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RJ Reynolds

the Health Consequences of Smoking. Cancer. A Report of the Surgeon General.

Date: 1982
Length: 164 pages
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the Health Consequences of Smoking, 820000. Federal Cigarette Smoking. Public Health Cigarette Smoking Act, 690000. Cautions Against the Immoderate Use of Snuff, by Hill J. Acs Nine-State Study. Advisory Committees Report, 640000. International Classifica
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27 Feb 1998
Named Person
Brandt, E.N. Jr
Burney, L.E.
Public Health Service
Surgeon General
Terry, L.
Stewart, W.
Steinfeld, J.
Richmond, J.
Koop, C.E.
Luoto, J.
Shopland, D.R.
Hill, J.
Soemmerring
Lombard
Doering
Muller
Schrek
Schairer
Porter
Mills
Levin
Wynder
Graham
Doll
Hill
Hammond
Horn
Surgeon Generals Advisory Comm
Schoeniger
Aristotle
Hume, D.
Mill, J.S.
Macmahon
Pugh
Susser
Evans
Lilienfeld
Rogot
Congressional Off, O.F. Technology Ass
Mayo Clinic
Who
British Medical Assn
Veterans Administration Lung Cancer
Working Party For Therapy, O.F. Lung, C.
Canadian Dept, O.F. Natl Health & Welf
List, O.F. Researchers
American Health Foundation
Stellman
Kunze
Vutuc
Remington
Garfinkel
Hoffmann
Gori
Stullman
Lyon
Peto
Natl Center For Health Statistics
Auerbach
Kahn
Mccoy
Williams
Horm
Goldsmith
Wilm
Murray
Bernard
Weiss
Moolgavkar
Stevens
Olearchyk
Thomas
Man Tzel Haenszel
Intl, A.G. For Research, O.N. Cancer
Epa
Fda
Health & Welfare, O.F. Canada
Sprague Dawley
Health Council, O.F. Netherlands
Burley
Dontenwill
Bock
Clausen
Adams
Hecht
Bernf Eld
Schmeltz
Patrianakos
Archer
Us Natl Academy, O.F. Sciences
Ivankovic
Harris
Brunnemann
Radford
Hunt
Guthrie
Ko Zlowski
Royal College, O.F. Physicians, O.F. Lond
Dumouchel
Trichopoulos
Hirayama
British Medical Journal
Franks
Wilson
Glasgow
Danaher
Lichtenstein
Pomerleau
Raw
Ro, S.E.
Hamilton
Eysenck
Russell
Gallup Poll
Dubren
Rozensky
Bellack
Friedman
Matarazzo
Lane
F Isher
Natl Interagency Council, O.N. Smoking
Lando
Hackett
Horan
Schmahl
Relinger
Best
Rotter
Mar Latt
Gordon
Shiffman
Eisinger
Janis
Mermelstein
Lichstein
St Algaitis
Brownel
Powell
Mccann
Flaxman
Bandura
Colletti
Kope, L.
Cooney
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Holbrook, J.H.
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Gritz, E.R.
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Bennington
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Introduction , , Developmerit and Orl;auricution of the 1982 Report Tho content of this Report is the work or numerous scientists witlrin the Department of Ileulth and IJumun Services, as well us ~ scientific experts outside the orbanization. Individual manuscripts were reviewed by experts, both outside and within the Public HcalLh Service, and the entire Report was reviewed by a broad-bused panel of 12 distinguished scientists. Many of these scientists are, or have been, directly involved in research on Lite health effects of smoking. The 1982 Report consists of a Prefuce by Lite Surgeon General, a Foreword by the Assistant Secretary for llealth of Lite Depurtment of I lealth and Human Services, and rve Parts, as follows: • I'urt I. Introduction and Conclusions • ~ 1'urt II. Biomedical Evidence for 1)elermininl • Cuusality , • 1'art 111. Mechanisms of Curcinol;enesis • Nurt IV. Involuntary Smoking and Lung Cuncer • Part V. Cessation of Smoking Historical Perspective Tobacco use was associated with the possible developmerrt of cancer as early us 1761. According to one medical historian, I)r. John Hill (1716?-1775) should be credited with the first report document- ing an association between tobacco use and cancer for his work Cau[iorrs Against the Immoderate Use of SnufJ: I lill reported ou two case histories and observed that "snuff is uhle to produce...swcllint;x and excrescences" in Lite nose, and he believed these to be cunceruus. Others credit Soemrnerriut; in 1795 for noLinl; u relationship between cancer of the lip unil tobacco use. It was noL until the 1920s uand 1930s that investigators het;nn to examine scientifically Lite possible association uf smokint; und cancer. In 1928, J.ornhard and 1)oerinl;, in the United States, found an association between heavy smoking and cancer in general. Muller and Schuirer (Germany) in 19:3J and 1944 respc,•c:tively, and 1'orter (USA) in 1945, and others, noted higher percentages of smokers nmon6 lung cancer patients than amonl; controls. '1'ho first major developments in the modern history or investigation or the effects or smoking on health occurred in 1950 with the publiculion of four retrospective studies on smoking habits of lung cancer put.ientrs and controls in the United States by Schrek et ul., Mills and l'orler, l.evin et al., and Wynder and Cruharn. much of these noted u consistent, statistically significant association between smoking and cancer ur the lung. Other investigators proceeded to further exurnine tlre reluLionship by initiating prospective studies in which large numbers of healthy persons were followed over time and their subsequent mortality noted. 08ZS '9Z£05' `~ 't
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r. o # r I lll' I/1:•4 luatrl rt-l ll' /rt r;c ;I Il I'IN /IIII /:ISJIII (U(:11 suul r: ss; l I l : l y I jS specific morlulity was initinted in Octoler 1951 by Uoll and Ilil in the United Kingdom nmont; 40,0(X) llril.ish physicians. Ilnmmond and Ilorn followed 18H,0(X) mnles beginning in January 1952 in tlre United Stsrtes. 'I'Irese and subselluent prospective studies conducted in Elie United St•at.eF, Sweden, Cunnda, and Japan, found not only that smokers htrvo substantially elevated cancer rnortulity rates, but also that smokers experience significantly elevated overall death ru tes. Cancer has been the second ranking cause of death in the United States since 1937. 1'rovisionul vital stntistics data for 1980 indicate cancer accounted for almost 21 percent of all deaths in the United Stsrt.es. '1'his compares to 17 percent of all deaths in 1970 and 14.5 percenL of all deaths in 1950. Various investigators have suggested 011.11, 22 to 38 percent of these deaths can be attributed to smoking,, and therefore, are potentially "avoidable" if smoking did not exist as a huninn bchuvior. Since 1950, the aRe-ulljusted overall cancer death rate hus changed little, whereas the lung cancer death rate has increased dranurticully for both males and females. '!'he mule age-adjusted lung cancer rate increased 192 percent during the pet•iod 1950-1952 thru 197G-1978. Female lung cancer death rates during this same period increased even more: 263 percent. Since Elie 1950s, llung cancer has been the leading cause of cancer dcuth umong males in the United States, and if present trends continue, will become Elie leading cause of cancer death in fernnles during this decade; the age-ndjusLed female lung cancer death rnte is projected to possibly surpass the death rate for breast cancer next year. Toduy, deaths from cancer of the lung represent fully one quarter of ull deaths due to cancer in the United States. In 1962, the year when Elie Surgeon General's Advisory Committee on Smoking and Iletilth began deliberuLint; the evidence presented in its landmark reIrort, slightly more than 41,(X)n persons died of lung cancer annually, compared to 18,300 Iung cancer deaths in 1950. In 1982, the American Cancer Society estimates 111,0(X) Americuns will die of lung cancer, nearly a three-fold increase in the number of dent.hs in a 20-year time span. The Advisory CommiLtee's Report of 1964 judged the causal significance of the association of cigarette smoking and disease by rigid cril.eria, no one of which alone was sufficient for a causal judgment. The epidemiologic criteria included: a.'1'he consistency of the association b. The strength of the association c.'I'he specificity of the nssociation d. The temporal relationship of the association, and e. The coherence of Elie association 1•.i11vIl.irilllUn % .:C.:IC.U;..rl/l,rll% t1ulll lrl.lll'1 :..rlll~~•:.,:.Ill ll:l:.l /lnn:ll nutupsy und exper•imcsstnl rviclence. Si);nificant additional scicrntific evidence linkin/, ssnolcisl/: to cancer, as well as to other Lohncco-relatecl disenses, htrs nccumui:ll.c11 since the issuance of that Advisory Committce's Itetwrlt in WlA. Much of this hns heen collccted, reviewed, and pul/lislred in anntral rellorts by the Department of I lealth nnd llurnnn Services. The purpose of tlris' Itetxort is to review in depth the mnny sources of scientific evidence relating cigarette smoking to each cnncer by anatomic site, and to evnlunt.e this evidence by the r;nme cri(.erin first established by the Advisory (;unirnittee in its 1964 IReport, includin); experimental carcinogenesis and human epiderniolot;ic studies. Conclusions of the 1982 Report Overall Cancer Mortality 1. Cigarette smokers lurve overall mortality rntes sul>titnntinlly greater than those of nonsmokers. Overall cjrncer dcat h rlllcs of male smokers are approximately double those uf nemsmok- ers; overall cancer death rates of fem:ale smokers are approxi- mately 30 percent higher than nonsmokers, and are incrensing. 2. Overall cancer mortality rates nmonX smokers nr•e d/>se-relnte/l as measured by the number of cit;nrettes srnoked twr day. Iteavy smokers (over one pack per day) have more than three times the overall cancer death rate of nonsmokers. 3. Overall cancer death rates decline with the number of yenrs c/ff cit;arettes, approaching the death rate of nlmsmokers with increasing duration of cessat.ion. Site-Specific Cancer Mortality LtrrtK Cancer 1. Cignret.te smoking is the mujor cause of lung cancer in the United States. 2. Lung cancer mortality increases with incrensint; dosnge or srnoke exposure (ns measured by the number of cignrett.crs smoked daily, the duration of smokint;, and inhalation pat- terns) and is inversely related to age st.rrrted to smoke. Smuker:s who consume t.wo or more packs of cigarettes daily have lung cancer mortality rates 15 to 25 times greater than nonsrnc,kers. 3. Cigar and pipe smoking ure also causal factors for lung cancer. IJowever, the majority of lunt; cancer tnortarlity in the llnited States is due to cigarette smoking. 4. Cessation of srrnokint; reduces the risk of lung cancer mortnlily compared to that of the continuing smoker. Farmer smokers who have quit 15 or more years huve lung cancer murtalit.y 4 L6ZS 9ZE05 ~r
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rates only slibhtly above those for nonsmokers (uhout two thues greuter). The residual risk of developing lung cancer is directly pru3x,rtionul to overall life -time exposure to cigarette smoke. 5. Filtured lower tar cigarette smokers have a lower lung cancer risk compared to nonfilterod, higher tar cigarette smokers. llowever, the risk for these smokers is still substantially elevated uWve tlie risk of nonsmokers. 6. Since the early 1950s. lung cancer has been tlie leading cause of cancer death among males in the United States. Among females, tlke lung cancer death rate is accelerating and will likely surpass that of breast cancer in the 1980s. 7.'1'hu economic impact of lung cancer to the nation is consider- ablu. It is estimated that in 1975, lung cancer cost $3.8 billion in lost earnings, $379.5 million in short-term hospital costs, and $78 million in physician fees. 8. Lung cancer is largely a preventable disease. It is estimated that 85 Ix:rcent of lung cancer mortality could have been avoided if individuals never took up smoking. Furthermore, bubstuntiul reductions in the number of deaths from lung cancer could be achieved if a mujor portion of the smoking population (particularly young persons) could be persuaded not to smuke. Lmyng-cul (,itnccr 9. t,'iburette smoking is the major cuuse of laryngeal cancer in the llnitud St.utes. Cigar and pipe smokers experience a risk for lurynbeul cancer similar to thut uf u cigarette smoker. 111.'1'hu risk of duvelopin6 laryngeul cancer increuses with in- crvusud extu,sure as measured by the number of cigarettes nuiukcd daily as well as other dose meusuremenl.s. lleavy eiuukcrs huw laryngeal cancer murt.ulity risks 20 to 30 tintus bn:uter thun nonsnwkcrs. 11. Cessation uf' smoking reduces the risk of laryn6eul cancer murtulity compared to thut of the continuing smoker. The lunbur a lormer smoker is off cigarettes the lower Clio risk. 12. Siuokw•e who use filtcred lower tar cigarettes have lower l,irynt;uul cancer risks than those who use unfiltered higher tur tat;u ru l t es. I:3.'!'hu usu uf ulcohol in combination with cigaretl.e smoking upt,cars to ui:t synergistically to greatly increase Clio risk fiir c;uicur of Clio larynx. (1rul ('urirur !'it;nrul tosniokinb is a major cause uf cancers of Clio oral cuvity in lh.: I/nilcd 5tulus. Individual5 who smoke pipes or cigars 50326 5282 experience a risk for oral cancer similar to thut of the cigarette , in the development of cancers of the oral cavity, particularly cancers of the cheek and gum. increase the risk of oral cavity cuncers.i 17.l.ong term use of snuff appears to be a factor smoker. 15. Mortality ratios for oral cancer increase with tlie number of • cigarettes smoked daily and diminish with cessation of smok- ing. 16. Cigarette smoking and alcohol use act synergistically to Esophageal Cancer 18. Cigarette smoking is a major cause of esophageal cancer in the United States. Cigar and pipe smokers experience a risk of esophageal cancer similar to that of cigarette smokers. 19. The risk of esophdbeal cancer increases with increased smoke exposure, as measured by the number of cigarettes smoked daily, and is diminished by discontinuing the hubit. 20. The use of alcohol in combination with Ismolcin6 ucts synergisti- cally to greatly increase the risk for esophubeul cancer mortality. H 21. Cigarette smoking is a contributory factor in Clio development of bladder cancer in the United States.'1'his relationship is not as strong us that noted for the ussociiution hetween smoking •auJ cancers of the lung, larynx, oral cavity, und esot,hut;us.'1'he term "contributory factor" by no means excludles the tH,ssihili- ty of a causal role for smoking in cancers ut't•hih site. Kidney Cuncer 22. Cigarette smoking is a contributory fikctor in the development ot' kidney cnncer in the United Stut.c:s. Bladder Cancer Puncrealrc G'aitccr 23. Cigarette smoking is a contributory factor in the development of pancreatic cancer in Clio United States. Slomnch Canccr 24. Epidemiological studies have noted un association between cigarette smoking and stomach cuncer.i The ussuciutiun is small 6 7
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iu conil,;irisun willi 111111. l notcd lur sinokin{; :uul somo otlicr cullccrn. Uleruic ('eruix Curu-cr 25.'1'here are conflicting results in studies published to dute on the existence of a relationship between smoking and cervical cancer; further research is necesstu•y to define whether an association exists iund, if so, whether thut ussociution is direct or indirecl. Mechanisms of Curcinot;enesis '1'hib overview presents evidence find ubservntions on tobacco cnrcinuqenesis primurily developed since 1978. 1.'1'he biological activity of whole cil;iu•et.te smoke and its tar and t.ur fractions cun rlow be measured hy improved inhalation assays in addition to tests for t.umrn•-initiating, tumor-prornot- int;, und coc:ru•cinot;enic activities on mouse skin. 2. Studies un smoke inhulution with lhe hamster now aptocur suiliil,lc I'ur estimating the relative tumorigenic potential of whole smoke from commercial und experimental cigarettes. The identification of the smoke constituents that contribute to tumur induction in the respiratory tract is best achieved by frui;t.ionut.ions of tatr and by assays on mouse epidermis that determine th(. type und potency of the carcinogens. In combinu- Liun with biochemicul tests, mouse skin assays should also aid in evaluating the Ixossible role uf nicotine as a cocurcinot;en. 3.'1'he identificution, formation, find metabolic activation of ortiuirstxacific carcinogens have been sLudied which help ex- t,luin the increased risk to cigarette smokers of cancer of lho esul>hut;us, pancreas, kidney, and urinary bladder. Ln addition to certain aromatic nmines, tobucco-specific N-nitrosnmines ut)txsar to lxs iui iutportunt group of organ specific carcinogens in tobacco und tobacco smoke. Little is known of the in vivo formation of orgun-slK!cific cnrcinoy;ens from nicotine and other Niculiaunfr alkaloids. '1'he modification of their enzyntutic 1lctivuLiun to ultimate carcinogenic fonns needs to be explored by chemopreventive approaches. 9.'1'runsplucentul carcinogenesis ns it may relate to effects of cigarette smoking should be investigated more fully. It has been knowii for some time that inhulutiun of tobacco smoke uctivut.es en7ymes in the placenta and fetus and the conse- yuc:nces of such changes need to be studied. 6.'i'lic continuing modification ut' U.S. cigarettes has led to changes in the quantitative und perhaps also the qualitative coml,usit.ion of Lhe smoke. This ongoing development requires 50326 5283 cunl.inui d n~unitui in}; ul 111c tuxic and carcinutyvnic loul4-nti,il ul the smoke uf new cil;:u•et.tes. fi.'I'he changes in cigarette composition icud generally to re<lnced emission of mnjur toxic urtinstreanr smoke c.onsl.itttents us measured in analytical laboratories under machine-smnkinq conditions. Many smokers intensify puf/' volume and degree of inhalation when smoking a lower-yield cil;au•ette.'('herefore, it should be determined what effect different techniques of air dilution and filtrution have in counteracting the, incrr;tsed smoke exposure Lhat results from intensified smoking. Involuntary Smoking and Lung Cancer 1. Mainstream and sidestrenrn cigarette smoke contuiu similar chemical constituents. (Mainstream smoke is smoke which the smoker inhales directly during puffing. Sidestrezun smoke is smoke emitted fr•om it smoldering cigarette into the ambient air.) These constituents include known carcinogens, some of which are present in higher concentrations in sidrstrerun tltnn im mainstream smoke. Passive or involuntary smoking differs from voluntary cigarette smoking with respect to the concen- trntion of smoke components inhaled, the duration find fre- quency of smoke exposure, and the pattern of inhalation. 2.'1'wo epidemiologic studies have found ar+ increased risk of lunl; cancer in nonsmoking wives of smoking husbands. In these studies, the nonsmoking wife's risk of lunt,~ cancer increused in relation to the extent. of the husband's smoking. In at Lhird ' study, the risk of lung cancer atmonq nonsmoking wives ol' smoking husbands wtts also increased, but the (!ifference wns not statistically signific.int.. 3. Although the currently available evidence is not sufti- cient to conclude that pussive or involuntary smoking cnutit:s lung cancer in nonsmokers, the evidence does raise concern about a possible serious public health problem. Cessation of Smoking 1. Ninety-five percent of those who have quit smoking have done so without the aid of nn organized smoking cessation prut;rum, and most current smokers indicate a preference fur quitt.inl; with a procedure they may use on their own, and a disinclinu- tion to enter nn organized, comprehensive prot;r:un. 2. 12eseiirch evaluations of self-hellr aids have rerorted success rates up to 50 percent cctisution nt extended followups (6 to 15 months). Most estimates, however, fall below this, around 5 to 20 percent.
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J.llrief und simNle advice to qµrit. smoking delivered by u physician has substantial potentiul for producin6 cessation in a cc)st-effective manner. 4.'1'clevisod smoking cessation clinics result in variable rutes of ubstincnce at followup. The use of television and other muss media ure a cost-effective intervention because of their large potential uudiences. 5. I(eLrospcctivo studies revealed greater use of self-reward and active prublem-solving strategies among those who quit or reduced smoking on their own than umong those who were unsuccessful in quitting or reducing smoking. 6. Until recently, the long-term outcome of intensive smoking cessatian clinics has remained at 25 to 30 percent abstinence. New emphasis on techniques to improve the maintenance phase of cessation promises to improve these rates, with several reports of greater than 50 percent abstinence at folluwups of 6 months or longer. 7. Reinforcement needs to be built into the natural environment to improve maintenance of nonsmoking after intensive treut- menL prob%rums have ended. Smoking cessation programs in the workplace may offer an opportunity for this. . 8. G)rnprchensive self-manu6ement packages which have been shown to boost maintenance rates, include a wide variety of techniques. 9. Treut.ment outcome can be improved by focusing on the uutecedents of relapse. These include feelings of frustration, anxiety, anger, und depression as well us social models and anrukint;-rcluLed cues and settings. Behavioral and cognitive skills for dealing with such antecedents should be develol)ed. I(1. S)ciul support interventions are promising. Iteliuble findiu(,s link social cues, smoking frienils, and smoking stx)ust,~ to relnpse, whereas the presence of group support, nonsmoking spouses, and professional contact decreases recidivism. 11. Slwntuneuus smoking cessation run)ong regulur users (upproxi- mutely once a week or more often) is estinwted to bu on t.he order of 25 percent during adolescence. 12. I'robuhility af quitting was greater for tlrose adolesc:enl Hmok- ers firsL interviewed in 1974 wwho had at least started to attend college by 1979 tthan for those smokers who did not attend college (4'L.(1 I)ercent vs. 24.(i percent). 13. 1'rot)trbilit.y ot' quitting decreuses lineurly with durutiou of the simrkint; pructice, changing from'G4.5 tx.-rcent in' Ihc first year rrf srnuking to 14.3 percent after 7 yeurs. 14. (2uitLing "culd turkey" np)wurs to be u)nore effective cessation btrJtegy thnn cutting down without trying to stoj) entirely. 0 15. Success at quitting increased with the number of effort.s made: about 48.5 percent of adolescents who kept trying eventually succeeded, with about hulf of the successes occurring after the second try. 1G. Smoking prevention progrnms are desirable alternutiveH to cessation programs aimed at youth. Successful programs have been based on social psychological theory and research, and are school based. Results • have shown a 50 percent or more reduction in smoking onset. 17. The most successful programs were those ernphasizing the social and immediate consequences of smoking rather thun long-term health consequences. These programs have placed special emphasis on teaching skills in recognizing and resisting social pressures to smoke. 1 II I(1 ' hBZS 9Z£0S
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50326 5285 i PART 11. BIOMEDICAL EVIDENCE FOR DETERMINING CAUSALITY
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It+dTRODUCTION . Provisional mortality data for 1980 indicate that cancer was responsible for approximately 412,000 deaths in the United States (199). 1t is estimated that in 1982 there will be 430,000 danths duo to cancer, 233,000 among men and 197,000 among women (2). Various investigators (70, 78, 106) have suggested that 22 to 38 percent of these deaths can be attributed to smoking, and therefore are potentially "avoidable" if smoking did not exist as a human behavior. ' A relationship between smoking and cancer was first suggested for ncoplusms of the lung in scientific reports from the 1920s and eurly 1930s (203, 266). Muller (191) in 1935 and Schairer and Schoeni6er (237) in 1943 reported that most lung cancer patients were smokers. Subsequently, 8 major prospective studies and more than 50 retrospective studies have examined this relationship. In 1964, the Advisory Committee to the Surgeon General of the U.S. I'ublic Health Service (272) published n comprehensive review of the then available data. They concluded that "cigarette smoking is ciwsnlly related to lung cancer in men; the magnitude of the effect of cigarette smoking far outweighs all other factors. Data for women, though less extensive, point in the same direction. The risk of developing lung cancer increases with the duration of smoking and the number of cigarettes smoked per day and is diminished by discontinuing smoking." Over the last 17 years, thousands of scientific investigations have confirmed the Committee's conclusion und prnvided u<1<litiunnl evidence concerning the relationship of ciqarel.te smoking to lunt; cancers. Smoking has been implicated us a causc uf cuncer uf the larynx, oral cavity, and esophagus, and associated with cancer of the urinary bladder, kidney, and pancreas. 't'his is the first reliort devoted exclusively to a comprehensive assessment of the as.,aciu- tions reported between smoking and various cancers. !n the follow- ing sectious of this Part of the Report, the nature of these associations is appraised in Lhe light of currently available knowl- edt;e. 99ZS 9ZEOS ' . 15
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• Lt'tl)L1~11c)LUC~II; t;ii.lTi,,R1[l, Vutc t:AUSAL1TY ' The cunceht of causality hus been deirnted by students of philoso- phy plty since t1w days af Aristotle. David I lurne (1711-1776) and lohn j Stuart Mill (18U(i•-1t373) arc credited with mujor contribut.ions to ~ contemporary insight and theory of causality. More recently, rnenr j hers of Llie Advisory Committee to the Surgeon General (272), Ilill (11'l), MucMulron and Pugh (168), Susser (2G(!), Evans (Hf1), and l.ilienfcld (158) have examined Lhe concet>t of cntrsality in the health sciences. '1'lre ability to totally control the experimental environ- i mcnL, to randomir.e exposure, and t.o measure discrete outcomes allows n clear experimental demonstration of causality. ilowever, . the application o/' these rigid laboratory techniques for establishing causality to tite study of cancer in humans is clearly impossible. '1'lie idea of exposing human subjects to potentially cancer-producing uqents in order to establish causulity is morally and ethically unuccel>tuble. '1'herefore, other criteria have been developed to establish cnusulity with a very high degree of scientific probability (80. 112. 158. 260. 272, 280). In pructice, elriderniolot;ic methods have been employed to study cancer in rnun. These studies result in observational data that may establish n stutistic,rl ly significant association between variables or • attributes. '1'his association may be urtifuctual, indirect, or direct. '1'he possibility of an urtifnctual (or spurious) result can be eliminat- ed if the design and conduct of the studies are adequate, and if ' studies cunducteci in different geographical areas and among differ- ent population groups produce the same or similar strttisticnl associations. Once an artifactual association has been ruled out, it is , then nece:ssury to determine whether the association is an indirect or direct (causal) one. ltundnmi•r.uLion is an attempt to eliminate the effect of all variables other than the one under study. ]Iuwever, n personal 1 choice behavior such as smoking is impossible to randomize (i.e., to i, dictate smoking behavior). Therefore, in order to establish that an ~ i ti ; b t ki di i t d f d t d us ccx ,„ tr on ween smo n6 nn sease s no oun e a ue o a con - int; variable, an entire body of data must exist to satisfy specific criteria, none of which by itself is an all-sufficient basis for judgment. Thus, when a scientific judgment is made that all plausible confounding variables have been considered, an association may be considered to be direct. In this Relxort, the same definition of the term "cause" that was used in I.he Iteport of the Advisory Committee to the Surgeon ' General in 1964 has been adopted. "'The word cause is the one in ~ - general usage in connection with matters considered in this study, and it is capable u: conveying the notion of a significant, effectual ~ relationship between an agent and an associated disorder or disease ~,in the hust" (272).''1'he term "cause" should not be construed to 1 16 G8Z5 9ZEOS exclude uther nt;entti us crruties; rntlner, it is usccl in full t•ecfq;riil.irrn N thut biulot;icu) processes ure conrlrlcx nnd mult.iplc in etiolrrgir :q. In this Report, as in the carlier one, the nl.trihutinn 0f "cnusr, lity" to a discase-rrssociuted vnrialrlc (e.g.. smrrkin);) inclwlt•s full rccrq;ni• tiun thut "l.he causal significance of un nssociuLiun is a nurt.tr.r of jtuhment which goes beyond nny statement of statistical prulrrrlrilit.y. 'I'u judge or evaluate the causal significance of t)re nssociirt.iun between nn attribute or nt;ent and i the disease, or the cffect. ui,un henlth, a number of crif.crin musL be utilized, no one of which is rtn nli-sufficient basis for judt;ment.'1'hese criteria include: n. The consistency of tlie association b.'1'he strength of the itssocint.ion" c.'l'he specificity of the association d.'1'he temporal relationship of the association, and e. The coherence of the as.~crciut.ion" These criteria are utilized herein for evulunticm of the rcportcd associations between cigarette smoking and cancers of various sites in humans. Consiytency of the Association This criterion implies that diver§e methods of uppronclr in the study of an association will provide similar conclusiuns. (;onsintt,ncy requires thnt the association be repeatedly observed by mull iple investigators, in different locations and situations, utt diffcrent Linues, using different methods of study. Such replication nssures that the association is not likely to Ie, an artifact due to bins in study methodology or subject selection, and that it is not indirect (file to confoundinK variables such as diet, occupation, or genet.ics. Strength of the Association The most direct measure of the strength of the association is the ratio of cancer rates for smokers to the rates for nonsmokers. Tlre relative risk ratio yields evidence on thetiiTR of the effecLof a factor on disease occurrence and which, even in the presence of another nssuciated factor without causal effect but coincident with the causal agent, will not be obscured by the presence of the non-caugal ngent. A relative risk ratio measurca the strength of nn association ruid provides an evaluation of the ini¢ortance of that factor in the production of a discase. If all cases of the disease under study, but none of the controls, have a history of exposure to the suspected etiologic nt;ent or characteristic (assuming thnt an adequate number of cases nnd controls exist in the population under study), a one-to-one correrpon- dence between the disense and the factor exists, and a cnusnl hypothesis would be credible. Most diseases are influenced by mnny 17
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fuctoru, Itowever, and thereforo u one-to-one correspondence would not l,u exlwcted. '1'lte strength of un association is measured by relative risk ratios, incidence ratios, or mortality ratios.'l'he greater the relutive risk ratio or the mortality ratio, the stronger the relutiunblrip between the etiologic agent and the disease. Prospective studies have shown that the death rute from cancer of the lung among ci6urette smokers is approximately 10 times the rate in nunsmokers, and the rate in heavy ciburette smokers is 20 to 30 times 6reuter than in nonsmokers. 7b account for such high relative risk in terms of an indirect association would require that an unknown causal factor be present at least 10 times more frequently in the smokers and 20 to 30 timcs more frequently among heavy smokers than among nonsmokers. Such a confounding factor should be easily detectable, and if it cannot be detected or reasonably inferred, Llie finding of such a strong association makes a conclusion , concerning causality more probable. Important to the strength, as well us to Lite coherence of the association, is the presence of a dose- rer;punse phenomenon in which a positive gradient between degree of exposure to the agent aud incidence or mortality rates of the disease cun be demonstruted. Specificity of the Association This concept cannot be entirely dissociated from Lite concept inherentt in the strength of the association. It implies the precision with which one component of an associated pair can be utilized to Irredict thu occurrence of the other, i.e., how frequently the presence of unu vuriuble will predict, in the same individual, the presence of unutlrer. Stwcificity implies that a causal agent invariably leads to a single r,iwcific di,euse, an event rarely observed. A one-to-one relationship between Llro presence of an etiologic agent and disease would reflect a causal relationship. Ilowever, several points must be kept in mind in inlurpretin6 s;lx;cificity in biological systems. First, an agent may tx: uc;smiuted with multiple diseuses. Second, many responses , coueiderul to he diseube states have multiple causes. CAmt,•enital uurltirrmalions, for exumple, result from prenatal radiation ns well ius frurn some drugs administered during pregnancy lutd other factors. Variations in the relative risk of disease muy lx: pr(xiuced by vuriul iuna in Lite number of cuusul agents its well as by the specificity ut' ugiven causal agent. '1'hird, u bingle pure substance in Lhc enviruntfiunt rnuy produce n numbwr of different diseases. '1'he ext,crimentul production ofa vurieLy ufdiseuses in mice by exl„tsure (A) X-ri,ya is a goo<l example uf this. iourt.lt, a sitr6le factor may be the velricle lin• several different substances. '1'ubucco smoke is it complex ruixtur•u ot'severul thousand individuul cunstituents, und therefore it wuuld nut lie surtrriaint; to find Lhnt these diverse subsluncc.-i are able IH SSZS 9ZEOS to produce more thun ono adverse biologic roshnnso. It irs also not surprising that these constituents may have possible additive, synergistic, or competitive actions with each other and with other agents in the environment. And fifth, there is no reason to assume tltut the relationships between one factor and different diseases have similar explanations. The association between. smoking and lung cancer, for example, is considered direct and causal, whereas that between cigarette smoking and cirrhosis of Lite liver is thought to be indirect, reflecting the association of cigarette smoking and heavy alcohol use by some segments of tite population. In summary, despite the fact that the demonstration of specificity in an association makes a causal hypothesis more acceptable, lack of specificity does not negate such an hypothesis, since many biologic and epidemiologic aspects of the association must be considered. Temporal Relationship of the Association In chronic diseases, insidious onset and the lack of knowledge of precise induction periods automatically present problems on which came first-the suspected agent or the disease. In any evuluution of the significance of an association, exposure to an agent hresumed to be causal must precede, temporally, the onset of a disease which it is purported to produce. The criterion of temporal relationship requires t.hut exposure to the suspect etiologic factor precede the disense. Temporality is more difficult to establish for diseases with long latency periods, such as cancer. Prospective studies minimize this difficulty, although even prospective studies do not exclude the possibility that. t.he diseuse wus, present in an undetected forni prior to uxlx>sure to the agent. lliatologic evidence demonstratinR prernulil;nant chunt;e:; nntont; individuals exposed to the ubent, but not among unexlx)sed controls, provides evidence that temporality is present. l:xperimenlatl studies may ulso demonstrate a temporal association. (:oherence of the Association '1'he final criterion for the appraisal of causal significance of an tt&Scx;inLion is its coherence with known facts in the nuturul history and biology of the disease. (Wherence requireti that descriptive epidemiulngic results on disease occurrence correlate with measures of 'extxistu•e to thc t,u5pected ngent. Yerhalx•t the most important consideration here is Lite observation of a dose-reslionse relationship between agent unrl disease, Lhut is, the progressively increasing cxxurrence of diseuse in increasingly heavily ex{x,sed I;roups. in some cttses, multiple meu- sures of dosage are available. '1'he natural history of tiisease would include observations on the progression of disease witlt continuing t!r ' .- . . . .--------- ---- -~ -- - - • --- - .f
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FEMALE so 70 .o 46 - IIUNlY1N 0 _ ~~ ~NIA37 - ~~-f COIOY ~-~- lC1W tIOYwCN V7[NUa / me uv[N ...~. oVANr - N! l ~ - w3o 1935 040 1945 roeo 193s 1960 ross roio 1973 Oaeo YEM MALE to 75 45 30 10 0 aw 6036 . 040 u.. nw ~ [UNG caoN NI CrVY tLl .1NJi1Nf[ Af.N t /VIM ~ 1 A,N;NI A1 ~~ _ .. Ilw[rr.~. I .u.. uae YEM 1940 n.e nro ® uw 1.-Mulu and Luuiule cancer deuth rutes* by site, ! United Stules, 1930-1978 d ' A/.'.~ .NI+IIFL\I IL I/N• I ~ y,NI~MIINIMNI NN W1YINtl1'NIl'1~ {M II/(11 ~ ti/NIN('F, ANNVN•NNI'NNr.•rluwlylLh ' . 69ZS 9ZEOS 0 mnle lung cancer rate, an cxuminution of the a6e-specific rates In Figures 3 and 4 reveals that the lung cancer rates are still markedly greater in males than in females. In tho white population, these trends resulted in a decrease in tho sex ratio of lung cancer mortality rates between males and females. In 1950, the age-adjusted lung cancer death rate was 4.7 times higher in white males than in white females. By 1977, the mortality sex ratio had dropped to 3.6. In the white populvtion 5 to 43- yeors of age, the mortality sex ratio decreosed from 3.74 to 1.72 over this period. In contrast, the mortality sex ratio (mn)e/femalo) of the other than white group increased from 4.11 to 4.54 from 1950 to 1977. Particularly in the early part of the study period, mortality among' males other than white climbed sharply. Iq 1950, the ratio of the uge- ~ adjusteddeathrAte of alI other males_to that_ of..while males was 0.77: by_1977,_, a6•e_adjusted death rates.-of all other. mules luadd surpnssed those of white mules. The mortality_color ratio (otlier- ~_ -- thun-whit.e/white) had risen to 1.25. Amon6 females, t.l~e mortulity color ratio shifted from 0.88 in 1950 to 1.00 in 1957, after which it remained stable. In females 5•to~44)years of age, however, rates were consistently higher in the other than white group than in the white group. When uge-specific lung cancer death rul.es ure plotted by calendar year and age, a three-dimensional graph is prcxluced (Figures 5 and 6) which can be exumined from 1J50-1977, or from the reverse (back " side) perspective. The broad, ascending peaks reflect the dramutic rise in lung cancer rates for men and women over LhiH lime iiitcrval. '1'he lower age-specific lung cancer death rates seert in lhe olclest ;il;e group (Figures 5 und 6) reflect changing cohort pul.terns (il'ex{x)sure. Thus, what appears to be a decline in mortality rates with old age is r actuully an qrlifuct_orisinb front the combining of cohorts with / different cigarette smoke extlosure und mnrtulit.y exl,aricmces. As / will be discussed later, the ul;c-spc:citic morlulity rate for eoch specific birth cohort actually continues to increase steudily with increasinl,• age in both men and women (Figures 13 ,uid 15). Lung cancer has a consideruble economic impact. ltice and 1lcHltson (218) estimate thut the health cost of lunl; cuncer in I~J75 was $3.8 billion in lost eurninES, $379.5 million in short-term hospital churges, and $78 million ih physician feK:s. Less than 10 percent of patienla with lung cancer will survivc 5 or more years. This bleak survival rut.c has not changed 5il;nitic:Intly over the lust 15 years. Ilence, the prevention uf lung cancer is uf paramount imllortance. According to a recent study for lhe ('onl;res- sionul nffice of Technoloby Assessment, approximately 85 I,ercent of United Slates lung cancer deaths in 1978 were ultrihutahle to smoking, and thus were "avoidable" if individuals had not smoked eit;:u'el les (70).

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