoose (28) reported a greater mean per- cent recovery of grip strength after the nonsmoking trial than after the smoking trial. Kay and Karpovich (15) and'i Anderson and Brown (1) all followed a protocol similar to that of Willgooseexcept thatt theyrandomiaed the smoking, and nonsmoking trials, andsubstitutied 241'

ai "placebo" cigarette for the nonsmoking triaL In neither of these studies were statistically significant diff'erences observed between the grip scores for the smoking and nonsmoking trials. Reeves and Morehouse (24) administered ai battery of tests to 15 collegesstudents.Thetest~swere:! A tapping t.est~, a strength, testl, a jumping test,and t'~heshortforrnof theHa~rvard steptest., Npstatis~- ticall'ysigni'ficant differences in perfoiniancewerenoted under con- ditions of smoking or nonsmoking. A total of 32 college studentls. from intermediate swimming classess abstained from smoking for 15 minutes„2liours, and 12 hours in a study conducted by Pleasants, et al. (23). Following the abstinence, they swain distances of 100 and 200 yards. Althouglx act~ual' swim,mingtiimeswere not published, the authors reported no statistically significant differences betaz-een the mean swimming times after the different periods of' abstinence for either distance. In 1946, Juurup: and '-NIuido (13) carried out several experiments in whi'ch three young cigarette smokers exercised on a Krogh's bi'- cycle ergometer. Smoking was found to increase the pulse rate at rest as well as during exercise. Although the effect was less con- sistent than on the heart rateT smoking was also associated with elevatedd blood pressure. Smoking had no effect on oxygen consump- tion. Henry and! Fitzhenry (12), in 1949, using the bicycle ergometer, also found that smoking exerted no effect on, oxygen consumption. In the same year,K~arpoviclii and Hale (14) studied bicy.cleergometerperformance in eight young men. In all subjects, the average riding time was better in, nonsmoking tests than, in smoking testei, how- ever, the results were statistically significant for only three of' thee eight subjects. Kerrigan, et al. (16), more recently measured direct arterial blood pressure, heart rat'e; and cardiac output in 25 habitual smokers at rest and after exercise. Smoking two cigarettes produced statistically significant (P<0.01) increases in cardiac index, heart rate; and arter- ial mean pressure compared to the immediately preceding controll period. Exercise after smoking resulted in~ an increase in cardiac in~ dex over either t'heresting, period, or the exercise peri'od, which fol- lbwed abstinence; the resultant cardiac index appeared to be approxi'- mat'ely the sum of the exercise and smoking, effects.. Exercise tests preceded by smoking, were also associated wtih sigi7ificantly higher (P<0:01) and more prolonged elevations of'bloodpressurethanthosenot preceded by smoking:. In the study by Goldbarg; et al. (,1'1)of nine habitual smokersper,formingsubmaximal exercise on a bicycle ergometer;car.diovas- cularresponses were measured via pulmonary and subclavian artery catheters. At rest, after smoking, the mean cardiac indlex and mean heart rate increased.D'urialg successively increa6ing levels of exercise, thehcart rate was ;reater and stroke indexl,o~~-er than values for 242 i

e t ~~ yl U h cotnpalrabl'ework before smoking : The, net effect of smoking was to decrease theeffi;icency of the heart duringexercise in the upright position by causing ai smaller stroke volume and a higher heart rat'e. Rode and Shephard (wS)' investigatedi near maximal treadmill exer-cise performance in six habitual smokers. A 1-dity abstinence froml cigarette smoking was associatedl with a, 13- to 70-percent dpcrease in the oxygen cost of breathing. Abstinence was also followed by a slmv- ing of the heart rate and a decrease in expiratory minute volume after exercise. The study of KrtunhoTz;Iet al. (18) is different from those cited pre- viouslyy in that bicycle ergometer exercise performance was measured in habitual smoliers, both before andl after 3' to ~ G weeks~of I abstinence. Among the 10 subaects who abstained from smoking for 3i «eeks,Ithere was alstatisticallysignificant (P< 0.05) decrease in heartrate; oxygen debt, and ratio of oxygen debt t'o: total increase in oxygen uptake pro- duced by the 5i minutes of exercise.. Using a "double 9-inch progressive step test" Rode and Shephard (25~) studiedi several hund'redparoticipants of a smoking withdrawall clinic at the time of entry andl at a 1-year foll'owup. Among, those R ho returned for the followup andl `sho gave up smoking, absolute aerobic power increased insigniticalntly, ; however, the relative aerobic power diminished in both sexes among those who q,uit smoking because of the veight gain experienced. Studies Comparing Smokers to Nonsmokers t V Ath;letic Per f'orm-ance In 1968 Cooper,,et al. (6) evaluated 419 airmen during their initial 6.reeks on active duty in the USAF. A 12-minute rnaximuml running test .vas performed at least 1 hour after cigarette smoking. The meann distance covered in 12 minutes by the nonsmokers was sigiiificantly greater (PG0:05) than that covered by the smokers at the beginning, tliemiddle, and the end of training. All cat'legoriesofsmokers and non-smokers improved their performance at the end of training; however,l the maximum change in performance oflthose smoking 10 to1:30 cig- arettes per day was significantly(P<a:001) less than that ofnon-smokers.. David (y )~ administered a battery of t'leststo88 milritary.personliel~ aged 19 to 39 y.ears. A 1I-mille run ,%vasinchided in theAesting. and cig.-arette smok~ing«-as associated .vithasignificant decrease in perform, ance in this event. 243

Some 45~ special forces soldiers were investigated' at sea level and 13,000: feet above sea level by Fine (8). The subjects were randomly: assigned to a placebo group or an acetazolamide treated group. Cig- arett'e smoking was positively correlated to decrements in 600-yardd running performance from sea level to: altitude in both groups. Pleasants (22)1 studied 106 students from intermediate university swimming classes.Swimmingtimeswere: measured for 100-and 200- y"urd distanees, before and after tlrainingand for 800-yard distancesaf'ter training. The: mean swimming times of nonsmokers were less than thoseof' srnokers, insix of' seven listed categories,, bu~tt these dif- ferences were not statistically signiificant.. Bzcycle Ergometer Performancz Chevalier, et al. (5) investigated'r cardiovascular parameters in 32 young physicians after a stiandard 5-minute ergometer test.Oxy,gen debt accumulation among smokers was significantly (P'G0.01) greater than among nonsmokers. The heart rate at rest and 3 minutes after exercise was significantly (P<0:02') faster in smokers than in non- smokers. Using a 5-minute ergometer test, 18' housestaff physici'ans„ half' of whom smoked, were investigated by Krumholz, et al. (17). They noted the foldowi'ng:, Oxygen debt accumulation after exercise was signifi- cantly (P'G'0.02) greater insmokers thannon-smokersT t'he ratio~of thee oxygen debt' to totall increased oxygen uptake during exercise was sig- nificantly (P<0:001) greater in smokers than in nonsmokers" andd the diffusing capacity at rest and with exercise was significantly (;P < 0.05 )! decreasedi ini smokers compared to nonsmokers.. Kerrigan, et al. (16) studied cardiovascular parameters in smokers and nonsmokers at rest, during, and after a 5-minute bicycle ergometer ride. Cardiac index andd blood pressure values obtained during exercise performed' immediately after smoking were greater than those found in nonsmokers performing the same exercise. Similarly„heart rate and bloodd pressure remained elevated forlbnger periods in thosewlio: exercised immediately after smoking t~han in nonsmokers performing the same task. Aerobic capacity scores were. examined in 60 university stud'ent vol~ unteers~by Peterson and Kelley. (20)1. Subjects worked at submaximal levels on ai bi~cycleergometer before;during; andl afteratra2ning program. At all of these interti-.alis, nonsmokers had significantly (Ia<0.05)i higher mean aerobic capacitiy scores thani smokers. Both groups increased their aerobic capacity during training but non- smokers consistently performed better t;hroughout training, 244

T readmall Per f orma rure H In 11960 Blackburn,, et all. (4) carriedl out, severall measurements of' II cardiovasculiir function after different amounts of treadmill exercise were performed by 2?33' professional men, 15'J~ university students„and 414 railroad workers. The differences between the smokers and non- smokerswereof' smalll magnitude. Basal otygen consumption was ' slightly higher in smokers than in nansnolcers., Also, re sting, pulse rates were higher in smokers of most groups. Coope«,et al. (6)~ studied 47outof' 410' airmen with, treadmill test-ing. Cardiopulmonaryindileesmeasured on the treadmill, including maximum indices, w.ere comparable in smnkers and nonsmokers ex- cept for a significant (1''<0:01) reduction itn the maximum minute vollume auiong, t he sniokers. I A total of 377 proslaectiveC~aanidfian firemen performed the: I3'alke- Ware test of «rork capacityy in treaKhuill' studies carried out by Glass- ford and FIowell (10). The meatt perforniaiice scores of nonsmokers were significantly (P< 0.01)greatertlian those of smokers. The effect of vitamin C suphlhnientation ou t'readmill exercise: per- formance~ was investigated in 40 ~ mal,e volunteers by Bailey, et all (13). Significant differences in orygen utiliaation andventilatoryf'unction between sm~okeisandl nonsmokers were noted in only two, ofthe2I separate ana~lj:ses of variance perforined.. Masinial oxygen intake during treadmill exercise was esamined by McDbnough, et al., (l9)' in 86heallhy, middls-aged male~ volunteers.Cigarette smoking was one of six variables which together provided al mult'i2~le correla~tioni coefficient of 0: i:3'.. Perf'armanee zn Other Test's of Fi,t'n,ess When physical fitness tests were administered tlo 88 military per- sonnel by David (7), cigarette smokingwas~ floundl to be associated with, a significant (P'<0:001)dtcreasein performance:in the dodge and jump test, andl a significant, (P<0.02) decrease in performance in the crawling test: L; singa st'~eptest, a breathholdfing test,and an, ergometer test,, Franks(',9)examiiied 58' middle-agedi men. Nonsmokeiswere able t.ohokl their breath longer and had greater vital capacityrresidual after t he stelr te st than the smolters. In 19711. «''ysokinski (,2,9)~ studied 200! young Polish soldiers usingLetunnv'stest which inclnderll301knee-bendincexercises,,a fast run for :.>0 seconds, and a run for3 minutes. C~igai.•ette,snloking Nvas a:ssociatedd withi a significant (IP'<0.01)i reduction iiu thevi'talcahacity andl a ~ 245,

marked rise in the pulse rate at rest and after exercise. Intense exer- cise also caused a greater rise in the systolic blood pressure.in~smokers than in nonsmokers. Dliscussvon. Most of'the studies in habitual cigarette smokers compared exercise performance in "smoking"' and "nonsmoking" runs after onIyy a f'ew hours of abstinence. In some studies, smoking ad'versel'y~, affected per- fbrmance (11, 13,,14,, 16; 18, 06, 28) ,, while in others it did not (1, 12„ 15„23,,2/).Some of these apparently discrepant results are due to dif- ferences in methodolbgy and in amounts and types of work performed.. l[n, al1 ofl the more recent studies of habitual smokers in which, moderate to near maximal amounts of work were performed and sophisticatedl measurements of oxygen transport and cardiopulmonary function were made, impairment of function during smoking trials was found. (11;16;18, 26')i. Thedataof'Krumholz, et al.(18): alsoraisethe question of whether residual effects ofe cigarette smoking infllaence "nonsmoking"'trials per= formed after a, fe.vhours ofl abstinence; they found statistiicall'y sig- nificant decreases in heart rate and oxygen debt produced by exercise after 3 weeks of cessation. The work ofl Rode and Shephard (25)' suggests that physical fitness improves with cessation, but t'1iisimprovement maybenegatedl if the subject gains a substantial amount of~ weight after~giving up smoking; Several investigators compared exercise performance or postexer- cise cardiopulmonary function of smokers to nonsmokers. Although only minor differences between smokers andl nonsmokers were found in a few of these studies (3; 4', 22),, in most of them (5, 6; 7, 8,,10, 16;. 17,,20, 29): the performance or function of the nonsmokers was better than that of the smokers: Both nonsmokers and smokers improved their performance wi'th~ tiraining, but nonsmokers maintained their ad- vantage throughouttraining (6, 20). Biomechanisms The citedlstudies indicate that cigarette smoking exerts it'sadverse eff'ect on exercise performance through several mechanisns.. Cigarette smoking appears to impair cardiac l~erformance during exercise by increasing, the heart rate and exerting a variable effect on cardiac 246

output (.5,11;,13, 1'6;18„26, 29). Cigarette smoking is associ'ated' with. an increased osygen, debt after exercise (5, 18). Also, one study indi- cated that the oxygen cost of hyperventilation was greater among smokers than among nonsmokers (26). Some of these adverse effects of' smoking, on oxidative metabolism are mediated by the elevated carboxyhemogTobini leuels found in smokers. COexerts these effectsthroughone~or moreofl the following, mechanisms: (a) Reduction of the amount of hemoglobin avaiIablie for oxygen transport, (b): shift of the oxygen-hemoglobin dissociation, curve to the left~ with, consequentiRlterference~ in oxygen release at the~ tissue level~ (c)~ induction of arterial hypoxemia4 and (d) possible interference with tliehomeost'a~tic mechanism by which 2,3,DPG controlsthe affinity of hemoglobin for oxygen (2T);. Because carboxy- hemoglobin has a half'Iife in the body of'~ at least 3 to:4 hours„its infi!uL ence may: still be measurable several hours after abstinence from smoking (27). AX recent investigation of' maximal muscular exercise d'uring CO in- toxication in five male volunteers demonstrated reduced maximal Oz consumption in spite of a much higher heart rate and a relative hyper- ventilation (21). Astrand and Rodahl'' (2) commented recently on the adverse effect of' cigarette smoking on oxygen transport :"Al1 other factors being, equal~ a reduction in the oxygen-transporting capacity is associated, with a corresponding reduction in physicali performance capacity dur- ing, heavyormaximall work ***. Because a regwl'arphysical train- ing program only increases the maximal oxygen uptake by some 10 to 20 percent, a 5- to 10~percent reduction in maximal aerobic power duee to smoking may play a si'gnificantrole in many types of'athletic events and in very heavy work." Other studies cited in this review document the adverse effect of smoking on pulmonary diffusing capacity (18) and on pulmonary function with exercise (6,29). Summary il Clinical st'udies in hea~~lthy,~ young men ha~~~~e~ shown that~ cigarette~ smoking~ i'mpa~iR•s~ exercise~ performa~nce,~ especi'all,y~ for~~ mnny' types, of at~hletic events~and activi'ties inv.ol~ving~ma~xi7m~l work capacity:~ .S'ome~ of'these~ et£ects~~ are mediEitedi by~ redu~cedl oxygen transport and re~ducedi cardiac and pulmonary function. 247

U Exercise Pirformlanee References ( (1) ANDERSON, J. M., Bxowx4 C: W. A. study of the effects of smoking upon grip ~ strength and recuperation from local muscular fatigue. Research Quar- ' terly 22 (1) : 102-108, March 1951. ~ (2) As^rRANn,, P'.-0:,, ROnAHL, K. Factors affecting performance. In: Textbook of Work Physiology. New York, 3dcG'raw-Hill: Book Co., 1970, 669 pp. ' (3) BAU.EY; D. A., CARROxs A. V.,, TEEeE,, R. G.,, WEHSER, H. J. Vitamin C' 1 supplementation related to physiological response to exercise in smoking, ` \ iti ki A i l f li i l t 23 7 I i ca r ion and nonsmo mer cani Journa , o n l u ( J : , ng, subjects: C 90,5r912; July 1970. (¢) BzACgBUR,x, H., BsoZER:, J_ TAYLOR,, H. L. Common circulatory measure- ments in smokers and nonsmokers. Circulation, 22':, 1112-1124, December 1960. (5) CHEVALIER, R: B'., BowERS, J. A.,, BONDURANT, S., Ross, J. C1 Circulatory and ventilat'org effects of exercise in smokers and nonsmokers. Journal of' Applied Physiology 18(2) : 357-360, March 1963: (6) COOPER, K. H., GEY, G. 0.,. BOTTENBER4., R... A. EffectsOfcigarette. smoking on endurance performance. Journal of' the Ameriiean Medical Association 203!(3) : 189-192,,Jan. 15; 1968. (7): DAVm,, K. H. Age, cigarette smoking, and tests of physical fitness. Journail of Applied Psychology 52'(4) : 296-29E3, August 196& (8) FtxEy B. J. Personality traits as related to symptomatology and running, performance at altitude under normali and drug (acetazoleamide) condi- tions. Perceptual and Motor Skills 27:: 97:,-990, 1968: (9) FRANKS, B; D. Smoking and selected cardiovascular-respiratory measures. Research Quart'erly 41(2) : 14'0-144:, riLay,1970: (10), GLASSFORD, R. G.,, HOWELL, 11. L. Smoking, and physical fitness : A prelim- inary report. Canadian Family Physician 15(10:)~: 60-&2, October 1969: U ~ (11) GOIinBARa, A. N., KROSE, R. J., RES:cEKOV, L. Effects af' cigarette smoking ~ on hemodynamics atl rest and during exercise. I. Normal subjects. Chest ~ 1 60(6) : 531-536, December 1971. (12) HE:vRY, F. M., FrrzHEVaY, J. R. OO xSgen metabolism of' moderate exercise, ' with some observations on the effects of tobacco smoking. Journall of' ~ Applied Physiology 2: 464-468,,February 1950: (13) JuuRI;P, A., MLxno, L. On acute effects of'~ cigarette smoking, on oxygen ` consumption, pulse rate; breathing rate and bloodl pressure ini «•orking, organisms. Acta Physiologica Scandinavica 11: 48-60, 1946. (14), KARPovica, P. V., HALE, C. J. Tobacco smoking andl physical performance. Journal of Applied Physiology 3: 616-621, April' 1951. (1'5) KAY,, H. W., KARrovlcH„ P. V. Effect of smoking upon recuperation from 1or {I cal muscular fatigue. Research Quarterly 20: 250-256',, 1949. (16). KIIRRI6A\, R:, JAIS„ A. C~, DOYLE,. J., T. Thee circulatorfreSponse: too eigarI rette smoking, at rest and after exercise. American Journal of the 1Sedi: cal Sciences 255: : 113-119;, February 196& (17) KsuMHOLZ, R. A., CaEVAZ,IFR,, R. B,. Ross,, J. C: Cardiopulmonary function in young smokers. A comparison of pulmonary function measurements ~ and some cardiopulmonary responses to exercise between ai group of, y!oung i smokers and a comparable group of nonsmokers:,Annals of'Internal Medi- cine 60(4) : 603'-610;, Apri11964. ~ (l8)KRIP\LHOLZ, R:. A., ('HEVALIER, R. B., Ross, J. C:(Vhangess ini cardiopuI- I monary functions related to abstinence from smoking. St'udies in, young ~ cigarette smokers at rest and exercise at 3' and 6 weeks of abstinence. Annals of Internal Medicine 6`?(`?)~: 197-207, F.ebruarS 19654 248

I (19) rilaDoNoucn4 J. R:, Kusuun; F., BeuCE, R. A. Variations in maxiniali oxygen intake with physical activity in middle-aged men. Circulation 41(5 ) : 743-751, May 1970. (20) PETassox, F. J., KELLEY, D: T.. The effect of cigarette smoking upon the acquisition of physical fitness during: training, as measured by aerobic capacity. Journali of the American College Health, Association 17(3) : 250-254, February 1969. (21) Pia:vAr, F., DUJARDIN, J., DeaoANTxE; R., PErtrr, JL M. Muscular exercise during intoxication by carbon: monoxide. Journal of Applied: Physiology . 31(4) : 573-575, October 1971., (22) PieASASTS, F~_ Jr. Pretraioling, and post-training, swimming endurance of'f smokers and nonsmokers. Research Quarterly 40'(4)i: 779-782, 1969. (23)~ PT:EASArrTS; F:,,Jr., GttucAN„J., R'sTLiFF, J- W:,,Jr. Effects of short periodss of abstinence from cigarette smoking on swimming, endurance of ehronic, smokers. Research Quarterly 38 (3'); :•174-479, 1966. (2h), RkEVBS, AV: E., 1loxeliarsE, L. E: The acute effect of smokinguponi the physi- call performance of' habitual smokers. Research Quarterly 211: 245-248, 1950! (2:5) RonE, A., SAEraARn, R. Js Smoking withdrawal and changes of cardiores- piratory fithess: American Review: of' Respiratory Disease 104(6) : 933- 935, December 1971. (26) RonE, A., SaE.raAto, R. Jl. The influence of cigarette smoking upon the oxy- gen cost of breathing in near-maximal exercise. Medicine and Science in Sports 3'(2),: 51-55, summer 1971.. (27) U.S, PusLIc HizanTa, SERvicE: The Health Cbnsequences of Smoking:, A Re- portl of'the Surgeon General : 1972. U.S. Department of'~ Health, Education, and Welfare. washington~ DHEW Publication No. (HSM) 72-7516, 1972, 158 pp. (28) Wira,aoosE; C. E. Tobacco smoking, st'rength, and muscular endurance. Re- search Quarterly 18':,219--225, 1947. (i29) WYSOffrNsxi„Z. Effects of'tobacco smoking on, certain parameters reflecting, the condition of t'he circulatory system at rest and during exercise. Polish Jiedicali Science and, History 14(2)~: 73-76, April 1971. b- I I U.S. GOWERNMENT.PRINTING OFFICH : 1973-CH495-028 249'

03764537

The Health Consequences of Smoking, JJanuary 1973 INDEX Pages 2'511-261 U.S'. DEPARTN~IENTOF HEALTI1„ E:DL;OATI~.ONI, AND WELFARE. Public Health Service

DHEW'Publication No: (HSM) 73.8704

INDEX ' Abortion, spontaneous effect of maternal smoking, 123,1124 Acenaphthylene in cigary pipe, and cigarette smoke;,1'78' Acetaldehyde as ciliatoxic agent in cigarette smoke, 51 Aerobic capacityy effect of cessation of,smoking, 243 effect of exercise and smoking, 243,244 Air pollution and' bronchitis; in smokers vs. nonsmokers, 36,37 effecU on mortality rates from lung cancer, 73 as factor in lung cancer development, 72,73' imOsakat Japan, 44 prevalence of respiratory diseases:and„441 andl smoking in military and civilian air- craft, 45, Alcohol consumption interaction with smoking, andl other, risk factors in CHD,,10 and smoking, in cancer developments 71 and smoking; _in esophageal, cancer deveL opments 76,200 and smoking, in laryngeal cancer etiology,, 197 and smoking„in,oral cancer etiology, 193 Alveolar macrophages effect of cigarette smoke, 5'2;53 effect of nitrogen dioxide, 54 Alveolar rupture in pipe/cigar smokers vs, cigarette smokers and nonsmokers, 217 Angina pectoris carbonimonoxide inhalation and„17,18 incidence ini pipe and cigar smokers„21',5 Anthracene in cigar, pipe„and cigarette smoke, 178 Arterioles effect of smoking, 22,23 Arteriosclerosis obfiterans smoking as cause; 1'9;20 Aryl hydrocarbon hydroxylase effect of'benzo(a)pyrene in pregnant rats, 119 role in metabolism of chemical carcino- gens, 82,83 Asbestos effect on pulmonary, function in smokers vs. nonsmokers, 411 eff.ect! on radiological findings in smokerss vs. nonsmokers, 411 effecYon respiratory symptoms in smokers vs. nonsmokers, 41 andl smoking, effect on mortality rates from lung cancer, 73' Athletic performance running, effectof smoking;,243;24'4 smokers vs. nonsmokers;,24'3',244 swimming, effect of smoking, 244 Autopsy studies COPD and smoking, 45-48 lung cancer in U.SI veterans, 73,74 Bacterial flora in smokers vs. nonsmokers with COPD, 54 Benzo(a)pyrene carcinogenic effect in laboratory animals, 78-80 in cigar, pipe, and cigarette smoke„ 177;178' effect on DNA and': RNA, 86 s87, effects: during pregnancy in laboratory animals, 117,118' Bicarbonate inipancreatic secretions, effect of smoking, 159,1601 Bicycle Ergometer performancee cardiovascular parameters in smokers vs: nonsmokers, 242-244 Birth weight effect of' maternal smoking, 103-114; 119-122 effect' of maternal, smoking before andl during current pregnancy by cigarette consumption, 1107-109 effect of maternal smoking during pre- vious pregnancies,112'-114' effect of maternal, smoking, mechanism of action, 119,120: effect of paternal smoking,,110,1111 effect~ of tobacco smoke, nicotine, or carbon monoxide in laboratory animals, 11I4'-118' gesta4ioni duration in smokers vs. non- smokers, 103-106 and maternal smoking, epidemiologicall studies, 103-114 timing of influence of smoking, 1120,121 Bladder, cancer see also Renal,cancer incidence in smokers vs, nonsmokers, 77',78' smoking in etiology of, 77,78' Blood flow effect of smoking, 19,22;23 Blood lipids effect of smoking; 11,12. 251

effect of smoking and relative weight; in male Parisian,civil servants; lil effect ofl smoking in middle-aged patientsi with anginai pectoris„ 12 effect of smoking in young hlorwegian, military recruits, 11 elevated, as risk, factor in CHD, 11 Blood pressure effect of exercise and smoking,,. 242;244L246' effect of pipe and cigar smoking, 216 effect of smoking in middle-aged patients: with angina pectoris„ 12 Body height interaction with smoking as factor in cerebrovaseuiar disease, 19. Body weightt interaction with, smoking, as factor in cerebrovasoular disease„19 and smoking, as factors in CHD' incidence„ 4-6 and smoking, eff'ect:on blood lipids, 11 Bronchial, epitheliumm histological changes at autopsy and smok- ing habit, 74 histological changes in cigar, pipe,,cigar- ette smokers ~s: nonsmokers, 203, 204„ 209 premalignant changes in smokers, 67 Bronchiolo-alveolar cancer smoking and„71 Bronchitis and disability„in smokers vs. nonsmokers, 43 dust exposure as a factor; 44 mortality ratios in male pipe and cigar smokers, 2117;219' prevalence in Duisburg, Germany, by age and cigarette consumption, 39' prevalence in ex-coal miners andi non- miners by smoking habit, 42 prevalence ini miners and farmers in Hlun- gary, by smoking,habit, 42 prevalence in pipe and cigar smokers, 220,22'11 prevalence in smokers vs: nonsmokers in Bordeaux;, France; 36 prevalence in smokers vs. nonsmokers in, mountainous or low-lying areas, 36,37 prevalence in smokers vs. nonsmokers in Osaka, Japan, 44: prevalence: in smoking vs: nonsmoking yarn miB!workers, 40 in, smokers vs. nonsmokers, autops,y stu- dies„4'5 „46 smoking vs:,coallmining inietiology of, 42 smoking vs., dustl inhalation in etiology of',, 42 Bronchitis, chronic see Bronchopulmonary diseases, chronicc obstructive 252 Bronchopulmonary diseases; chronic ob- structive see also Emphysema and bronchitis autopsy studies,,45-18 as cause listed on death certificates vs. at autopsy, 47' epidemiologicalI studies„36'-45 mortality and morbidity studies„36-39 mortality rates in British, citizens by rttigra- tion patterns,, 36 mortality ratios in, male pipe and cigar smokers, 21'6,217,219 summary ofl previous findings, 35,36 summary of! recent findings,,55 Byssinosis, prevalence in, cotton mill employees,, smokers vs. nonsmokers, 55 prevalence in men by index of severity and smoking,habits, 440,411 prevalence in smoking va nonsmoking, cotton milllworkers,,39 smoking,and„39-41 Cancer see also Specific site, e.g;, Lung cancer mortality rates in alcoholics, 7L recurrent, primary„ incidence in smokerss vs. nonsmokers, 71!,74 summary of previous findings,b7,68 summary of recent findings„88 Capillaries eff.eata of smoking„ 22. Carbon monoxide cardiovascular effect6„ experimental stu- dies;,17-19 effecYt on birthweight and neonatal mortal- ity in aninsals, 133 effect on cholesterol biosynthesis,,imvitro„ 18 effect on cholesterol level in aorta in, rabbits, 18 effect on coronary hemodynamics and, ventricular, function imdogs, 18 effect, on exercise performance in:smokerss vs. nonsmokers„246,24'7 effect, on maximal, oxygeni eonsumption,. 18 effect, on, platelet stickiness in rabbits„ 1'8 effect, on reflex vasoconstrictOr responses;. 18,23 effect on vascular resistance and reflex vasoconstriction„22,23 effects during pregnancy in laboratory animalk,,116411,7 Carboxyhemoglobin levels : effect on exercise pr,rformance inismokers vs. nonsmokers„246,24T ~ following smoking of non-nicotine ciga- rettes, 17,18. ~ 4~. ~. ~

in, neonates of smoicing, mothers, 118;,1!1'S' Carcinogenesis cell and tissue culture studies, 84'-86' effect of:tobacco curing methods; 212 experimental, 78-87' initiating, and promoting agents in, cigar- ette smoke,,68 mechanism of action, 78, 80-87 of respiratory tract in laboratory animals:,, 78-80 role of cigarette smoke condensate, W84 Carcinogens effect on cell transformations, 84-86 effect, on respiratory tract in laboratory animals„78-80 Cardiac index effect of exercise and' smoking, 24'2-2441 Cardiovascular diseases see also Coronary heart disease mortality ratios in male pipe and cigarr smokers, 215,216 smoking and, 3•23 summary of previous findings, 3 summary of prospective epidemiological studies for cigar and pipe smokers, 216' summary of recent findings, 23 Catecholamine levels effect of' cigar, pipe, and cigarette smoke in dogs, 216 Cell and tissue:culture studies tobacco carcinogenesis and~ 84•86 Cell cultures, malignant transformations induced': by to• bacco tars oncarcino&ens,,84-86 Cells„atypical, in ex-smokers, smokers,, and nonsmokers at autopsy, 74 Cerebrovascular disease interaction of smoking and, other risk factors, 19 mortality ratios in pipe:and cigar smokers, 215,216 Cessation of smoking compared benefits in cigarette vs: pipe/ cigar smokers, 172,173 effect on absolute aerobic power„243 effect on infant birth weight, 107-109 1124114: effect on pultnonary surfactant level§, 55' as preventive measure in ocelusive disease: 21,22 CHDD Cholesterol levels effect of carbon, monoxide in rabbits, 18' effect of smoking and!body weight, 111 effect of smoking aed clinical parameters iniBritish,business executives, 1,1 inipipe:and cigar smokers„215,2'16 Chronic obstructive bronchopultnonary di- sease see Bronchopultnonary disease, chronic obstructive Cigarettes definition and processing, 175'' filtered, effecL on respiratory symptoms, 55 modified, effect on respiratory symptoms and ventilat'ory capacity, 37,38'8 plainivs: filtered, effect on sputumiproduc- tion„37,38 similarities with little eigars, 224,22'5' Cigarette smoke condensate, effect on RNA, 86 N-nitrosamines:in, 87,88 role in experimentallcareinogenesis, 80-84 Cigarettes, non-nicotine effect on carboxyhemoglobin levels; 17,18 Cigars definition and processing, 175,1'76 Cigars, Gttle chemical composition of, 224',2'25,2'28 evaluation of potential public health im- pact, 22'2=228' shipment for domestic consumption. 1970-1972,222~224,227. similarity to cigarettes, 224,225 sugar and pH differences withi large cigars and cigarettes, 222'-224' tar and nicotzne :content,, 224•226',228 Cigar smokers relative risk in lung, cancer development; 67,68 Cigar, smoking, effect, on mortality and morbidity com• pared to cigarette smoking, 171-173 in esophageal cancer development4, 197,200-202' gastrointestinal disorders and, 222, health consequences of,,179 histoIogical effects on bronchial, epithe- lium„203',204I 209 histological effects on esophagus; 200 histological effects on larynx, 197 inhalation,patterns and„184-L89 see Coronary heart'disease Chest illness in laryngeal cancer development, 197-199' prevalence in pipe and' cigar smoker:s,. 220,221 in lung cancer development, by amount smoked, 203-206' Cholesterol, effect of carbon monoxide biosynthesis mortality ratios from cardiovascular~ di- seases and, 215,216 0 , in vitro 1'8' mortality ratios from COPD: and, 217,219 ~ , ~ ~ 253' ~ f .i~ N

mortality ratios from esophageal cancer and, 197,2W mortality ratios from laryngeal cancer and, 193,196,1197 mortality ratios from lung, cancer and 203-205 mortality ratios from oral cancer, and 191,193 oral cancer development and, 193-195 overall mortality rates by amount smoked., 180-182 overall mortality rates fromi cancer and; 189 prevalence in Great Britain, 173,174 prevalence in United States, 173,174 pulmonary histological changes and, 217 Ciliary activity effect of pipe/cigar smoke vs. cigarette smoke in cats, 217,218'. Clinical laboratory tests effect of aging and smoking,, in, healthy, male veterans„ 11 Coal dust effect on pulmonary function in smokers vs: nonsmokers, 41-43 effect on respiratory symptoms in smokers vs. nonsmokers, 41-43 Combustion temperature effect on tumorigenic activity of pipe and cigarette tobacco; 210,211 Congenital' malformations mate,rnal,srnoking and, 136,137 Coronary heart disease epidemiological studies, 4-11I experimental studies, 13-19 incidence in European vs. American men, 9 incidence in farmers vs. nonfarmers by smoking habit,, 7 incidence in Hawaiian men of Japanes, ancestry, 10 incidence in male bank employees ir Brussels, Belgium, 10 incidence in men in Yugoslavia, 99 incidence in miners in Sardinia, 10 incidence in pipe and cigar smokers„ 215,216' incidence in white males by body weight and smoking habit, 5 incidence in whites vs. blacks in Evans County, Georgia, 4,5 in India, 11 interaction ofi smoking with other risk~ factors, 4'-11 mortality rates in Japanese men and wo- men by cigarette consumption and age av initiation of habit, 7,8 mortality rates in smoking men in Finland, 99 mortality ratios in pipe and cigar smokers, 215,216 in Nepal„ 11 in New Zealand;,11 ' smoking;, in individuals under 40 y%~ars, 10 and' smoking, in myocardial' ischemic pa- tients in Iltaly,,10 COPD see Btonchopulmonary diseases, chronic obstructive Cough effect of asbestos exposure im smokers vs. nonsmokers, 41' effect' of coal dust exposure in smokers vs., nonsmokers, 41,42 efl'ect, of filtered cigarettes, 55 effect of modifiedi cigarettes„38 prevalence in pipe and cigar smokers,. 220',221i prevalence in, smoking vs: nonsmoking women in Bordeaux, France,, 36 Cresols in cigar,,pipe; andlcigarette smoke, 177' Curing methods incidence of respiratory infections in rats and„218;219 Cyanide detoxification in pregnant smokers vs: nonsmokers, 119 7 H-Dibenz (c,g)carbazole carcinogenic effect' in laboratory animals; 791 Diet, and smoking, effecton.blood lipids,,12 DNA binding of polycyclic hydrocarbons to, 86,87 Dust exposure bronchitis and, 44 as occupational i hazard, 43,44 smoking and, 44 Dynamic compliance in smokers vs. nonsmokers under 30, 50: Dyspneaa prevalence in cigar and pipe smokers,. 220,221 Electrocardiogram abnormalities, effect of smoking and other factors, 13 effect of smoking, im middle-aged Dutchi men; 112' effect of smoking„ in young military re- cruits in Poland, 112. Einphysema see also Bronchopulmonary disease, chronic obstructive f 2'54

incidence in cigar/pipe smoking coal mi'- ners vs: cigarette: smokers and non- smokers, 217 mortality ratios in male pipe and' cigar smokers, 217,219 prevalence: in males by smoking category, at, au topsy, 48' prevalenee in, pipe/cigar and cigarette smo- kers vs. nonsmakers, autopsy studies, 45,46' prevalence in smokers vs. nonsmokers, 55 in smokers vs. nonsmokers, autopsy stu- dies, 454'7 Epidemiological studies bronchopulmonary diseases and smoking,, 36-455 coronary heart disease and smoking, 4-13,23 lung cancer and smoking, 68-72 peptic ulcer and smoking, 155-157' Esophageal ~ cancer alcohol consumption and, smoking in de- velopment of 200 inhalationpatterns and4,197 mortality ratios for cigar, pipe,, and ciga- rette smokers vs: nonsmokers, 197,2000 mortality ratios in Japanese male smokers vs. nonsmokers, 76 relative risk in cigarrs pipe„ and cigarette smokers vs. nonsmokers, 197,200-202' smoking and alcohol consumption in de- velopment of, 76 summary of retrospective studies,, 201,202 Esophagus histological changes in cigar, pipe,, ciga- rette smokers vs, nonsmokers, 200 Exercise performance on bicycle ergometer, effect of' smoking, 24'2,243' cardiac index, effect of smoking, 242,243 effect of smoking and smoking,abstinenee; 241,242,246,247' influencing factors, 2411',246,247' summary of findings and mechanism of action, 246,247 on treadmill, effect of smoking, 243,245 Experimental! studies COPD and,smoking, 48-55 coronary heart disease and smoking, 13-19 effect, of carbon monoxide on pregnantt animals, 132;13:3'. pregnancy in laboratory animals„eff'ect,of tobacco smoke, nicotine,, carbon mono- xide, and polycyelic hydrocarbons; 1i14L118 Ex-smokers compared mortality rates:for cigarette vs. pipe/cigar: smokers, 172,173 histologjcal' changes in bronchial epithe- lium at autopsy, 74 low birth1weig3it, infants of, 112-1I14 mortality rates from lung cancen, 71-72' prevalence of respiratory, symptoms,,39 pulmonary function, 39 relative risk in lung cancer development, 71-72 survival after treatment for pharyngeal, laryngeal, or oral cancers, 75 Fatty acid!levels effect; of eigar,, pipe, and cigarette smoke in dogs„21fi: effect, of smoking, 12 Fetal mortality effect of'maternal smoking, 123-135 epidemiological studies in smokers vs„non- smokers, 126-132 Fibrosi's in pipe/eigar smokers vs. cigarette smokers and nonsmokers, 217. Fitness tests various, smokers vs. nonsmokers„245 Framingham study interaction ofl smoking and other risk factors in CHD;,8 Gastric secretion effect of nicotine in laboratory animals,, 158,159~ effect of smoking in ulber patients; 157,158 isastrointestinal disorders prevalence in cigarette and pipe/cigar smo- kers, 222 Gestatiom and low birth weighY infants, effect of maternal smoking, 103-106: Gestatlonal age effect on perinatal mortality rates in smo+ king, vs, nonsmoking m,others;, 126-132' Glucose intolerance as a risk factor in CHD, 8 Grip sttength, effect of:smoking, 241,242: H'eart rate effect of exercise and smoking, 242-246 Histological studies hrrlg cancer in U.S'~ veterans, 73 Histopathological studies in laboratory animals„49,50 in smokers vs. nonsmokers„48,99. Honolulu Heart Study interaction of smoking and other risk factors:in CHD; 8,9 ' 255

q relative risk in pipe/cigar smokers, 67;68: smoking as cause, 67' summary of retrospective studies,,206-208' Maternal-fetaLexchange polycyclic hydrocarbons and; 119 Maternal smoking see Smoking, maternal. 3-Methylcholanthrenes effects during pregnancy in laboratory animals, 117 Morbidity from chronic:bronchopulmonary diseases, 36-39 IVlortalityy compared rates for cigarette vs, pipe/cigar ex-smokers;,172,173 from chronic bronchopulmonary diseases, 36-39 from, COPD, in cigar/pipe smokers vs. cigarette smokers and nonsmokers„ 216,217 overall rates for cigar smokers, vs„ pipee smokers, 179,180 overall rates: for pipe/cigar smokers and' dbse-response relationships„180-189 overall rates for pipe/cigar smokers vs.. nonsmokers„179;180 overall rates from eancer in pipe and cigar smokers, 189 ratio in pipe and cigar smokers by age and inhalation, 184',187' Mortality rates CHD in Japanese: men and women by cigarette consumption and age at initia- tion,of habit, 7,8 Myocardial infarct incidence in European vs. American men, 99 incidence in men in I'ugpslavia„9' incidence in miners in Sardinia, 10 incidence in pipe and cigar smokers, 2'15' prevalence in smoking, vs. nonsmoking, men in Czechoslovakia, 10 and smoking,, in patients in. Leningrad hospitals, 10 Nicotine in cigar, pipe, and'cigaretrce smoke„17,7 clinical effects on offspring of smoking motfiers; 14'0,1i41 in duodenal ulcer induction in, cats„ 158,159 effect on cardiovascular, systemiin dogs, 1'7' effect on gastric secretion incats, 15$,1591 effect on gastric secretion in rats, 159 effect on heart, blood,flow in dogs, 17 effect on lactation in laboratory animals, 138,139 effect on lactation in smokers vs. non- smokers;,1'39;140 effect on lipid biosynthesis in aorta in! dogs„ 17 effect on microcirculation in atrium in cats„17 effecti on pancreatic secretions in animals, 161,162 effect on pipe/cigar smoke inhalation, L83;184 effect on rat and mouse fetus, site of action, 1211 effects during, pregnancy in laboratory animals, 115,11& experimentall studies, 16,17 in little cigars compared to:cigarettes andd cigars, 223-226,228' in milk:of laboratory anim,als,, 138,139 in milk of'smoking mothers, 139 as potentiator of duodenal, ulcers in ani- mal's„ 161-L63 Nicotine levels iniblood, new assay method, 15,23' Nicotine secretionn effect of cigar, pipe,, and cigarette smoke in dbgs; 216 Nitrogen dioxide effect on, alveolar wall cells iwguinea pigs, 50 effect on bacterial retention in, hamsters, 541 effect on rat; lung, 49,50 Nitrosamines, effect, on lactating hamsters, 139 N-Nitrosamines determination in cigarette and tobacco smoke condensate, 87,88 Obesity as a risk factor for CEID, 9 Occlusive disease smoking and, 21 Occupationn andl smoking, as factor in, CHD incidence,. 5,7 Occupational diseases asbestosis, 41 byssinosis; 394'1 coal workers pneumoconiosis, 42 Occupational exposure pancreatic cancer and„77. andi smoking, bladder cancer andt, 78 Occupational hazards asbestos exposure, 41,73 coal dust exposure„4!1 43 cotton; tlax, and'' hemp, dUst exposure, 39-41 257

dust exposure, 43',44 1007o pure oxygen exposure, 43' radiation exposure in uranium miners, 72 smoking and~ 39-44 smoking as:additive risk for COPD, 55 Otal,cancer alcohol, consumption and smoking in etio- logy of, 193 inhalation patterns and, 19 11 mortality rates in Japanese male smokers vs: nonsmokers, 74 mortality ratios for pipe, cigar, and cigar- ette smokers vs. nonsmokers, 191!-193 recurrent, incidence in smokers vs. ex- smokers, 71,74;75 relative risk ofi development in pipe, cigar,, and' cigarette smokers vs~ nonsmokers,. 191i,194,195 reverse smoking and, 7,6, smoking in etiology of', 74L76 summary of retrospective studies, 1194,195 Oxygen debtt effect of smoking, 246,247' exercise performance and, 246,247 Pancreatic cancerr occupational exposure and, 77 smoking,and, 77 Pancreatic secretions, bicarbonate content, effect of: smoking, 15'9;160 effect of nicotine in animals, 1'61,162effect of smoking,,159,160 Passive smoking, effect on cardiovascular function inidogs; 14 Peptic ulcer see Ulcer, peptic Per?natall mortality effect of maternal smoking, summary of findings, 1,34,1135 Peripheral arteriosclerosis smoking and, 21 Peripheral vascular disease smoking and,,19!-23' pH pipe/cigar smoke inhalation and, 182 of smoke in cigarettes, cigars, and little cigars; 223',2241,228 Phagocytosis effect' of cigarette smoke in laboratory animals, 53,54! Pharyngealcancer recurrent,, incidence in smokers vs. ex- smokers, 74,75 Pharyngeal fungi smokers vs. nonsmokers in South Africa, 54 Phenols inicigar„pipe; and cigarette smoke, 177 Phenylmethyloxadiazole (PNIO) protection against adverse effects of cigar, ette smoke in animals;,49;53 Physical activity as a factor in coronary heart disease, 4,5 Pipe smokers relative risk in lung cancer development,, 67.68 Pipe smoking effect on mortality and morbidity com- paredlto cigarette smoking; 171-173 in esophageal cancer d0velopment, 197,200-202 gastrointestinalidisorders and, 222 health consequences of, 179' histological effects on bronchial epithe- lium, 203',204',209 histological effects on esophagus, 200 histological effects on larynx, 1977 inhalatlonpatternsand, 184F189in laryngeal cancer development,, 197-199 in lung, cancer; development by amount smokedi, 203-206 mortality ra.ios from cardiovascular di+ seases.and,,21!5,2'16 moitality, ratios from COPD' and„21'7;219 mortality ratios from laryngeal cancer and~. 193,196,197,2000 mortality ratios from lung cancer and,. 203-205' mortality ratios from oral cancer and, 1911,193 oral cancer development and, 1i93'-195 overall mortality rates by'amount'smoked, 180+182' overall mortality rates from cancer and„ 189, prevalence in Great Britain„173,174 prevalenee:in United States, 173,174 pulmonary histological changes and, 217 Pipe tobacco definition and processing, 176, Plethysmogram abnormalities;, ini smokers vs. nonsmokers,, 22' Pneumoconiosiss in coal miners, smokers vs. nonsmokers,. 42 Pneumothorax, spontaneous smoking,and„37. Polycyclic hydrocarbons binding to DNA and RNA, 86,87' effects during pregnancy in laboratory animals„ 117:118' nraternal-fetalexchange and~ 119 Post-operative complications in duodenal! ulcer removal, smokers vs. nonsmokers, 1'57 258'

smoking„obe:sity, anesthesia and„ 39 Preeclampsia maternal smoking and, 114'2 in, smoking,vs. nonsmoking women, 142 P>:egnancy effect of maternal smoking, 103'-1422 effect of maternal smoking„mechanism ofl action, 119,120 effect of tobacco smoke, nicotine,, and carbon: monoxide in laboratory animals, 114'-118' and previous smoking habits,, effect onn infan ti bir th: weight, 112-114 timing of intluence of smoking on birth weight, 120321 Ptematurity effect of smoking„ 112. Pulmonary arterioles histological effects of pipe/cigar smoking, vs, cigarette smoking, 217 Pulmonary clearance effect,of heavy smoking; 52;53 effect of smoking, 55'5 mechanical vs. bactericidal clearance: in gpinea pigs,,53 mechanismy, in smokers vs. nonsmokers, 52,53 in monozygotic vs. dizygotic twins, 51 particle: deposition in smokers vs. non« smokers, 53' Pulmonary diffusing capacity in smokers vs. nonsmokers in Berlin, New Hampshire, 50,51. Pulmonary emphysema see Emphysema Pulmonary function in asymptomatic young men in Romania, 39 in, coal miners, smokers vs. nonsmokers,. 42,4'3' in, coal miners vs. nonminers, 42 effecti of asbestos, exposure and smoking, 41, effect, of coal dust exposure and smoking„ 41-43 effect of lung, hyperinflfttion in coal mi- ners„412,43effect on exercise,penformance in smokers vs. nonsmokers, 246',247 iniex-smokers, 39 in jet fighter pilots, smokers vs: non- smokers„43 in pipe/cigar smokers vs: nonsmokers, 217,221 pulmonary hypertension and, 43' in smokers vs. nonsmokers, 55 in smokers vs: nonsmokers in Berlin, New Hampshire, 50,511 in smokers,vss nonsmokers, under 30 years of age„50 smoking and, 38;39' ` Pulmonary histology of' pipe/cigar smokers vs. cigarette smokers and nonsmokers, 217 Pubnonary macrophagess effea of, smoking„55 Pulmonary surfactanti levels effect of smoking; 55 Pulmonary tissue histopathological differences in smokers vs. nonsmokers, 48',49 Pyrene in cigar, pipe, and' cigaret:te smoke„ 17 8' Race as a factor in coronary heart disease, 4,5,23' as a fact'or in perinatal,mortality in smok- ing vs. nonsmoking mothers, 129-132' as a factor in stillbirth rates, 124,125 Radiation exposure and smoking; as cause of respiratory can- cers„72' Radioactive particles in tobacco leaf.,, tobacco smoke, and smo- kers' lungs; 72'. Renal cancer, mortality ratio in Japanese men and wo- men,, smokers vs. nonsmokers, 77' smoking in etiology of77,7,8. Respiratory symptoms see alsoCoughy,Sputum product'~ioneffecY of asbestos exposure ini smokers vs. nonsmokers, 41 prevalence in, Duisburg, Germany by age and cigarette consumption, 399 prevalence in ex-smokers, 399 prevalence in pipe and cigar smokers, 217,220,221 prevalence in smokers vs. nonsmokers, 55 prevalence in smokers: vs. nonsmokers in Bordeaux, France, 36 in smokers vs: nonsmokers by amountt smoked, 37' Reverse smoking leukoplakia and; 76 oral,cancars and,,76 RNA binding ofl polycyclic hydrocarbons to, 86,87 Running effect of smoking; 243, 244 Sex ratio effect of maternal smoking, 135,136 Single-breath tests smokers vs. nonsmokers, 51 259'

a Smoke, cigar chemical constituents in, 177=1179 ciliotoxicity,, 218 effect of curing methods,,218',219 effect of pft on inhalation of, 183 tumorigenic activity in laboratory animals,, 210-214 Smoke„cigarette chemical constituents in, comparedl to pipejcigar, smoke, 177,178 effect of curing methods,, 218,219 effect on bacteriall retention in, hamsters, 541 effect' on bronchial' epithelium inidogs, 49 effzct on phagocytosis in laboratory ani- mais, 53,54 effectonpulmonary clearance, 51-53 effect, on rat and mouse fetus, site of action, 121 effect, on ventricular fibrillation threshold in dbgs, 13;14 experimental studies, in dogs, 13,141 reduction of adverse effects in animals by phenylmethyloxadiazole (P:1fO), 49,53 and sulphur dioxide, effect on glands in, laboratory animals, 49' Smoke„little cigar pH of; compared to cigarette and cigar smoke, 224,228 Smoke; pipe chemical constitlrents in„177,178' ciliotoxicity of, 218 effect ofI pH on inhalation of', 183' tumorigenic activity, in laboratory animals, 210-214 Sinoke, tobacco. eflfect,onair pollutioniin aircraft, 45 effect on nonsmokers, in aircraft, 45 effect on stillbirth rate in1aboratory ani- mals, 125 effects during pregnancy in laboratory animals, 1114,115 pH', of„ef fect of leafl constituents„224 tumorigenic activity, 210-214 Smoking effect on blood lipids,,11,112 effect on cardiac lactate metabolismy 13effect on leg,blood mean-flow capacity, 22'1 effect on plasma nicotine levels,,15-17' effect on precapillary sphineters„22 health hazards:of, s,imilarities, of cigarettes with little cigars„224,225 interaction withiother risk factors in CHD,. 4-111 as most important cause of COPD, 35,36' prevalence in U.S., andl Great Britain, 173,174 Smoking abstinence effect on exercise performance, 241,242;246,247 260 Smoking, maternal, as cause of birth of'small-for-dates infants, 1106-111 congenital malformations and, 136,137' effect on birth~ weight, 103'-114,119-L22 effect on birth weight, summary of find- ings, 122 effect on gestation durationt,103'-106 effect on lactation, 1!38-1411 effect on neonatal carboxyhemoglobin levels,,118,119 effect on sex ratio„13'5,136. effects: during pregnancy, 1'03-142'1 effects during pregnancy, mechanism of action~ 1:19,120 indirect association with~ small-for-dates int'ants, 110-114 preeclampsialand, 142 selective action on, fetus of certain, womenn vs. others, 131 spontaneous abortions :and,,123;124 stillbirths and„ 124,1125 timing of influence on birth weight, 120,121 Smoking,,paternal effect an infant, birth weight,,111A',1 T li Sputum prodtrction effect of asbestos exposure in smokers vs, nonsmokers, 41 effect of filtered cigarettes,,55 effect of modified cigarettes„37,38effect of plain vs. fiiteredlcigarettes, 37,38 in males by amount smoked and'type : of~ cigarette;, 37;38 prevalence in pipe and cigar, smokers,, 220,22~1' Stillbirths effect of maternal smoking, 124,125 rates in blacks vs, whites„ 124,1125 in,smokers vs. nonsmokers, 124',1125. Sudden death incidence in pipe and cigar smokers„ 215 Sulphur dioxide and! cigarette smoke, effect on glands in laboratory animals„49Swimming effect of' smoking„242,24'4 Tar contenti effect, on respiratory symptoms and venti- latory capacity, 38 Tars in little cigars, compared! to cigarettes and ci2ars, 223-226,228'. Thrombosis smoking andi, 19 Tobacco flue-cured vs: air-cured, effect on respira- tory system in animals, 217,2118 OW

Tobacco chewing leukoplakia and„75 Tobacco leaf'extQacts effect on cell cultures, 85,86 Tiacheal cancer smoking and, 71 Tteadmill performance: cardiovascular parameters in smokers vs. nonsmokers, 242-24!5' effect of vitammC; 24'5'5 oxygem intake in smokers vs. nonsmokers, 245 Triglyceride levels CHDiand, 8' Tumarigenic :activitq of cigpr„pipe, and cigarette smoke conden- sate in skin painting experiments in animals, 210-214 of tobacco;smoke, 210-2141 Ulber, duodenal mortality ratios in male cigar and pipe smokers, 222 nicotine'induced', in cats,,158,159 post-operative complications in smokers vs: nonsmokers, 157 potentiating action of nicotine, in animals,. 161I-163 prevalence in smokers, mechanism of~ acY- ion, 160! Ulcer, peptic clinical studies, 155-157 epidemiological studies, 155-157 gastric secretion, in smokers vs. nonsmok- ers, 157,; 58 increased mortality in' Japanese smokers vs. nonsrnokers,,155',15fi. mortality ratios in Japanese adults by age at initiation of smoking habit,, 155,156 mortality ratios in male cigar and pipe smokers, 222 predisposing factors, 157' recurrence in smokers vs& nonsmokers, 157 andl smoking, summary of previous find ings, 155' Urinary bladder cancer see Bladder cancer; Vascular disease, peripheral smoking and„19-23 Vascular reconstructionn effect of smoking, 22,23 Ventilatory function effect of exercise and'smoking„244';245 Ventricular fibrillation effect of cigarette s,moke in dogs, 13,14 Ventricular hypertrophy as a risk factor in CHD,, 8 Vitamin B, Z, in pregnant smokers vs. nonsmokers, 119 Vitamin C effect on treadmill performance in smo- kers vs. nonsmokers,, 245 in milk of smoking mothers;,141 in, pregnant smokers vs. nonsmokers; 119 Water hardness: and smoking as risk factors in CHD; 9;10 9U.5. GOVERNMENT PRINTING GFFICE::197:3' 727-647:/2181-d261.

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