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Smoking and Health Report of the Advisory Committee to the Surgeon General of the Public Health Service - Part 2 of 3

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LEi7CHTENBERGER, RUDOLF, M.D.-Professor Eidgenossische Technische Hochschule, Institut fiir Aligemeine Botanik, Zurich, Switzerlan& LEVIN, MORTON L., M.D.-Professor of Epidemiology, Roswell Park Me- moriall Institute, Buffalo, N.Y. LIEBOw, AVERILL A., M.D.-Professor of Pathology, Yale.University School of Medicine, New Haven, Conn. LIGGETT & MYERS, INC., New York, N.Y. LILIENFELD,, ABRAHAM, M.D.-Professor of Chronic Diseases, The Johns Hopkins School of Hygiene and Public: Health, Baltimore, Md. Lisco, HERMAN, M.D.-Cancer Research Institute, New England Deaconess Hospital, Boston, Mass. LITTLE, CLARENCE Cootc, M.D.-Scientific Director, Tobacco Institute Re- searchi Committee, New York, N:Y. LouDON, R. G., M.B.-Assistant Professor of Internal Medicine, The Uni« versity of Texas Southwestern Medical'School, Dallas, Tex. MxNOS, NICxoLAS E.-Statistician, Division of Occupationall Health, U.S. Public Health Service, Washington, D.C. MARDER, MARTIN, Ph: D.-Research Psychologist„ Behavioral Sciences Sec- tion, Division of Community Health Services, U.S. Public Health Service, Washington, D.C.. MATARAZZO, J. D., Ph. D.-Professor of Medicall Psychology, Department of Medical Psychology, University of Oregon Medical School, Portland, Oreg. McFARLAND, JAIaIES J.,, M.D: Professor of Otolaryngology, School of Medi- cine, George Washington University Hospital, Washington, D.C. McGILU, HENRY C., M.D.-Professor of Pat'hology, Louisiana State Uni- versity School of Medicine, New Orleans, La. McHucH, RICHARD B., PhL D.-Associate Professor of BiostatistScs, School of Public Health, University of Minnesota, Minneapolis, Minn. McKENNIS, HERBERT, Jr.-Professor of Pharmacology, Medical College of Virginia, Richmond, Va. MEDALIA, NAHUM Z,, Ph. D.-Executive Secretary, Mental HealYh~ Small Grants Committee,,N'ational Institute of Mental Health, U.S. Public Health Service, Bethesda, Md. MEHLER, MRS. ANN-Resear& Assistant, National Cancer Institute, U.S. Public Health Service, Bethesda, Md. MILLER, JACK, M.D.-Research Fellow in Medicine, The University of Texas Southwestern Medical School, Dallas, Tex. MILLER, ROBERT W., M.D.-Chief, Epid'emiology Section,, National Cancer Institute, U.S. Public Health Service, Bethesda, Md. MILLER, WILLIAM F., M.D.-Associate Professor of Internal Medicine, The University of Texas Southwestern Medical School, Dallas, Tex. MITCHELL, ROGER S., M.D.-Associate Professor, University of Colorado School of Medicine, Denver, Colo: MURPHY, EDMOND A., M.D.-Attending Physician,, The Moore Clinic, The Johns Hopkins University Hospital, Baltimore, Md. NASH, HARVEY, Ph. D.-Illinois State Psychiatric Institute, Northwestern University Medical School, Chicago~ Ill.. xiv
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NELSON; NORTON, Ph~ D.-Professor an& Chairman, Department of Indus- trial b'Iedicine,, New York University Medical Center, New York, N:Y. ORCHIN, MILTON, Ph. D.-Professor of Chemistry, University of Cincinnatiy Cincinnati, Ohio. P. LORILLARD Co.,, New York, N.Y. PAFFENBARGER, RALPH S., Jr., M.D.-Medical Director, Field Epidemiology Research Section, National Heart Institute, U.S. Public Health Service, Framingham, Mass. PAUL, OGLESBY, M.D.-Chairman, Committee on Epid'emiological Studies,. Passavant Memorial Hospital, Chicago, 111. PFAELZER, ANNE I.-Concord, Mass. PHILLIP 1bIoRRIS, INC., New York, N'.Y. PICKREN, JOHN W., M.D.-Chiefy Department of Pathology, Roswell Park Memorial Institute, Buffalo, N.Y. PIERCE, JOHN A., M.D.-Associate Professor, Department of Medicine, Uni- versityof Arkansas Medical Center, Little Rock, Ark. POTTS, ALBERT M., M.D.-Professor of' Ophthalmology, University of! Chi- cago Sehool of Medicine, Chicago, Ill. PftINDLE; RICHARD A., M.D.-Chief, Division of Public Health Methods, US. Public Health Service, Washington, D.C. R. J. REYNOLDS TOBACCO Co., Winston-Salem; N.C. REED, SHELDON C., Ph. D.-Professor of Zoology, Departmentl of Zoology, University of Minnesota, Minneapolis, Minn. REMINGTONRAND, LaD:(Ottawa). Roos, CHARLES A.-Head, Reference Services Section,, National Library of! Medicine, U.S, Public Health Service, Bethesda, Md. ROSEN, S.aM[iEL, M.D.-Chief, Pulmonary Mediastinall and ENT Pathology Branch, Armed Forces Institute of Pathology, Washington, D.C. ROSENsnATT ,, MILTON B., M.D.-Associate Clinical Professor of Medicine, New York MedicallCollege, and Visiting Physician, Metropolitan Hospital,. New York,N.Y. Ross, JOSEPH,N'I.D.-Associate Professor of Medicine, University of Indiana Schooll of Medicine and Head of' Chest Division, Robert Long Hospital, Indianapolis, Ind. SANFORD, J. P.,, M.D.-Associate Professor of Internal Medicine, The Uni- versity of Texas Southwestern Medical Schooly Dallas, Tex. SAVAGE, I. RICHARD, Ph. D.-Professor of Statistics, Florida State University, Tallahassee, Fla. ScHaFFMAN, ZELDA-Special Assistant to Executive Officer, National Cancer Institute, U.S+ Public Health Service, Bethesd'a, Md'. SaHNEIDERMAN,, MARVIN. A-Associate Chief, Biometry Branch, National Cancer Institute, U.S. Public Health Service, Bethesda; Md. SCHWARTZ, JOHN THEODORE; M.D.-Head, Ophthalmology Project, Na- tional Institute of Neurological Diseasesand'Blindness, U.S. Public Health. Service, Bethesda, Md. SCOTT, OWEN-Executive Officer, National Institute of General Medical Sci- ences, U.S. Public Health Service, Bethesda, Md. SELIGMAN, ARNOLD M., M.D.-Chairman, Department of Surgery, Sinai' Hos- pital, Baltimore, Md. 0 I xv
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SELTSER; RAYMOND, M.D.-The Johns Hopkins University School of Public Health, Baltimore, Md. SELTZER, CARL C., Ph. D.-Research Associate in Physical Anthropology,. Peabody Museum, Harvard Uhiversity„ Cambridge, Mass. SHAPIRO, HARRY, M.D.-Curator of Anthropolbgy., American Museum of Natural History, New York, N.Y. SHUBIx, PHILLIPE, M.D.-Professor of Oncology, Chicago Medical School, Chicago, Ill. SILVETTE, HERBERT, Ph. D.-Visiting Professor of Pharmacology, Medical College of Virginia, Richmond, Va. SIRKEN, Mo:vROE; Ph. D.-Acting Chief, Division of Health Records, The National Center for Health Statistics, U.S. Public Health~ Service, Wash. ington, D.C. SLOAN, MARGARET H., M~D.-Special Assistant to Director, National Cancer Institute, U.S. Public Health Service, Bethesda; Md. SPIEGELMAN, MORTIMER-Associate Statistician, Metropolitan Life Insurance Company, New York, N'.Y. STALLONES, REUEL, M.D.-University of California Schooll of Public Health, Berkeley, Calif. STEINBERG, ARTHUR; Ph. D.-Biologist, Professor in Department of Biology, Western Reserve University, Cleveland, Ohio STEWART, HAROLD L., M.D.-Chief, Laboratory of Pathology, National Can- cer Institute;, U.S. Public Health Service, Bethesda, Md. STOCKS, PERCY, M.D.-World HealtL Organization Consultant, Former Chief Medical Statistician in the Office of the General Registrar (1933-50), London,, England STOUT, ARTHUR P., M.D.-Professor Emeritus of'~ Surgery, Laboratory of Sur- gical Pathology, College of Physicians and Surgeons„Columbia University, New York, N.Y. STOWELL, ROBERT, M.D., Ph. D.-Scientific Director, Armed Forces Institute of Pathology, Washington, D.C. SYME, SHERMAN LEONARn-Sociologist, San Francisco Field and Training Station, U.S. Public Health Service Hospital, San Francisco, Calif. TAEUBER, K. E.-Research Associate, Population Research and Training Center, University of Chicago, Chicago, Ill. TOBACCO INSTITUTE, INC., Washington, D.C: TOBACCO INSTITUTE RESEARCH COMMITTEE, New York, N.Y. TOKUHATA, GEORGE, Ph. D., D.P.H.-Chief of Epidemiolbgy, St. Jude Re- search Hospital, Institute of Biology and Pediatrics, Memphis. Tenny and Assistant Professor of Preventive Medicine, University of' Tennessee, Col- lege of Medicine, Memphis; Tenn. ToMPSETT, RALPH, M.D.-Professor of Internal Medicine, The University of Texas Southwestern Medical' School, Dallas, Tex., and Director of Medical Education„ Baylor University Medical Center, Dallas, Tex. TbTTEN; ROBERT S., M.D.-Associate Professor of! Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pa. TURNER, CLAUnE G.-Director, Tobacco Policy Staff, Agriculture Stabiliza• tion~ and Conservation~ Service, United States Department of Agriculture, Washington, D.C. xvi M I
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VINCENT, WILLIAM J.-Student, University of California, Los Angeles, Calif. VON SALLMANN, LUDWIG, MsD.-Chief, Ophthalmology Branch, National In- stitute of Neurological Diseases and Blindness, U.S. Public Health Service, Bethesda, Md. VORWALD, ARTHUR„ M.D.-Chairman, Department! of IndustrialJ Medicine and Hygiene„ Wayne University College of Medicine, Detroit, Mich. WALKER, C. B., B.A.-Biostatistics Section, Research and Statistics Division, Department of National Health and Welfare, Ottawa, Canada WALLENSTEIN, MERRILL, Ph. D.-Chief, Physical Chemistry Division, Na- tional Bureau of Standards, Washington, D.C. WEBB, BLAIR M., M.D.-Otolaryngologist and ENT Consultant at the National Institutes of Health, U.S. Public Health Service, Bethesda, Md. WE1:vSTEIrr, HOWARD I., M.D.-Director, Division of Medical Review, Foo& and Drug,Administration, Washingtony D.C. WOOLSEY, THEODORE D.-Assistant Director, National Center for Health~ Statistics, U:S. Public Health Service, Washingteny D.C. WYATT, JOHN P., M.D.-Professor of Pathology, St. Louis University Schooll of Medicine, St. Louis, Mo.. 7,E:RZavY, FRED M.,, M.D.-Department of Maternal and! Child Health, The Johns Hopkins School of Public Health, Baltimore, MdL 7.UKEL, WTLLIAni, M.D.-Associate Director, Collaborative Studies, Nationall Cancer Institute, U.S. Public Health Service,,Bethesd'a, Md. 714-422' 0-64'-2' xvii 9
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Introduction,. Summaries,, and Conclusions :.wrr~ , . _._ ... ,,4 ..-« _ .. .. _+. .-..--.,
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Y 649994E0
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Chapter 1 Realizing that for the convenience of all' types of serious readers it~ would be desirable to simplify language, condense chapters and bring opinions to the forefront. t'be Committee offers Part I as'sueh a presentation. This Part includes: (a) ani introduction comprising, among other items, a chro- nology especially pertinent to the subject of this study and to the establish- ment and activities of the Committee, (b)! a short account ofl how the study was conducted, (c) the chief criteria used in making jNd=ments, and' (d) a brief overview of the entire Report. HISTORICAL NOTES AND CHRONOLOGY In the early part of the 16th century, soon after the introductSon, of' tobacco into Spain and England by explorers returning from t'he New World, controversy developed from differing opinions as to the effects of the human use of the leaf and prodhcts derived from it by combustion or other means. Pipe-smoking, chewing, and snuffing of tobacco were praised for pleasura- ble and reputed medicinal actions. At the same time, smoking was con- demned as a foul-smeliing, lbathsome custom, harmful to the brain and' lungs. The chief question was then as it is now: is the use of tobacco bad or `rood for health, or devoid of effects on health? Parallel with~ the increas- ing prodtiction and use of t'obacco, especiall~, with the constantly increasing smoking of ci-arettes, the controversy has become more and more intense. Scientific attack upon the problems has increased proportionately. The design, scope and penetration of studies have improved, and the yield of significant results has been abundant. The modern~ period of' inuestigatiom of smoking and healthis include& within the past sixty-three years. In 1900 an increase in cancer of the lung was notedl particularly by vital statisticians, andl their data are usually taken as the st'arting point for studies on the possible relationship of smoking and other uses of tobacco t'o cancer of the lung and of cert'aini other organs, to diseases of the heart and blood vessels (cardiovascular diseases in gen- eral; coronary artery disease in, particular) „ and to the non-cancerious (non- neoplastic) diseases of the lower respiratory tract (especially chronic bronchitis and! emphysemal . The next important basic date for starting comparisons is 1930, when the definite trends in mortality and disease-inci- dence considered in this Report became more eonspicuous. Since then a: areat variety of investigations have been carried out. Many of the chem- ical compounds in~ tohacco, andd in tobacco smoke havebeem isolatedl and tested. Numerous experimental studies in lower animals have been made by exposing them to smokeand'~ to tars, gases and various constituents in tobacco~ and tobacco smoke. It is not feasible to~ submit human beings to 5 -4::-. v-.::.e";:,:,.: ik'AM .._
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experiments that might produce cancers or other serious damage, or to expose them to possibly noxious agents over the prolonged periods under strictly controlled conditions that wouldl be necessary for a valid test. Therefore, the main evidence of the effects of smoking andl other uses of tobacco upon the health of human beings has been secured through clinical and pat!holbgical observations of conditions occurring in men, women and children in the course of their lives, and by the application of epid'emio- logiealand statistical methods by which a vast array of information has been assembled and analyzed~ Among the epidemiolbgical methods which have been used in attempts to determine whether smoking and other uses of tobacco affect! the health of man, two types have been particularly useful and have furnished information of the greatest value for the work ofl this Committee. These are (!l ) retro- spective studies which deal with data from the personal histories and medical and mortalityrecords of human individuals in groups; and (2)~ prospeetit;estudies, in~ which men and women are chosen randomly or f'rom~ somee special group; such as a profession, and are follbaed from the time of their entry into the study for an indefinite period, or until they die or are lost on account of other event's. Since 1939 there have been 29 retrospectiive studies of lung cancer alone which have varying degrees of completeness andl validity. Following, the publication of several notable retrospective studies in the years 11952-1'956, the medical evidence tending to link cigarette smoking to cancer of the lung, received particularly widespread attention. At this time, al'so, the criticali counterattack upon retrospective studies and upon conclusions drawn from them was launched by unconvinced individuals and groups. The same types of criticism and skepticism have been, and are, marshalled against the meth- ods, findings; and conclusions of the later prospective studies. They will be discussed further in Chapter 3, Criteria for Judgment, and in other chapters, especially ChapterII, Mortality, and Chapter 9, Cancer. Durin- the decade 1950-1960, at various dates„statements based upon the accumulated evidence were issued by a number of organizations. These included the British Medical Research Council; the cancer societies of Den- mark,'orway; Sweden, Finland, and the Netherlands; the American Cancer Society; the American Heart Association; the Joint Tuberculosis Couneit of' Great Britain; andlthe Canadian Nationall Department of' Health and~''Velfare. The consensus, publicly declaned, was that smoking is an important health hazard, particularly with respect to: lung cancer and! cardiovascular disease. Early in 1954. the Tobacco Industry Research Committee (T:I.R.C.) was established by representatives of tobacco manufacturers.. growers, and ware- housemen to sponsor a program of research into questions of tobacco use and health~ Sincethen, under a Scientific Director and a Scientific AdvisoryBoard composed of nine scientists w,homaintain t'heirrespecthve institutional affiliations, the Tobacco Industry Research Committee has conducted a grants-in-aid program, collected information, and i'ssued reports. The U.S. Public Health Service first became officially engaged in an appraisal of the available data on smoking and health~ in~ June; 1956, when, under the instfigation of the Surgeon General, a scientific Study Group on 6
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the subject was established jointly by the National Cancer Instfitute;, the National Heart Institute, the American Cancer Society, and the American Heart Association. After appraising 16,independent studiesearried on in five countries over aperiod'of 18 years, this group concluded that there is al causal, relationship between excessive smokingoflcigarettesandilungcancer. Impressed by the report of the Study Committee and by other new evi- dence. Surgeon General Leroy E. Burney issued a statemea on July 12, 1957, reviewing the matter and declaring, than "The Public Health Service feels the wci_ht of the evidence is increasingly pointing, in one direct'2on;, that Axcessive smoking is one of the causative factors in ltmg cancer." Again, in a special article entitled "Smoking andlLung,Caneer A St'at'ement of the Pi ublicHealthService;"published in the Journall of the American Medicall 1ssociation on November 20', 1959. Surgeon Generall Burnev referred too his statement issued in 1957 and reiterated the belief of the Public HealthServ,ice that: "The weight of evidence at present implicates smoking as the. Eirincipal factor in the increased incidence of lung cancer," and that: "Ciga- rette smoking particularly is associated with an increased chance of de- Nelbpinn lung cancer." These quotations state the position of the Publfc. Flealth Service taken in 1957 and 111959 ont'he question of smoking and health. That position has not changed in the succeeding, years, dhring «hichseveral units of the Service conducted extensive investigations on t-moking and airpollution; and theService maintained a; constant scrutiny '?freportsandlpublications in this field. ESTABLISHi~-TENT OF THE COMMITTEE The immediateantecedent's of the establishment of the Surgeon Gen- eral's Advisory Committee on Smoking and Health: began in mid-1961. On June t of that vear, a letter was sent to4hePresident' of the I:Tnited States: qi;ned' bvt'he presidents of the American CancerSociety; the American Public Health Association: the American Heart Association; and theNa- tional Tuberculosis Association. It urged the formation of a Presidential'commission t~o~ study the "widespread implications ofl the tobacco problem."' On January 4, 11962, representatives of the various organizations met with Surgeon General Luther L. Terry: who shortly thereafter proposed to the Secretary of Health, Education, and Welfare the formation ofi an advi- sorv committee composed of "outstanding experts who would assess avail- able knowledgein this areai [smoking vs. health] and make appropriate rec- ommendations, . . ." On April! . 16. the Surgeon General sent a moredetail'ed' proposal t'o: theSecretarv for the f'ormation of the advisory group, calling for re-evaluation ofl thePublficHealth Service position taken by Dr. Burnev in the Journal of the American Medical Association. Dr. Terry felt the need for a; new look at the Service's position in the light of' a number of significant': develop- ments since 1959 which emphasized the need f'or further action. He listed t'heseas: 7
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1. New studies indicating that smoking has maior adverse health effects. 2. Representations from national voluntary health agencies for action on the part of the Service. 3. The recent study and report of the Royal College of Physicians of London. 4. Action of the Italian Government to forbid cigarette and tobacco ad- vertising; curtailed advertising of cigarettes by Britain's major tobacco companies on TV; and a similar decision on the part of the Danish tobacco industry. 5: A proposal by Senator Maurine Neuberger that Congress create a com- mission to investigate the health effects of smoking: 6. A request for technicall guidance by the Service from the FederalTrad'e Commission on labeling and advertising of tobacco products. 7~. Evidence that medical opinion has shiftedsianificantly against smoking~ The recent study and report cited by Surgeon General Terry was the highlay important volume: "Smoking and Healt'h+-Summary and Report of the Royal College of Physicians of London on Smoking in Relation to Cancer of the LunT and Other Diseases." The Committee of the Royal College ofiPhysicians dealing with these matters had beem at its work of appraisal of data since April 1959. Its main conclusions, issuedi: early in 11962, were: "Cigarette smoking,is a cause of lung cancer and, bronchitis, and probably contributes to the development of coronary heart disease and various other less common diseases. It delays healing of gastric and duodenal ulcers." On June 7, 1962, the Surgeon General announced that he was establishing an expert committee to undertake a comprehensive review of all data; on smok- ina and health. The President, later in the same day at his press conference acknowledged the Surgeon General's action andl approved it. On July 2-1, 1962; the Surgeon General met' with, representatives of the American Cancer Society, the Americani College of Chest Physicians, the American Heart Association, the American Medical Association„the.Tobacco Institute, Inc:. the Food' and Drug Adtninistration, the National Tuberculosis Association, the Federal Trade Commission, and the President's Office of Science and Technology. At this meeting, it was agreed that the proposed work should be undertaken in two consecutive phases, as follbws: Phase I-An objective assessment of the nature and magnitude of the health hazard, t'o, be made by an expert scientific advisory committee which would review critically all available data but would'not conduct new research. This committee would produce and submit to the Surgeon General a technical report containing evaluations and conclusions. Phase II--Recommendations for actions were not to be a part of the Phase I committee's responsibility. No decisions on how Phase II would be conducted were to be made until the Phase I report was available. It was recognize'that different competencies would be need'ed& in the second phase and that many possible recommendations for action would extend beyond the health field and into the purview and competence: of other Federal agencies. The participants in the meeting of July 27 compiled a list of more than 150 scientists and physicians working in the fields of biology and medicine, 8 ~,.
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with interests and competence im the broad range of medical sciences and with capacit'yy to evaluate t'he elements and factors in the complex relation- shi'p between~ tobacco smoking and health. During, thenext' month, these lists were screened' by the representatives of' organizations present at t'he July 27meetiiig. Any organization coul& veto any of the names on the list, no reasons being required. Particular care was taken to eliminate the names of any persons who had1'aken a public position on the questions at issue. From the final list~ of! names the Surgeon General selected ten men who agreed to serve om the Phase I commit'tee. which was named The Surgeon General's Advisory Committee on; Smoking, and Health. The com- mititee members, their positions, and their fields of competence are: Stanhope Bavne-Jlones, M.D., LL.d., (Retired ), Former Dean, Yale School (4 Medicine (19351-40), former President. Joint Administrative Board. Cor- nell University.., New York Hospital Medical Center (1947-52) ; former President. S'ociety of American Bacteriologists (19291. and American Society of'~ Pathology-andl Bact'eriolog,v(11940). Field: Nature and Causation of Di-~ea<e in Human Populations. Dr. Bavne-Jones served also as a special consultant to the Committee ~ta fl'. Walter J. Burdette, M.D:, Ph. D., Head of Department'of Surgery; Uiti- versitv of Utah Schooli ofl Medicine. Salt Lake City. Fields: Clinical & Trxperimental Surgery; Genetics. William G. Cochran. NI.A., Professor of Statisttics., Harvard University. Field: Mathematical Statistics, with Special Application to Biological Prohl lerns. Enunanuel Farber. M.D., Ph. D., Chairman, Department of Pathology; 1 niversitw of Pittsburgh. Field: Experimental and Clinical Pathology. Louia F. Fieser, Ph. D.. Sheldon Emory, Professor of Oiganic ChemiEtry; i{arvard University. Field: Chemistry of Carcinogenic Hydrocarbons. Jacob~ Farth. MLD., Professor of Pathology. Columbia University. and I)iiector of Pathology Laboratories, Francis Delafield Hospital, New York. N.Y. Field: Cancer Biology. John B. Hickarn, M.D., Chairrnan, Department of Internal Medicine; Uni- versity of Indiana, Indianapolis. Fields: Internal Medicine, Physiology of Cardiopulmonary Disease. Charles LeMaistre, M.D., Professor of Internal' Medicine, 'I1heUniversity of Texas Southwestern Medical'School, and Medical Director, a'oodlaNN n Hos- pital, Dallas, Texas. Fields: Internal Medicine, Pulsnonary Diseases,. Preventive Medicine.. Leonard M.. Schuman, M.D.. Professor of Epidemiology, L niversity of 1linnesota School of Public Health, Minneapolis. Field'i:~ Health and Its. Belationshipto the Total Environment. Maurice H. Seevers, :11.D.,,Ph. D.. Chairmam Department of Pharmacology. Fniversity of Michigan, Anni Arbor. Field': Pharmacology of Anesthesia and Habit-Forming Drugs. Chairman: Luther L. Terry,, MI.D., Surgeon General of the United! States Public Health Service.
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Vice-Chairman: James M. Hundley, M.D., Assistant Surgeon General for Operations, United States Public Health Service. Staff 1)irector Medical'Coordinator Eugene H. Guthrie, M.D., M.P.H. Peter V. V. Hamill, M.D., M.P.H. Public Health Service Public Health Service 10.
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.:;.~<. _ ..~:,,:. ~, ..
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i 4
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Chapter 2 CONDUCT OF THE STUDY The work of the Surgeon General°s Advisory Committee on Sinoking and llealth was undertaken, organieeds and pursued with independence, a deep sense of responsibility, and with full appreciation of the national' importance 4 the task. The Committee's constanfl desire was to carry out in its own way. with the best obtainable advice and cooperation from experts outside it; membership, a thorough and objective review and evaluation of available information about the effectsof the use of various forms ofl tbbaccoupon the hvalth ofl human beings. It desired that the Report of its studies andijud'g- nwnts should! be unquestionably the product of its lhbors and its authorship. With an,enormous amount of' assistance from 155 consultants, from members and associates of the supporting staff, and' from several organizations and institutions. the Committee feelsthat, adocument of adequate scope, integrity, and individualitv has been produced. It is emphasized, however, that the ;,untent and judgments of the: Report are the sole responsibility of the Committee. at the outset, the Surgeon General emphasized his respect f'or the freedom 4 the Committee to proceed with the study and! to report as it saw fit, and he i4ecl,t*ed all support'; possible from the Unit'ed! S'tatesPublic Health~ Service,. ['he Service; represented~ chiefly by his office, the National Institutes oflH'ealth, the National Library of Medicine, the Bureau of State Services, and the Na- tionall Center for Health~ Statistics, furnished the able and devoted personnel :hat constituted the st~aff at the Committee's headqparters iniWashington, and provided an extraordinary variety and volume of supplies, facilities an& re- ~:ources. In addition, the necessary financial support! was made available by the Service. It is the purpose of this sectioni to present an outline of the important features of the manner in which the Committee conducted its study and com- posed this Report. A retrospective outline of procedures and events tends to convey an appearance of orderliness that did not pertain at all times. A plan, was adopted at the first meeting of the Committee on November 9-10, 1962,, but this had to be modified from time to time as new lines of inquiry led into unanticipated explorations. At first an encyclopedic approach was con- sidered to deal with all aspects of the use of tobacco and the resulting effects, with all relevant aspects of air pollution, and all pertinent characteristics of the external and internali environments and make-up of humani beings. It 1Nas soon found to be impracticable to attemptito d'o all of this in any reason. able length of time, and certainly not under the urgencies of the existing sit~uation., The finallplan was to give partieularattention to the cores of prob- lems of the relationshipof uses of tobacco, especially the smoking of ciga- rettes, to the health of men and women, primarilyy in the United States, and 13 I
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to deal with' the material from both a general viewpoint and on the basis of so dlsease categories. u~. As may be seen in a glance at the Table of Contents of this Report, the main topical divisions of the study were: ~ • Tobacco and tobacco smoke, chemical and physical characteristics ~ (Chapter 6). f • Nicotine, pharmacology and toxicology (Chapter 7). • Mortality, general and specific, according to age, sex„disease, and smok- n ing habits, and other faators (Chapter 8). n: • Cancer of the lungs and' other organs; carcinogenesis; pathology; artd ti epid'emiology (Chapter 9). n• Non-neoplastic diseases of the respiratory tract, parrticularly chronic r bronahitis and emphysema. with some consideration of the eff'ects of '1 air pollution (Chapter 1O). i • Cardiovascular diseases; particularly coronary artery diGeases (Chapter v 111. • Other conditions, a miscellanv including gastric and duodenal ulcer, peri'natal disorders, tobacco amblvopia, accidents (Chapter 12)'. • Characterization: of' the tobacco habit and'beneficial effects of~ tobacco (Chapter 13). 1 • Psycho-social aspects of smoking(Chapter 14)'_ ~ • llorpholbgical cons6itution of smoker~s (IChapterl5). As the primary d'uti of the Committee was to assess information about th ki * " ki d h l i h l h f' ng an ma ng e smo ea t rement was t at o , a major genera requ information available. That requirement was met in three ways. The first and most im>>ortant was the bibliographic service provided by the National Library ofl Medicine. _1s the annotated monograph by Larson; Haag; and ~ ~ Silkettte-compiled from more than 6,000 articles published in some 1,200 journals up to and largely into 1959-was available as a basic reference souree_ the National Library of Medicine wasreqpested tocompile a bibllog- raph}• (by author and by subject): covering the world literature from 1958 to the present. In compliance with this request, the National Libr:ary of Medicine furnished the Committee bibliographies containing, approximately 1100 titles. Fortunately; the Committee staff was housed in the National Library of Medicine on the grounds of the National Institutes of Health, and through this locat2on: had ready access to books and periodicals, as well as to scientists working in its field of interests. 1Vlodern apparatus for photo-reproduction of articles was used constantly to provide copies need'ed for study by members of the Committ'ee. In addition, the members drew upon the libraries and bibliographic services of those institutions in: which they held academic positions. A considerable volume of copies of reports and a number of special articles were received from a variety of additional sources. Alll of the major companiesmanufacturing cigarettes and other tobacco products were invited to submit statements and any information pertinent to the inquiry.. The replies which were received were taken into consideration by the Committee. Through a system of contracts with individuals competent in certain fields, special reports were prepared for the use of the Committee. Through these 14
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sourc.e-, much valuahle information was obtained; son-ie of it new and hithertoo unpublished. In addition to the special reports prepared under contracts. manv,con- flerencesv seminar-like meetings. consultations. visits and correspondence madeavailablp to the Committeeal lar,e amount of material and ai consider- able amount ofwell-inform4and well-reasoned opinion and' advice. To deal in depth and! discrimination with thetopics listedlabove. the Com- mittee at it's first meeting formed subcommittees with much overlapping in~ ineneber=hip. Tihesesubcommitteesw-eretihe main forces engaged in collec- tion. analn-.sir. and evaluation ofl data from published reports. contractual' r,,ports. discussions at confierences: and from sorne new prospective studies"'Programmecl and carried out generously at' the request of theCommittiee.'Iiir~e will' heacknowledged more fully el~esclier~einthisReport. The first i1,rmulations of conelusionswere made by these subcommittees. andl these~ MT(' submittled tot'he fulll Committee for revision and adoption after debate. 1t the beginnin,, and until the Committ'eebegan to meet routinely in I vo4uti~e session, it had the adkantage of attendance at its meetings of oh- -t•r%,0rsfrom otlier Federalagencies: There were representatives fromthet,~)llhm,inr• a=encies: EsecutiveOffice of t'hePresident ofl the United States. Fr~_lural Trad!* Commission. Department of Commerce. Department ofA-ri- ~ulturc. and theFood and Drug~ Admiilistration., Serving as moret'hani ob- ~~r~f n, and reporters to their agencies. when thev were present or by «,rittrn communication, they supplied the Committee with much useful infii,rmatlion. Thcre were an uncountednuunber of inectiii_s of subcommittees and other i0 ~=er gatherings. Petweeni Aovemlier 119f>2 and December 1963, the full t:ommi'ttee heldlnine sessions each lasting from two tof'ourd'aysin Washing- h,u or Bethesda. The main matters consi'deredl at the meet6n_sin October. \on-ember, and December196.3' were the review and revision of chauters. l is f l i ' ca scrut !IN o cone us ons; andlt he innumerabldtilf thi eeas oecompos- t:iun and editin~ of this comprehensive Report. 714-422 0-64-3' 15 - ~.._._.~_.,~:.~....
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U37sss93
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Chapter 3 Criter ia f or Judgment
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Chapter 3 CRITERIA FOR JUDGMENT Tn makinl- critical appraisals of datal and! interpretations andin, formulat- in; its own conclusions; the Surgeorr General's Advisory Committ'ee on ~'mfokinaand, Health-its individual members and it's subcommittees and the (`ommitt'eeas a: whole-made decisions or judgments at three levels. These I,~velswere: I. JIudgment as to the validity of a publication or report. Entering intoo the making of this judgment were such elements as estimates of the com- petence and training of the investigator, the degree of freedom from bias. designand scope of the investigation, adequacy of facilities and resource;, adequacy of controls. 11. Judgment as to the validity of the interpret'ations placed by investigators upon their observations and dlita. and as to the logic and justification of their conclusions~ 111. Judgments necessarv for theformulatiion of eonclhsions within the. Committee. The priniary reviews. analyses and evaluations cnfl publications and unpub- lil,hed reports cont'aining, data,, interpretations and conclusions of authors ~+eremadeMv inditi,idual members of the Committee and'. in sonreinst'ances„ hn- consultants. Their statements were next reviewed and evaluated by a; ~.ubcoinmittee. This was followedlat aniappropriaUe time by the Committee's cniticali consideration of a~ subcommittee's report. and bvy decisions as to the selection of material for inclusion inithe drafts of the Report, together with drafts oftheconelusionssubmitted bv subcommittees. Finallv; after re- peatedlcritical reviews of drafts ofi chapters. conclusions were formulat'ed and ,idopted by the whole Committee. setting forth the considered j udbmcnt of the Committee. It is not the intention of this section to present an essay on decision,making. Nor does it seem necessary to describein detail the criteria used' for making, scientific judgments at each of the three levels mentioned above. All mem- bers of the Committee wcre schooled in the high standards and criteria im- plicit ini making scientific assessments; if any member lacked even: a small part of suchi schooling he received it in good measure from the strenuous debatesthat tookptaceat' consultations and at meetings of the subcommittees and the whole Committee. CRITERIA OF THE EFIDEDIIOLOGIC METHOD It is advisable, however., to discuss briefly certain criteria which; although applicable walU judgments involved in this ReportL were esper_iallysignificant for judgments based upon the epidkmiologicmethod. Im thisinquir~ythe. 19
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epidemiologic method was used extensively in the assessment of causal fac- tors in the relationship of smoking to health among human beinrs upon whom direct' experimentation could not be imposed: Clfinieal; pathological and ex- perimental evidence was thoroughly considered and' often served to suggest an hypothesis or confirm or contradict other findings. When coupled witL the other data, results from the epidemiologic studies can provide the basis upon which judgments of causality may be made. Iwcarrying out studies through the use of this epid'emiologic method„many factors, variables, and~ results of investigations must be considered' to deter- mine first whether an association actually exists between, an attribute or agent and a disease. Judgment on this point is based upon indirect and direct measures of the suggested association. If it be shown that an asso- ciation exists, thenithe question is asked: "Does the association have a causal significance?" Statistical methods cannot establish proof of a causal relationship in an association. The causal significance of an association is a matter of judgment which, goesbey.ond any statement of statisticali probability. To judge or evaluate the causal significance of the association between theatt'ribute or agent and the disease, or effect upon health, ai number of criteria must be utilized, no one oflwhichiis an all-sufficient basis for judgment. These criteria: include: a) ' The consistency of the association b) The strength of the association c) The specificity of the associationi d) The temporal relationship of the association e) The coherence of the associationi These criteria were utilized in various sections of this Report'. The most extensive and illuminating account of their utilization is to be found in Chapter 9' in the section entitled "Evaluation of the Association Between Smoking and Lung Cancer". CAUSALITY Various meanings and conceptions of! the term cause were discussed vigorously at! a number of meetings of the Committee and! its subcommit- tees. These debates took place usually after data and reports had been studied and evaluated, and at the times when critical scrutiny was being given to conclusions and to the wording, of conclusive statements. In addi- tion, thoughts about causality in the realm ofl this inquiry were constantly and inevitably aroused in the minds of the members because they were preoecupied! with~ the subject of theirinvestigat'2on-"Smoking, and Health." Without summarizing the more important concepts of causality that have determined human attitudes and actions from, the days even before Aristotle, through the continuing era of observation and experiment, to, the statistical certainties of the present atomic age, the point of view of the Committee with rregard to causality an& to the language used in this respect in this report may be stated briefly as follows: 1. The situation of smoking in relation to the health of mankind includes a host (variable man)' and a complex agent (tobacco and its products, partic- 20.
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66SS911E0
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Summaries and Conclusions 0 w ~ U1 M 0 0
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Contents Pa e g A. BACKGROUND AND HIGHLIGHTS .......... 25 Kinds of Evidence . . . . . . . . . . . . . . . . . . 26 Evidence From the Combined Results of Prospective Studies . 28 Other Findings of the Prospective Studies ...... 29 Excess Mortality . . . . . . . . . . . . . . . . . 30. Associations and' Causality . . . . . . . . . . . . . . 30 The Effects of Smoking; Principal Findings 31 Lung Cancer . . . . . . . . . . . 31 Chronic Bronchitis and Emphy sema . 31 Cardiovascular Diseases . . . . . . . . . . . . . . 32 Other Cancer Sites . . . . . . . . . . . . . . 32 The Tobacco Habit and Nicotine . . . . . . . . . . . 32 The Committee's Judgment in Brief . . . . . . . . . . 33 B. COMMENTS AND DETAILED CON'CLUSIONS .... (A Guide to Part II of the Report). 33 Smoke . . . . . . . . . . . . . . . . . . . . 33 Characterization of the Tobacco Habit . . . . . . . . . . 34 Pathology and Morphology . . . . . . . . . . . . . . . 34 Mortality . . . . . . . . . . . . . . . . . . . . . . 35 Cancer by Site . . . . . . . . . . . . . . . . . . . . 37 Lung C an cer . . . . . . . . . . . . . . . . . . . 37 Oral Cancer . . . . . . . . . . . . . . . . . . . . 37 Cancer of the Larynx . . . . . . . . . . . . . . . 37 Cancer of the Esophagus . . . . . . . . . . . . . . 37 Cancer of the Urinary Bladdler . . . . . . . . . . . 37 Stomach Cancer . . . . . . . . . . . . 38 Nbn-Neoplastic Respiratory Diseases, Particularly Chronic Bronchitis and Pulmonary Emphy sema . . . . . . . . 38 Cardiovascular Disease . . . . . . . . . . . . . . . . . 38 Other Conditions . . . . . . . . . . . . . . . . . . . 39 Peptic Ulcer . . . . . . . . . . . . . . . . . . . 39 Tobacco Amblyopia . . . . . . . . . . . . . . . . 39 Cirrhosis of the Liver . . . . . . . . . . . 39 Maternal Smoking and Infant Birth Weight ..... 39 Smoking and Accidents . . . . . . . . . . . . . 39 Morphological Constitution of Smokers . . . . . . . . . 39 Psycho-Social Aspects of Smoking . . . . . . . . . . . . 40 List of Tables 1. Deaths from selected disease categories, United States, 1962 . 26 2. Expected and observed deaths for smokers of cigarettes only and mortality ratios in seven prospective studies ..... 29 24 Chemistry an& Carcinogenicity of Tobacco and Tobacco
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Chapter 4 This chapter is presented in two sections. Section A contains background information, the gist of the Committee's findings and conclusions on tobacco and health, and an assessment of the nature and magnitude of the health hazard. Section B presents all formal conclusions adopted by the Committee and selected comments abridged from the detailed Summaries that' appear in each~ chapter of Part II of the Report. The full scope and depth of the Committee's inquiry may be comprehended only by study of'~ the complete Report. A. BACKGROUND AND HIGHLIGHTS In previous studies, the use of tobacco, especially cigarette smoking, has been causally linked' to several diseases. Such use has been associated with increased deaths from l.ung cancer and other diseases, notably coronary artery disease, chronic bronchitis, and emphysema. These widely reported findings, which have been the cause of much public concern over the past'.decade, have been accepted in many countries by official health agencies, medical associations, and voluntary health organizations. The potential hazard is great because these diseases are major causes of death and disability. In 1962, over 500;000, people in the United States died of arteriosclerotic heart disease (principally coronary artery disease), 41,000 died of lung cancer, and 15~000' die& of bronchitis and emphysema. The numbers of deaths in some important disease categories that have been, reported to have a relationship with tobacco use are shown in Table 1. This table presents one aspect of the size of the potential hazard; the degree of association with the use of tobacco will be discussed later. Another cause for concern, is that deaths from some of these diseases have been increasing with great rapidity over the past few decades. Lung cancer deaths, less than 3,000 in 1930, increased to 18,000 in 1950: Ini the short period since 1955, deaths from lung cancer rose from less than 27;000 to the 1962 total of 41,000. This extraordinary rise has not been recorded for cancer ofl any other site. While part of the rising trend for lung cancer is attributable to improvements in diagnosis and the changing age-composition and size of the population, the evidence leaves little doubt that a true increase in lung cancer has taken place. Deaths from~ arteriosclerotic, coronary, and degenerative heart; disease rose from 273;000 in 1940, to 396,000 im 1950, and to 578,000 in 1962. Reported deaths from chronic bronchitis and emphysema rose from 2,300 in 1945 to 15,000 in 1962. The changing patterns and extent of tobacco use are a pertinent aspect of the tobacco-health problem. 25
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TABLE 1.-Deaths from selected disease categories, United'Sta2es, 1962~ Cause of death' Degenerative andiarteriosclerotic heart disease, including coronaryy disease (420„ 422) -------------------------------------------------- Hypertensive heart disease (440-3)!______-_ ---------------- Cancer oflune~(16'2-3)-.-____________________________________________ Ciirhosia ofliven (581)---------------------------------------------- i3ronchitis and emphysema (502, 527.1) :________________________-_--- Stomach and duodenal ulcers (51I1-1) -.__-_------------------------- Cancer~.ot bladder.(181)--------------------------------------------- Cancer~of oral cavity(140-8)------------------------------ Caneer ofesophacns (180)------------------------------------------- Canoer of larynx (lCll.. ----------------------------- A11 above causos------------------------ ------- All othcr cauxrs --------------------------------------------------- .alllcrausc.s.---------------------------------------------------- •International Statistical Cl9ssiflcationmumbers in parentheses. 'Potal 577;918 6'2.17fi 41, 376 21,824 15,104 12, 22S 8,081 fi. 481 5, 0R4 2,417 752,691 1,004,027 1, 7.56, 720 Males ' 349,604 26. ,654 35,312 14; 329 12,937, 8, FL'iB 5,,R7.5 4,920 3,973 2;172 Females 229,314 35,522 fi, 0fi4 7,495 2,167 3.392'. 2. Sbr' 1,561 1, 115 245 994, 79 ~ 761.931 Nearly 70 million people in~ the United States consume tobacco regularly. Cigarette consumptioni in the United States has increased markedly since the turni of the Century, when per capita consumption was less than 50' cigarettes a year. Since 1910, when cigarette consumptioni per person (15 years and older) was 138;it rose to1,365 in 1930, to 1,828 in 1940: to 3,322 in 1'950, and to a peak of 3,986 in 1961. The 1955 Current Population Survey showedl that 68 percenC of the: male population and 32.4 percent of the female population 18 years of age andl over were regular smokers of cigarettes. In contrast with this sharp increase in cigarette smoking, per capita use of tobacco in other forms has gone down. Per eapit'a consumption of cigars declined f'roum 117 in 1920 to 55 in 1962. Consumption of pipe t'obacco; which reached a peak of 21/Z lbs. per person in 1910, fell to a little more than half a pound per person in 1962. Use of chewing tobacco has declined from about four pounds per person in 1900 to half a pound in 1962. The background for the Committee's study thus included much general information and findings from previous investigations which associated the increase in cigarette smoking withi increased deat'hs in a; number of majpr disease categories. It was in this setting that the Committee began its work to assess the nature and magnitude of the health hazar~d attributable to smoking. KINDS OF EVIDENCE In order to judge whether smoking and ot'her tobacco uses are injurious to health or related to specific diseases, the Committee evaluated three main kinds of scientific evidence: 1. Ani.mal experirnents:-In numerous studies, animals have been exposed to tobacco smoke and tars, and to the various chemical compounds they con- tain. Seven of these compounds (polycyclic aromatic aompoundh) have been~ established as cancer-produoing (carginogenic). Other substances in tobaccoo and smoke, though not carcinogenic themselves, promote cancer production or lbwer the threshold to a known~ carcinogen. Several toxic or irritant gases contained in tobacco smoke produce experimentally the kinds of non-cant cerous damage seen in the tissues and cells of heavy smokers. This includes 26
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f,uppression of ciliary action that normally cleanses the trachea and bronchi, damage to the lung air sacs, and to mucous glands and goblet eells which produce mucus. 2. Clinical aad autopsy studies: Observations of thousands of patients and autopsy studies of smokers and non-smokers show that many kinds of damage to body functions and to organs, cells, and tissues occur more fre- quently and! severely in smokers. Three kinds of cellular changes-loss of ciliated cells, thickening (more thanl two layers of basal ce115), and presencee of atvpical cells-are much more common in the lining, laver (epithelium) (if the tracheal and bronchi of cigarette smokers than of non-smokers. Some of the advanced lesions seen, in the bronchi of cigarette smokers are probably premalignant. Cellular changesregularly found at autopsy in patients with chronic bronchitis are more often present in the bronchil of smokers than non-smokers. Pathologicallchanges in the air sacs and other functional tissue (,f the lung (parenchyma) have a remarkably close association with past hi.~torv of cigarette smoking. 3. Population studies.-Another kind of evidence regarding ani associatfion, bo«-een smoking and disease comes fYom epidemiological studies. In retrospective studies; the smoking histories of persons with a specified! liQea~e (for example, lung cancer), are compared with those of appropriate control groups without the disease. For lung cancer alone, 29suchiretrospec+ tiN e studies have been made in recent years. Despite many variations in de- sign and method, all but, one (which dealt with females) showed that pro- prnrtionatelymore cigarette smokers are found among the lung cancer patients than in the controll populations without lung cancer. Extensive retrospective studies of the prevalence of specific symptoms and signs-chronic eough, sputum production; breathlessness, chest, illness, and decreased lungf'nznctuon-consistently show that these occur more often in cigarette smokers than in non-smokers. Some of these signs and symptomss are the clinical expressions of chronic bronchitis, and some are associated more with emphysema; in general, they increase with amount of smoking and decrease after cessation of smoking. Another type of epid'emiological evidence on the relation of smoking and mortality comes from seven prospective studies which have beenl conducted since 1951. In these: studies, large numbers of men answered questions about'. their smoking or non-smoking habits. Death certificates have been obtained for those who died since entering the studies, permitting tbt~aldeath rates and death rates by cause to be computed for smokers ofi various types as well as for non-smokers. The prospective studies thus add several im- portant dimensions to information on the smoking-health problem. Their data permit direct' comparisons of the death rates of smokers and non- smokers, both overalll and for individual causes of death, and indicate the strength of the association between smoking and specific diseases. Each of' these three lines of'~ evidence was evaluated and then con, sidered! together in drawing aonclhisions. The Committee was aware that the mere establishment of a statistical association between the use of tobacco and' a disease is not enough. The causal significance of the use of tobacco in relationl to the disease is the crucial question. For such judgments all three
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lines of evidence are essential, as discussed in more detail on pages 26-27 of' this Chapter, and in Chapter 3. The experimental, clinicali and pathological evidence, as well as data from population studies, is highlighted in Section B of this Chapter, which im turn refers the reader to specific places in Part II of the Report where this evidence is presented' in detail. In the paragraphs which follow, the Committee has chosen to summarize the results of'the seven prospective population studies which, as noted above, constitute only one type of evidence. They illustrate the nature and potential magnitude of the smoking-health problem, and bring out a number of factors which are involved. EVIDENCE FROM THE' COMBINED RESULTS OF PROSPECTIVE STUDIES The Committee examined the seven prospective studies separately as well as their combined results. Considerable weight was attached to the con- sistency of findings among the several studies. However, to simplify presen- tation; only the combined results are highlighted here. Of the 1,123,000' men who entered the seven prospective studies and who provided usable histories of smoking habits (and other characteristics such as age), 37,3911 men died during the sithsequent months or years of the studies. No analyses of data for females from prospective studies are presently available. To permit ready comparison of the mortality experience of smokers and non-smokers, two concepts are widely used in, the studies-excess deaths of smokers compared with non-smokers, and mortality ratio. After adjustments for differences in age and the number of cigarette smokers and non-smokers, an expected' number of deaths of smokers is derived on the basis of deaths among non-smokers. Excess deaths are thus the number of actual (observed) deaths among smokers in excess of the number expected. The mortality ratio, for which the method of computation is described! in Chapter 8, measures the relative death rates of smokers and non-smokers. If the age- adjusted death rates are the same, the mortality ratio will be 1.0; if the death rates of smokers are double those of non-smokers, the mortality ratio will be 2.0. (Expressed as a percentage,, this example would be equivalent to a 100 percent increase.). Table 2 presents the accumulated' and combined data on 114, disease cate- gories for which the mortality ratio of cigarette smokers to non-smokers was 11.5 or greater. The mortality ratio for male cigarette smokers compared! with non-smokers, for all causes of death taken together, is 1.68, representing a total death rate nearly 70 percent higher than for non-smokers. (This ratio includes death rates for diseases not lfisted'in the table as well as for the 14 disease categoriess shown. ) In the combined results from the seven studies, the mortality ratio of cig- arette smokers over non-smokers was particularlyy high for a number of diseases: cancer of the lung, (10:8) , bronchitis and emphysema (16.1), can- 28
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at the earlier ages (40-50) represented in these studies, and declines witli I than for non-smokers, even for men who smoke 10'or more pipefuls a day` and f'or men who have smoked pipes more than 30 years. who have been smoking more than 30' years and who inhale the smoke tq some degree. The death rates for pipe smokers are little if at all higher smoking more thani 5 cigars daily, death rates are slightly higher. There is some indication that these higher death rates occur primarily in men less than 5 eigars a day are about the same as for non-smokers. For men also investigated! in the seven studies. The death rates for meni smoking Possible relationships of death rates and other forms of tobaeco, use were increasing age. Excess Mortality A Several of the reports previously published on the prospective studies ' included a table showing the distributioni of the excess number of deaths ' of! cigarette smokers among the principal causes of death. The: hazard' must be measured not onlyy by the mortality ratio of deaths in smokers and non- smokers, but also by the importance of a particular disease as a cause of death. In all seven studies, coronary artery disease is the chief contributor too the excess number of deaths of cigarette smokers over non-smokers, with lung, cancer uniformly in~ second' place. For all seven stud'1es combined,, coronary artery disease (with a mortalitv ratio of 1.7) acaounts for 45 per- cent of the excess deaths among cigarette smokers, whereas lung cancer (with a ratio of 10.8) accounts for 16 percent. Some of the other categories of diseases that contribute to the higher death rates for cigarette smokers over non-smokers are diseases of the heart and blood vessels; other than coronary artery disease, 14 percent; cancer sites other than lung, 8 percent; and chronic bronchitis and emphysema, 4 percent. Since these diseases as a group are responsible f'or more than 85 percent of the higher death rate among cigarette smokers, they are of particular interest topulilic health authorities and the medicall profession. ASSOCIATIOnS AND CAUSALITY assessment! . of causal factors in the relationship of smoking to health~ among human beinns upon whom direct experimentation could not be imposed.Clinieal. pathologicaL,and experimental evidence was thoroughly considered: an& often served'to sumst an hypothesis or confirm or contradict other findings. Whern coupled with the other data, results, from the epidemiologic. The array of information fromi the prospective and retrospective studies of ~ smokers and non~smokers,clearlv establishes an association between cigarette ~smoking and substantially higher death rates. The mortality ratios ini Table ~ 2 provide arr approximate index of the relative strength of this association, _~ for all causes of death and for1I4disease categQries. In thisincluiry theepidemiologic method was used' extensively ini the ~ 30
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studies can provide the basis upon which judgments of causality may be made. It is recognized! that no simple cause-and-effect relationship is likely to exist between a complex product like tobacco smoke and a specific disease in the variable human organism. It is also recognized that often the coexistence of several factors is required for the occurrence of a disease, and that one of' the factors may play a determinant role; that is, without it, the other factors (such as genetic susceptibility) seldom lea& to the occurrence of the disease. THE EFFECTS OF SMOKING: PRINCIPAL FINDINGS Cigarette smoking is associated' with a 70, percent increase in the age- specific death rates of males, and to a lesser extent with, increased deat'h, rates of females. The total number of excess deaths causally related too cigarette smoking in the U.S: population cannot be accuratel, estimated. In view of the continuing and mounting evidence from many sources, it is the judgment of the Committee that cigarette smoking contributes sub- stantiallv to mortality from certain specific diseases and to the overall death rate. Lung Cancer Cigarette smoking is causally related to lung cancer in men; the maYni- tudeof the effect of cigarettesmoking, far outweighs all other factors. The data for women. though less extensive. point in the same direction.. The risk of developing lung cancer increases, with duration of smoking and the number of cigarettes smoked per dav, and is diminished by dis- continuing smoking. In comparison with~ non-smokers: average male smokers of cigarettes have approximatelv a 9- to 10-fold risk of developing lung cancer and heavy smokers at leasta 20-fold risk. The risk of developing cancer of the lung for the combined' group of pipe smokers, cigar smokers, an& pipe and cigar smokers is greater than for non-smokers„but much1essthan for cigarette smokers. Cigarette smoking, is much more important thani occupational exposures in the causation of lungcancerin the generallpopulation,. Chronic Bronchitis and Emphysema Cigarette: smoking is the most important of the causes of, chronic bronchi- tis in the United States, and increases the risk of dying from chronic bron- chitisand emphysema. Arelationshipexist's between cigarette smoking andemphysema; but it has not, been established that the relationship is causal. Studies demonstrate that fatalities from this disease are infrequent among non-smokers. For the bulkofithe population ofl the L nited! States, the relative importance of cigarette smoking as a: cause of chronic broncho~pul'tnonary, disease is muchi greater than atmospheric poll'ution or occupational exposures. 31 714-422 0-64-4
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Cardiovascular Diseases It is established that male cigarette smokers have a higher death rate from coronary artery disease than non«smoking males. Although the causative role of cigarette smoking in deaths from coronaryy disease is not proveni the Committee considers it more prudent from the public health viewpoint to assume that the established association has causative meaning than to suspend judgment until'no uncert'aintyremains. Although a causal relationship has, not been established, higher mortality of cigarette smokers is associated with many other cardiovascular diseases, including miscellaneous circulatory diseases, other heart diseases, hyper- tensive heart disease, an& general arteriosclerosis. Other Cancer Sites Pipe smoking appears to be causally related to lip cancer. Cigarette smoking is a significant! factor in the causation of cancer of the larynx. The evidence supports the belief that an associationi exists between tobaccoo use and cancer of! the esophagus, and between cigarette smoking and cancer of the urinary bladder in mens but the data are not adequate to decide whether these relationships are causaL Data oni an association between smoking and cancer of the stomach are contradictory and incomplete. THE TOBACCO: HABIT AND NtCOTIN'E The habitual use of tobacco is related primarily to: psychological and social drives, reinforced and perpetuated by the pharmacological act'ions of nicotine. Social stimulation appears to play a major role in a young person's early and first experiments with smoking. Nb scientific evidence supports the popular hypothesis that smoking among adolescents is an expression of rebellion against authority. Individual stress appears to be associated more with fluctuations in the amount of smoking than with the prevalence of smok- ing. The overwhelming evidence indicates that smoking-its begjnning, habituation, and occasional discontinuation-is to a very large extent psy- chologically and! socially determined. Nicotine is rapidly changed in the body to relatively inactive substances with low toxicity. The chronic toxicity of smalll d'oses of nicotine is low in experimental animals. These two facts, when taken, in conjunction with the low, mortality ratios of pipe and cigar smokers, indicate that the chronic toxicity of nicotine in quantities absorbed from smoking and other methods of tobacco use is very low and probably does not represent an, important health hazard! The significant beneficiall effects of smoking occur primarily in the area of mental health, and the habit originates in a search for contentment. Since no means of measuring the quantity of these benefits is apparent, the Com- mittee finds no basis for a judgment which would weigh~ benefits, against hazards of smoking as it may apply to the general population. rs
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,l i THE COMMITTEE'S JUDGMENT IN BRIEF On the basis of prolonged study and evaluation of many lines of converging evidence, the Committee makes the following, judgment: Cigarette smoking is a health hazard of sufficient importance in the Uhited States to warrant appropriate remedial action. B. COMMENTS AND DETAILED CONCLUSIONS (A Guide to Part II of the Report) All conclusions formally adopted by the Committee are presented at the en& of this section in bold-faced type for convenience of reference. In the interest of conciseness, the documentation and most of the discussioni are omitted from this condensation. Together withi the tables of contents which appear at the beginnina of, each chapter ini Part II, it is intended as a guide to the Report. CHEMISTRY AND CARCINOGENICITY OF TOBACCO AND TOBACCO SMOKE Condensates of tobacco smoke are carcinogenic when tested by application to the skin of mice and rabbits and by subcutaneous injection in rats (Chap- ter 9, pp. 143-145)'. Bronchogenic carcinoma has not been prodticed by the application of tobacco extracts, smoke, or condensates to the lung or the tracheobronchiall tree of experimentall animals with the possible exception of dogs (Chapter 9, p. 165). Bronchogenic carcinoma has been produced in laboratory animals by thee administration of polycyclic aromatic hydYocarbons, certain metals, radio- active substances, and viruses. The histopathologic characteristics of the: tumors produced are similar to those observed in man and are predominantly of the squamous variet'y (Chapter 9, pp. 166-1$7)l. Seven polycy,clic hydrocarbon compounds isolated from cigarette smokee have been established to be carcinogenic in laboratory animals. The resultss of a number of assays for carcinogenicity of tobacco smoke tars present a puzzling anomaly: the total tar fromi cigarettes has manyy t'imes the carcino- genic potency of benzo{a)'pyrene present in the tar. The other carcinogens . known to be present in tobacco smoke are, wit'h, the exception of dibenzo(a,i) pyrene,,much less potent'thanibenzo(a)pyrene and'.they are present in smaller amounts. Apparently, therefore, the whole is greater than the sumi of the known parts. This discrepancy may possibly be due to the presence of cocarcinogcns in tobacco smoke,, and;!or damage to mucus production and ciliary transport mechanism (Chapter 6, p. 61, Chapter 9; p. 144! and Chap- ter 10,, pp, 267-269). There is abundant evidence that cancer of the skin can be induced in man by industrial exposure to soots, coal tar, pitch, and'mineral oils. All of these 33 lo:
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contain various polycyclic aromatic hydrocarbons proven to~be carcinogenic in many species of animals. Some of these hydrocarbons are also~ present in tobacco smoke. It is reasonable to assume that these can be carcinogenic for mamalso (Chapter 9, pp. 146-148') . Genetic factors play a: significant role in the development of pulmonary adenomas ini mice. It is possiblc that genetic factors can influence the smok- ing habit and the response in man to carcinogens ini smoke. However, there is no evidence that they have played an appreciable role in the great increase of lung cancer in man since the beginning of this century (Chapter 9, p. 190). Components of the gas phase of cigarette smoke have been showni to pro- duce various undesirable effects on test animals or organs. One of these effects is suppression of ciliary transport activity, an important cleansing function in the trachea and bronchi (Chapter 6, p. 611 and Chapter 10, pp. 267-270). CHARACTERIZATION OF THE TOBACCO HABIT The: habitual use of tobacco is related primarily^ to psychological and social drives, reinforced and perpetuated by the pharmacological actions of nicotine on the central nervous system. Nicotine-free tobacco or other plant materials do not satisfy the needs of those who acquire the tobacco habit (Chapter 13i p. 354) . The tobacco habit should be characterized' as an habituation rather than~ ani ad'diction. Discontinuation of smoking, although possessing the difficul- ties attendant upon extinction ofany conditioned reflex, is accomplished best by reinforcing, factors which interrupt! the psychogenic drives: Nicotinee substitutes or supplementary medications have not been, proven to be of majpr benefit in breaking the habit (Chapter 13„p. 354). PATHOLOGY AND MORPHOL,OGY Several types of epithellal changes are much more eommoni in, the trachea and bronchi of cigarette smokers, with or without lung cancer, than of non- smokers and of patients without lung cancer. These epithelial changes are (a) loss of cilia, (b), basal cell hyperplasia, and (c) appearance of atypical cells with irregular hyperchromatic nucleiL The degree of each of the epithelial changes in general' increases with the number of cigarettes smoked. Extensive atypical changes have been seen most frequently in menwhosmoked, two or more packs of cigarettes a day. Women cigarette smokers, in general, have the same epithelial changes as men smokers. However, at given levels of cigarette use, women appear to, show fewer atypical cells than do men. Older men smokershavsmore:atypicalcells than younger men smokers. Men; who smoke either pipes or cigars have more epithelial changes than non-smokers, but have fewer changes than cigarette smokers consuming approximately the same amount, of' tobacco. Male ex-cigarette smokers have less hyperplasia and fewer atypical cells than current cigarette smokers. It may be concluded, on the basis of human and experimental evidence, that some of the advanced epitheliall hyperplastic ]ksions withi many atypical 34 i
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I cel.ls, as seen in the bronchi of cigarette smokers, are probably premalignant (Chapter 9,,pp.167-173 ) . T yping o f Tumors.-Squamous and oval-cell carcinomas (Group I of Kreyberg's classification) i comprise the predominant types associated with the increase of lung cancer in the male population. I'n several st'udies, adenocarcinomas (Group fI)have also shown, a definite increase, although to a much lesser degree. The histological typing of lung cancer is reliable, but the use of the ratio of histologicali types as an index of the magnitude ofl increase in lung cancer is of' limited value (Chapter 9, pp. 173-175). Functional and Pathological Ch.angvs.-Cigarette smoke produces signif- icant funtional alterations in the trachea, bronchus, and lung. Like several other agents, cigarette smoke can~ reduce or abolish ciliaryy motility in experi- mental animals. Postmortem examination of bronchi from smokers showss a decrease in the number of ciliated cells, shortening of the remaining cilia,, and changes ini goblet cells and mucous glands. The implication of these morphological observations is that functional impairment would result. In animal experiments, cigarette smoke appears to affect the physical characteristics of the lung-lining layer and to impair alveolar (air sac) stability. Alveolar phagocytes ingest tobacco smoke components and assist in their removal from the lung. This phagocytic elearance mechanism breaks down under the stress of protracted hi~h-level exposure to cigarette smoke, and smoke components accumulate in the lungs of experimental animals (Chapter 10, pp. 269-2 70) . The chronic effects of cigarette smoking upon pulmonary function aree manifested mainly by a reduction in- ventilatory function~ as measured by the forcedlexpiratory volume (Chapt'er 10, pp. 289-292 ). Histopathological alterations occur as a result of tobacco: smoke exposure in the tracheobronchiall tree and in the lung par~enchyma of man. Changes regularly found in chronic bronchitis-increase in the number of goblet cells, and' hypertrophy and hvperplasia of bronchial' mucous glands-are more, often present in, the bronchi ofl smokers than non-smokers. Cigarette smoke produces significant functional alterations in the upper and lower airways to the lungs. Such alterations could he expected to interfere with the cleansing mechanisms of the lung. Pathologieali changes in pulmonary parenchyma, such as rupture of alveolar septa (partitionsofl the: air sacs)~ and fibrosis, have a remarkably cl'ose association with past history of cigarette smoking. These latter changes cannot be related! with certainty to emphysema or other recognized diseases at the present time (Chapter 10, pp. 270-275) . MORTALITY The death rate for, smokers of cigarettes only, who were smoking at the time of entry into the particular prospective study. is about 70 percent higher than that for non-smokers. The death rates increase with the amount smoked.. For groups of inen smoking less than 10, 10-19, 20-39, and 40 cigarettes and over per day, respectively, the deathi rates are about 40 percent, 70 per- 35
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cent, 901percent„ and 120percent higher than for non-smokers. The ratio of the death rates of smokers to non-smokers is highest at the earlier ages (40- 50) represented1n these studies, and declines with increasing age. The same?-7 effect appears to hold for the ratio of the death rate of heavy smokers to that ~ of light smokers. In the studies that provided this information, the mortality ". ratio of cigarette smokers to non-smokers was substantially higher for men~~ who started to smoke under age 20 than for men who started after age 25. ~ The mortality ratio was increased as the number of'~ years of smoking, in- ~ creased. In two studies which recorded the degree of inhalation, the mor- tality ratio fbr al given amount of smoking, was greater for inhalers than for t' non-inhalers. Cigarette smokers who had stopped smoking prior to enrolb ment in the study had mortality ratios abouti 1.4 as against 1.7 for current cigarette smokers: The mortality ratio of ex-cigarette smokers increased with the number of years of smoking and was higher for those who stopped after age 55 than~for those who stopped at an earlier age (Chapter 8, p. 93). , The biases from non-response and from errors of measurement that are difficult to avoid in mass studies may have resulted in some over-estimation of the true mortality ratios for the complete populations. In our judgment„ however, such biases can account for only a part of the elevation in mortality ratios found for cigarette smokers (Chapter 8, p. 96). Death rates of cigar smokers are about the same as those of non-smokers for men smoking less tham five cigars daily. For men smoking five or more cigars daily, death rates were slightly higher (9 percent to 27 percent)' than for non-smokers in the four studies that gave this information. There is some indication that this higher deat4 rnate occurs primarily in meni who have been smoking for more than 30 years and in men who stated that they inhaled the smoke to some degree: Death rates for current pipe smokers were little if'~ at all higher than for non-smokers, eveni with men smoking 10 or more pipefuls per day and with meni who had smoked pipes for more than 30 years. Ex- cigar and ex-pipe smokers, on the other hand, showed higher death rates than both non~smokers, and current pipe or cigar smokers, in four out of five studies (Chapter 8, p. 94). The explanation is not clear but may be that a substantial number of such smokers stopped because of illness: Mortality by Cause o f Deatii.-In the combined results from the seven prospective studies, the mortality ratio of cigarette smokers was particularly high for a number of diseases. There is a further group of diseases, including some of the most important chronic diseases, for which the mortality ratio for cigarette smokers lay between 1.2 an& 2.0. The explanation of the moderate elevations in mortality ratios in this large group of causes 35 not clear. Part may be due to the sources of bias previously mentioned or to some constitutional and genetic difference between cigarette smokers and' non-smokers. There is alfio the possibility that cigarette smoking has some general debilitating,effect, although no medical evidence that clearly, supports this hypothesis can be cited (Chapter 8, p. 105). Im all sevem studies, coronary artery disease is the chief contributor to the excess number of deaths of cigarette smokers over non-smokers, with~ lung cancer uniformly in second place (Chapter 8, p:108):. 36
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For cigar and pipe smokers combined, there was a suggestion of high mortality ratios for cancers of the mouth, esophagus, larynx and lung, and for stomach and duodenal ulcers. These ratios are, however„based on small numbers of deaths (Chapter 8„p.107) . CANCER BY SITE Lung Cancer Cigarette smoking, is causally related to lung cancer in men; the magnitude of the effect of cigarette smoking far outweighs all other factors. The data for women, though less extensive, point in the same direction. The risk of developing lung, cancer increases with duration of smoking and the number of cigarettes smoked per day, and is diminished byy discontinuing smoking. The risk of developing cancer of the lung for the combined group of pipe smokers, cigar smokers, and pipe and cigar smokers, is greater than for non-smokers, but much less than for cigarette smokers. The data are insufficient to warrant a conclusion for each group individually (Chapter 9, p. 196). Oral Cancer The causal relationship of the smoking of pipes to the develop- ment of cancer of the lip appears to be established. Although there are suggestions of relationships between cancer of other specific sites of the oral cavity and the several forms of iobacco use, their causal implications cannot at present be stated (Chapter 9, pp. 204-205). Cancer o fthe Larynx Evaluation of the evidence leads to the judgment that cigarette smoking is a significant factor in the causation of laryngeal cancer i n the male (Chapter 9, p. 212). Cancer of the Esophagus The evidence on the tobacco-esophageal cancer relationship sup- ports the belief that an association exists. However, the data are not adequate to decide whether the relationship is causal (Chapter 9, p. 218). Cancer o f the Urinary Bladder Available data suggest an association between cigarette smoking and urinary bladder cancer in the male but are not sufficient to support a judgment on the causal significance of this association (Chapter 9, p. 225). 37
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Stomach Cancer No relationship has been established between tobacco use and stomach cancer (Chapter 9, p. 229). NON'-NEOPLASTIC RESPIRATORY DISEASES, PARTICULARLY CHRONIC BRONCHITIS' AND PULMONARY' EMPHYSEMA Cigarette smoking is the most important of the causes of chronic bronchitis in the United States, and increases the risk of dying from chronic bronchitis. A relationship exists between pulmonaryy emphysema and cig- arette smoking but it has not been established that the relationship is causal. The smoking of cigarettes is associated with an increased risk of dying froni pulmonary emphysema. For the bulk of the population of the United States, the impor- tance of cigarette smoking as a cause of chronic bronchopulmonary disease is much greater than that of atmospheric pollution or occupational exposures. Cough, sputum production, or the two combined are consistently more frequent among cigarette smokers than among non-smokers. Cigarette smoking is associated with a reduction in ventilatory function. Among, males, cigarette smokers have a greater preva- lence of breathlessness than non-smokers. Cigarette smoking does not appear to cause asthma. Although death certification shows that cigarette smokers have a moderately increased risk of death from influenza and pneumonia, an association of cigarette smoking and infectious diseases is not otherwise substantiated (Chapter 10, p. 302). CARDIOVASCULAR DISEASE Smoking and nicotine adkninist'ration cause acute cardiovascular effects similar t'o~ those induced by stimulation of the autonomic nervous system, but these effects do nott account well for the observed association between cigarette smoking and coronary disease: It is est'ablished that male cigarette smokers have a higher death rate from coronary disease than non-smoking males. The association of smoking with other cardiovascular disorders is less welll established. If cigarette smoking actually caused the higher death rate from coronary disease, it would on this account be responsible for many deaths of middle-age& and elderly males in the United States. Other factors such as high blood pressure, high serum eholesterol~ and excessive obesity are also known to be associated with an unusually high death rate from coronary disease. The causative role of these factors in coronary disease, though not proven, is suspected' stYongly enough to be a major reason for taking countermeasures against'~ them. It is al5o more prudent to assume that the established association bet«-een cigarette smoking and coro- 38
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nary disease has causative meaning than to suspend judgment until no un- certainty remains (Chapter 11, p. 327). Male cigarette smokers have a higher death rate from coronary arteryy disease than non-smoking males, but it is not clear that the association has causal significance. OTHER CONDITIONS Peptic Ulcer Epidemiological studies indicate an association between cigarette smoking and peptic ulcer which is greater for gastric than for duodenal ulcer (Chapter 12,p. 340). Tobacco Amblyopia Tobacco amblyopia (dimness of vision unexplained by an or- ganic lesion) has been related to pipe and cigar smoking by clini- cal impressions. The association has not been substantiated by epidemiological or experimental studies (Chapter 12, p. 342). [ Cirrliosis o f the Liver 4 Increased mortalitv of smokers from cirrhosis of the liver hass been shown in the prospective studies. The data are not sufficient to support a direct or causal association (Chapter 12, p. 342). Maternal Smoking and In. f ant Birth Weight Women who smoke cigarettes during pregnancy tend to have babies of lower birth weight. Information is lacking on the mechanism by which this decrease in birth weight is produced. It is not known whether this decrease in birth weight has an}- influence on the biological fitness of the newborn (Chapter 12, p. 343). Smoking and Accidents Smoking is associated with accidental deaths from fires in thee home. No conclusive information is available on the effects of smoking on traffic accidents (Chapter 12, p. 345). MORPHOLOGICAL CONSTITUTION OF SIVLOKERS The available evidence suggests the existence of some morpholog - M ical differences between smokers and non-smokers, but is too meagerYo permif a conclusion (Chapter 15, p. 387). 39 IN
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PSYCHO-SOCIAL ASPECTS OF SMOKING A clear cut smoker's personality has not emerged from the results so far published. While smokers differ from non-smokers in a variety of charac+ teristics, none of the studies has shown a single variable whi&is found solely in one group and is completelyy absent in another. Nor has any single varia- ble been verified in~ a sufficiently large proportion of smokers and' in suffi- ciently few non-smokers to consider it an "essential" aspect of smoking, The overwhelming evidence points to the conclusion that smok- ing-its beginning, habituation, and occasional discontinuation-is to a large extent psychologically and socially determined. This does not rule out physiological factors, especially in respect to habituation, nor the existence of predisposing constitutional or hereditary factors (Chapter 14, p. 377 ). 40 i
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PART II Evidence of the Relation Between Smoking and Health ~.#..
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03'765619
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List of Tables Page TABLE 1. Tobacco products: Consumption per capita, 15 years and over, United States, 1900-1962 ...... . 45 TABLE 2. Filter tip cigarettes: estimated output and percentage distribution . . . . . . . . . . . . . . . . . . 46 44 uk~ .: 4~' -.-__ :.
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Chapter 5 CONSUMPTION OFTOBACCO PRODUCTS IN THE UNITED STATES The U.S. Department of Agriculture estimates that~ the total number of persons ini the United States, including overseas members of the Armed Forces, who consume tobacco on a regular basis is close to 70 million (11). Consumption of! tobacco prod'ucts per capita, 15 years and over, has risen from 7.42 pounds in 1900 to 10.85 pounds in 1962. Cigarette consumption increased steadily from 1910. when the per capita consumption was 138 cigarettes, to the 1962 figure of 3,958. Per capita cigar consumption re- mained steady at slightlv over 100 in the first two d'ecades of the century, but started to decrease in 1921. The figure for 1920 is 1117, and for 1962 it is 55. Per capita consumptionof'pipe tobacco remained steady until'the mid-1!940's. In 1945 the figure was 1.59 pound's, but in 1962 it was just over half a pound (0S6)i. Consumption of chewing tobacco showed a de- cline during about the same period, from 1.09 pounds per, capita in 1945 to 0.50 ini 1962. Consumption ofl snuff has showni very little change (2) (Table 1). TABLE 1-Consumption of tobacco produets per person aged 15 years and over in the UhitedStates for selected years,,1900-1'962 1" •eu I All tobacco, ' Cigarettes, pounds number Cigars, ~ nu nbc•r Ripetohacoo, pounds Che~ing tobaccu; pounds Snue, pounds LLNbI-------------- 7.42 49 111 1.63 4.10 0.32 L910!--------- ----- 8.59'~ 138'. 113 2.58 3199. .50 L920j _-------__ 8, 66 '. 611 117 1.96 3:06 .50 1930, ---_----------. 8.88I I 1,365 72 1.87 1.90 .46 L940--------------- 8.91 1,828 56.1 2.05 1.00 .38 1950 - _------------ 11. 59 , 3,322 50. .94 .78 i .36 1960--------------- 10.97 3,.888 57. .59 ' .51 .29 1961-- ------------ 11.15 3,986 56. .59 .51 .27 Lt62--------------- 10.85 3,958 i 55 .56 .50 .26 Struroe: Department.of,Agriculture;Economic Research Service. Starting in 1950, production of filter tip cigarettes began t'o, rise. Un« official estimates for 1950 show that only about half of one percent of! ciga- rettes produced were filter tip. In 1952, unofHcisli estimates show 1.3 per- cent of cigarettes produced were filter tips. In 1956 the figure had! reached 27.6 percentL From 1959 on, official estimates, based on figures reported to the Department of Agriculture by the industry, show a continuous in- crease from 45.3 percent filter tip cigarettes produced ini 1958'to 54.6 percent produeedl in1962(3)(;Table 2)1.
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TAU[.E2.-Estinlatedoutput offiIter-tip cigarettes and percentage of total cigarette production, United, States, 1950-1962' 1-ear Filter cigare (billio ,tip, ttes ns) Percent of totall Year Filtff cigare (billio -tip trtes ns) PercenV of total 1950------------------ 2.2 0. 6 ~1957------------------ 16h13 38.0 1951i------------------ 3.0. 0:7 1958'----------------- 213. 0 46,3' 1952`----------------- 5.6 1.3 1959------------------ 238.8 4R:7 1953'---------- -------- 12: 4 2.9 1960.------------------ 25t3. 0 50:9 195t! 36. 9' 9.2 191i1--- ------ -- 277, 1 52.5 ----------------- 195 i- ---------------- 77. 0 18:7 ----- -- 19i;2-' ---------------- 292.5 54. 6' 193~6----------------- 116.9 27.6 'Data [ron11195'Sthrough 1962 are official estimates from Censusof3Yansifaeherera- Source: U.S:,Departmentof Agriculture; Economic Research Service: REFERENCES 1. U.S. Department of'~ Agriculture. Special report to the Surgeon General's Adt°isory, Committee on Smoking and Health. 2. UIS. Department of Agriculture. Economic Research Service. Tobaccoo products. Conbumption per capita. 115 y-ears and over, United States, 1900=62. 3. U.S. Departnlent' ufAgriculture. Economic Research~ Service. Thetobacco sit~uation.March 1962, .lkirch 1963, September11963. 4.6
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Chapter 6 Chemical and Physical Characteristics of 'I'obacco and Tobacco Smoke 714-422 0-64-5
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Contents' Page CHEMISTRY OF' TOBACCO . . . . . . . . . . . . . . . 49 COMPOSITION OF CIGARETTE SMOKE . . . . . . . . COMPOUNDS OF THE PARTICULATE PHASE OTHER THAN HIGHER POLYCYCLICS . . . . . . . . . . . . Aliphatic and Alicyclic Hydrocarbons . . . . . . . . . . Terpenes and Isoprenoid! Hydrocarbon . . . . . . . . . . Alcohols and' Esters . . . . . . . . . . . . . . . . . . Sterols . . . . . . . . . . . . . . . . . . . . . . . . Aldehydes and Ketones . . . . . . . . . . . . . . . . . Acids . . . . . . . . . . . . . . . . . . . . . . . . Phenols and Polyphenols . . . . . . . . . . . . . . . . Alkaloids, Nitrogen, Bases, and Heterocyclics . . . . . . . Amino Acids . . . . . . . . . . . . . . . . . . . . . Inorganic Components . . . . . . . . . . . . . . . . . Noncarcinogenic Aromatic Hydrocarbons . . . . . . . . . CARCI\OGENIC HYDROCARBONS AND HETEROCY- CLICS IN TOBACCO SMOKE . . . . . . . . . . . . . COCARCINOGENS . . . . . . . . . . . . . . . . . . . . MECHANISM OF THE FORMATION OF CARCI\OGI-;\S. THE GAS PHASE . . . . . . . . . . . . . . . . . . . . EFFECTS ON CILIARY ACTIVITY . . . . . . . . . . . PESTICIDES AND ADDITIVES . . . . . . . . . . . . . SUMMARY . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . List of Tables' TABLE 1. Major classes of compounds in the particulate phase of cigarette smoke . . . . . . . . . . . . . . TABLE 2. Carcinogenic polycyclic compaunds isolated from cigarette smoke . . . . . . . . . . . . . . . . TABLE 3. Polycyclic hydrocarbons isolated from tobacco smoke . . . . . . . . . . . . . . . . . . . . TABLE 4. Some gases found in cigarette smoke .... ... 48 50 55 58 59 60 61 61 62 63 51 56 58 60
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Chapter 6 Tobacco is an herb which man has smoked for over 300 years. The plant was given the generic name Nicotiana after Jean Nicot, French ambas- sador to Portugal, who~ in 1560 publicly extolled the virtue of t'obacco as a curative agent. The species Nicotiana tabacum is now the chief source of smoking tobacco and is the only species cultivated in the United States. CHEMISTRY OF TOBACCO The tobacco leaf contains a complex mixture of chemical components: cellulosic prodUcts, starches, proteins,, sugars. alkaloid5, pectic substances, hydrocarbons, phenols;, fatty acids; isoprenoids, sterols, and' inorganic min~ erals. Many of the several hundred components isolated have been found to occur also in other plants. Two groups of components are specific to tobacco and have not as yet been isolated from other natural sources. One inclndess the alkalbid nicotine and the related companion substances nornicotine, myosmine, and anabasine. These nitrogen-containing substances are all ;V CHa N H Nicotine /\ I H Nornicotine Myosmine Anabasine basic and hence extYactable with acid. Seven members of a second group of compounds fairly distinctive to tobacco have been isolated and charac- terized (1962-63):byD. L. Roberts and R. L. Rowland(i36). They are de- scribed as isoprenoids, since the structures are divisiblb into units of isoprene, the building principle of rubber, ofl the red pigment of the tomato, and of the yellbw pigment of! the carrot, as illustrated in the f'ollowing formulas: HaC~ C /CHa C"'C/C 1 HaC CElia C~r~~C'i C\('i C~~C .17 OH I I C C/C-"C,C C/C ~ C Isoprenoidltobacco component 4 Isoprene unit's Althoueh none of the 7 isoprenoid' components of tobacco has been isolated from another source, the hydrocarboni cernbrene from a pine exudate has the same ll4-membered ring with the same complement of an isopropyll group at Cl and methyl groups at G, Ce, and C=, (9). 49
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COMPOSITION OF CIGARETTE SMOKE Cigarette smoke is an heterogeneous mixture of gases, uncondensed vapors, and liquid particulate matter (32) 1. As it, enters the mouth the: smoke is a concentrated aerosol with millions or billions of particles per cubic centimeter (25, 30). The median size of' the particles is about 0.5 micron (1). For purposes of investigating, chemical composition and biolbgical properties, smoke is separated into a particulate phase and a gas phase, and the gas phase is frequently subdivided into materials which condense at liquid-air tempera- ture and those which do not. The large quantities of material required for investigation of the chemical components are prepared on smoking machines (25) in which large numbers, of' cigarettes are smoked simultaneously in a fashion designed to simulate average smoking habits,, and a yellbw-brown condensate known as tobacco tar is collected in traps cooled to the temperature of dry ice (-70° C.) or liquid nitrogen (-196° C.). The tar thus contains all of the particulate phase of smoke as well as condensable.component's of the gas phase. The amounti of tar from the smoke of one cigarette is between 3 and'40 mg„ the quantity varying,according to the burning and condensing conditions, the length of the cigarette, the use of a filter, porosity of! paper, content' of tobacco, weight and kind of tobacco. An important factor determining the composition of cigarette smoke is the temperature in the burning zone. While air is being drawn through the cigarette the temperature of the burning zone reaches approximately 884° C. and when~ the cigarette is burning without air being, drawn through it the temperature is approximately 835°' C. (42). The smoke generated during puffing, when air is being drawn through the cigarette, is called main«stream smoke; that generated when the cigarette is burning at rest is called side- stream smoke. At the temperatures cited extensive pyrolytic reactions occur. Some of the many constituents of tobacco are stable enough to distil un: changed, but many others suffer extensive reactions involving oxidation, dehydrogenation, cracking, rearrangement, and condensation. The large number and variety of compounds in tobacco smoke tar is reminiscent of the composition of the tar formed on carbonization of coal,,which in many cases is conducted at temperatures lower than those of a burning cigarette. It is thus not surprising that some 500:different compounds have been identified in either the particulate phase of cigarette smoke or in the:gas phase. In one study (50) regular cigarettes (70 mm. long; about 1 g. each) with- out filter tips produced 17-40 mg, of tar per cigarette. In another investiga tion (43) 174,000 regular size American, cigarettes afforded a total of 4 kg. of tar, an average of 23 mg. per cigarette. In stilllanotlier study (3!1') 34,000' 70-mm. cigarettes were smoked mechanically on a constant puff-volume typee machine with which 35-ml. puffs, each of two seconds duration, were taken at one minute intervals from eachi cigarette. Eight puffs were required t'o smoke each cigarette to an average butt length of 30 mm. The smoke wass condensed in a series of three glass traps cooled in liquid air. The conden- sate was rinsed out of the traps with ether, water, and hexane. The yield of condensate nonvolatile at, 25° C. and 25 mm. of mercury was 20.9 mg. per cigarette. 50 t i
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Proceduresfor gross separation into basic, acidic, phenolic, and neutral fractions and for further processing of these fractions vary from laboratory to laboratory. The criteria upon which identification is based also vary. The most reliable identifications are based upon an ultraviolet absorption spec- trum and,/or a fluorescence spectrum in good agreement over the entire range with that of an authentic sample and include one or more of the following: Rfl vallue observed in a paper chromatogram (41) ; order of elution from alumina; mass spectrometry. C0NNIPOIJNDS OF THE PARTICULATE' PHASE OTHER THAN HIGHER POLYCYCLICS This brief summary is based largely on the comprehensive review by. Johnstone and Pliinmer of the Medical Research Council at Ezet'er Uni- versitv, England! ( 241. It should be noted that water constitut'es 27 percent ofl the particulate phase. The major groups of compounds included are shown in Table 1. ALIPHATIC AND ALICYCLIc HYDROCARBONS rllnlost all ofl the possible hydrocarbons, C1 through, C4, saturated and unsaturated, straight-chain and branched-chaini have been reported to bee present in tobacco smoke. Intermediate, normally liquid' paraffins are pres- ent. All the CtG through Cg3 n-alkanes have been identified, as well as the Czr andCz,-C33isoparaffins. T,~BLE 1.-ll7ajor classes of compounds in the particulate phase o f cigarette smoke Class Pe p lat rcent in articu• e' phase Aciils----------------------------------- 7. 7-12 8 (,lveoroll,glgcol. alcrol ols---------------- 5. 3-8. 3 Aklehctiles anrl ketonas - -------------- 8.5 A9iphntic hydrocarhons,---------------- 4. 9 A'rom.uic h}..clror.ubons.---------------- 0i 44 I'hvnol -- - ---------------------------- 1 L 0-3. 8 Numher of compounds 25 18 21 64' 811 45 254 Toxic actibn on lung Some irritant Possible irritation Some irritant Some irritant Some carcinogenic Irritant'and possldlycocarcinogenio TERPENES AND ISOPRENOID HYDROCARBONS Isoprene;, the basic', unit of the terpenes and of higher terpenoids has been identified in cigarette smoke (i34) as have its dimers, dipentene and' 1',8-p- rnenthadiene. The triterpene squalene, consisting of six isoprene units and shown to be present in smoke (47,) is of, interest because of the possi- bility of its being cyclized to polycyclic compounds and because of its ready
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H,c CH3 CH3 CH3 CH' CH, CHa CHJ Squalene reaction with air to form hydr~operoxides (which would be destroyed! during attempted isolation)'; a hydroperoxide der~i'ved from cholcsterot has been shown to be.carcinogenic (cancer-causing)i„ at least under certain conditions of administration ( 12). Phytadfienes, products of the dehydration of the diterpene alcohol phytol, are also present ini smoke and subject to air oxida- tion to hydroperoxides. H3C Phytol ALCOHOLS AND ESTERS CHsOH A wide variety of mono- andl dihvdric alcohols, both aliphatic andl aro- matic, are present in tobacco smoke. Solanesol, a primary alcohol con- taining 9 isoprene units, has been found in both tobacco and! tobacco smoke; 20 g. of pure material was isolated from 10 lbs. of flue-cured aged tobacco. (i0.44 percent ). Grossman et al (13 ) found that pyrolysis of solhnesol at 500° C. gives isoprene, its dimer dipentene, and other terpenoid products and concluded that the alcohol is the sour~ceofl terpenoid compounds which are important factors in the flavor of tobacco smoke. 1 Ethylene glycol and g14-cerol have been found present ini smoke, but it is not clear from the literature whether they are present in smoke from un- treated tobacco or arise from addition of these humectant, substances to tobacco to improve moistness. Many common esters, such as the ethyll estersofl the Cz, C3, and C4 fatty acids, are present in smoke. Higher fatty acids are f'ound'lioth as free acids and as esters. STEROLS Stigmasterol„ /3:sitosterol, and y-sitosterol have been isolated from, to- bacco smoke. Indeed the: sterol fract'ion, is reported (,29) to constitute approximately 0:15 percent of whole, tar. The sterols are of interest as possible precursors of polycyclic aromatic hydrocarbons and because of, thee evid'ence, noted above, that sterol hydroperoxides can be carcinogenic. ALDEHYDES AND KETONES Most common aldehydes of lbw molecular weight (acetaldehyde, pro- pionaldehyde, acetone, methyl ethyl ketone, etc.) have been found present 52
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i CHv CHa. 5Q0°3, "Ilj~ Isoprene CH: H3C-"C'~"CHs HaC" I Dipentene Solanesol (major, product) H,C-*' C CHs H,C HiC HIC HSC HaG HJC CHa CHs CHa in tobacco smoke, as have such dicarbonyl compounds as glyoxal and di~ aceqL Dipalmityl ketone exemplifies ket'ones of high molecular weight isolated from tobacco smoke. Dipalmityl ketone ACIDS A large number of volatile and nonvolatile acids of 1'owmolecular weight are present in~ tobacco smoke. Fatty acids of chain length C13 t'o C,g are reported to constitute 1 percent of the whole tar and the bulk of these acids are present in the free: form 146). Unsaturated f'atty acids and keto acids (e.g., pyruvic acid ) are also present. 53
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PHENOLS AND POLYPHENOLS Since the phenols and polyphenols present in tobacco leaf play an im- portant role in the curing and smoking quality of tobacco, a great deal of investigative work has been done on the estimation, separation, and identifi- cation~ of complex tobacco phenols such as rutin and chlorogenic acid. The presence of simple phenol's in tobacco smoke was established as early as 1871. The phenol content of smoke became of increasing importance with OH HO Rutin O II' Ao"' CH = CHCO CO2H' HOi H OH Chlbrogenic acid' the demonstration that phenol and substituted' phenols can function as cocarcinogens; that is, they promote the appearance of skin tumors in mice following application of a single initiating dose of'' a known carcinogen~ (4). Furthermore, the smoke fromi one cigarette contains as much as 1 mg. of phenols (7)~. In addition to simple alky]phenols, naphthols, and the poly- phenols, resorcinol and hydroquinone are also present. ALKALOIDS, NITROGEN BASES, AND HETEROCYCLICS Pyridine, nicotine; nornicotine, and other substituted pyridine bases con- stitute some 8-15 percent of whole tar; nicotine and nornicotine constitute about 7-8 percent of the total tar. The companion bases are products of the pyrolysis of the alkaloids present in tobacco leaf. Quinoline and threee polh,cyclic heterocyclic compounds have also been identified in smoke (45)) and will be discussed later since:the three polycyclic compounds are carcino- genic. A pentacyclic compound related' to xanthene, namely 1,8,9-peri- naphthoxanthene, has been identified in smoke (45). 1,8,9-Perioaphthoxanthene AMINO ACIDS Although tobacco leaf contains a number of amino acids, relatively few have been found'present in smoke; among,these are glutamine and glutamic acid. 54 ,
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It is estimated that't the main-stream smoke from one cigarette contains about 150 µg. of metallic constituents, which are mainly potassium (90 percent ), sodium (5 percent ); and traces ofi aluminum, arsenic, calcium, and copper. Arsenic is reported' to be present to the extent of 0.3-1.4 µg. ini the smoke of one cigarette. The inorganic compounds are most likely chlorides, but metals themselves may be present. Apparently beryllium is present ini tobacco in trace quantities, but is not volatilized in the smoking process (48). Nickel is present in cigarettes in trace amount's and may occur in main-stream smoke to a small extent, probably as the chloride (31). Spectrographic analysis has shown the presence of chromium in smoke at a levell of less than 0.06 µg. per cigarette. This level appears too low to represent a hazard (48). NONCA'RCINOG'ENIC ARO1iATIC HYDROCARBONS The aromatic hydrocarbons present in tobacco smoke have received ani enormous amount of attention since some of them are carcinogenic. Noncarcinogenic hydrocarbons of smoke containing one to three rings include benzene. toluene and other alkylbenzenes, acenaphthene, acenaph- th,,lene. fluorene, anthracene, and phenanthrene. Hydrocarbons of estab- IMhed carcinogenicity to mice all containi from four to six condensed rings. Hos,ever„ no less than 27 hydrocarbons containing four or more condensed ring$ which have been t'ested for carcinogenicity with negative results have been isol'atedl from tobaacosmoke tar. As methods of! separation an& identification improve, it is almost certain that additional hydEocarbons will be foundi present in smoke, because ahnost every conceivable ring system has been demonstrated to be present and the number of possible alkylated polycr~-clics isv.ery large indeed. CARCINOGENIC HYDROCARBONS AND HETEROCYCLICS IN TOBACCO SMOKE In 1925-30 Kennaway et al. in seeking to identify the active substance in high-boiling fractions of coalltar distillates of established carcinogenicity to mice, discovered that dibenzo(a,h)anthracene(for f'ormul'a, seeTable 2 i preparedi by sN nthesis evokes skin cancer when applied to the skin of mice (11). The hvdrocarbon~ was recognized as different! from the carcino- gen of coal tar because its fluorescent spectrum did not match the character- istic three-banded spectrum of the tars. In 1933 Cook and co-workers (11) isolated the coal t'ar constittrent responsible for the characteristic fluorescence and identified iU as benzo,(a):pyrene. It is one of the most potent of all the carcinogens now knowns . ..~.::a..,_,. ~:.
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TABi.E2.---Careinogenic Polycyclic Compounds Isolated'FromC'igarette. Smoke Compound Structure Carcino- Amount reported, genicity µg/1000 cigarettes 1. Benzo(a)pyrene + + + + 16 (ave. of 10 reports) 2. Dibenzo(a,i)pyrene I I 11I +++i, 0.02-10 (2 reports) 3. Dibenzo(a,h)anthracene I 1I 11 1 ++ 4 (1 report)', 4. Benzo(p)phenanthrene ~ ~ + not stated .5. Dibenz(a,j)acridine + 2.7 (,1 report)', l 6. Dibenz(a,h)acridine 7. 7H-Dihenzo(a;g)carbazole 56 + 0.1 (1 report) + 0.7 (1 report), 1
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Since the discovery of carcinogenic hydrocarbons, a large number of polycyclic hydrocarbons and heterocyclic analogs have been~ tested for car- cinogenicity to mice and''to rats in many laboratories, both by application to the skin and by subcutaneous injection. Bioassays in different labora- tories, often on independently prepared samples, are remarkably consistent! and place a series ofi hydrocarbons in the same relative order of potency. A compilation (and its supplement) prepared by J. L. Hartwell (16)~ of the National Cancer Institute lists 2108' compounda of which 481 were reported to cause malignant tumors in animals. All but! one of the polycyclic hydro- carbons listed in Table 2 as having been idontified in tobacco smoke have already been documentedl in the Hartwell report and can be assigned a rating as very potent ( + . + + ) , potent ( -i- + + )~, moderately carcino- genic (+-f- ), or weakly carcinogenic ( i-- ) i( 31) . Many other such com- pounds studied are reported ini the Hartwell survey and in another by :A-rthur D. Little, Inc. (131). The rating assigned to dibenzo (ia,i) pyrene is based oni experiments with over 10,000 inbred mice in which one subcutaneous injection in the groin of 0.5 mg. of hydiocarbon in tricaprylin produced 50 percent sarcomas at the injection site in 14 weeks and 98 percent tumors in 24 weeks (20). Benzo(ia)pyrene is one of the two most potent of' the seven carcinogens detected in tobacco smoke and it is present in much larger quantity than any of the other carcinogens listed. Two polycyclic hydro• carbons isolated from tobacco smoke but not yet adequately tested for caroinogenieity, are: benzo(j)fluoranthene and dibenzo~(a,1)pyrene. Identification of benzo(a)pyrene is reported in 19 separate investiga- tions; the amount giveni in the table per 1000 cigarettes (170! mm. long, weighing about 11.0 g, eac4 is the average of 10 values selected on the basis of the quality, of criteria: used' for identification (31). Compounds 1, 2, 3, 4, and benzo ( j) fluoranthene were identified in one laboratory over a period of years and' are listed together in a review by Van Duuren (44) . Isolation of the. three heterocyclic carcinogens (5,6,7) is reported by Van~ Duuren (45). Because of losses in, the process of fractionation and purification, the amount of carcinogens reported in a given investigation may be less than the amount actuadly present. Wynder and' Hoffman~ (50) investigated this point by adding a know n amount of radioactive Cl}-labelled benzo (a) pyrene to a smoke condensate and applied the usual procedtire for isolation of benzo ( a) pyrene, which involved, in the last stages, chromatographing twice on silica gel and four times on paper. The activity of the benzo (ia) pyrene finally isolated indicated a loss of 35-40 percent of carcinogen during proc- essing, The amount of benzo(a)pyrene given in Table 2 thus should be multiplied by a factor of' 1.5 to give the estimated true amount. Probably the amounts of tlie:other carcinogens in smoke are also at' least 1.5 times the reported amounts. Relatively littlie work has been done on the components of smoke produced with cigars and pipes. Table 3 summarizing a comparative study made in one laboratory (5) indicates that the amount of benzo(a)pyrene„ the only carcinogen in the group studied, increases sharply from cigarettes to cigars to pipes.
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TABLE 3.-Polycyclic hydrocarbons isolated from tobacco smoke (µg. per 1000 g. of tobaea» consumed] Hydrocarbon Cigarett es Cigars Pipes ~ ----- Benzo(a)DSrene ---------------------------------------------- 9 34 85~ AeenaPhttiylene---------------------------------------------- 50 16 291 Anthracene------- ------------------------------------------- 109 119 1,100 Pyrene------------------------------------------------------- 125' 176 755 COCARCINOGENS Assays of'tobacco smoke tars for carcinogenicity are done by applying, a dilute solutiom of tar in an organic solvent with a camel's hair brush to the backs of mice beginning when the animals are about'six weeks old. Appliea- tion is repeated three times a week for a period of'~ a year or more. The results of a number of such assays present a puzzling anomaly: the t'otal tar from cigaretrtes has about 40 times the carcinogenic potency of the benzo(a)'pyrene present in the tar. The other carcinogens known to be present in, tobacco smoke are, with the exception of' dibenzo(a,i) pyrene, much less potent than benzo(a)pyrene and: they are present in smaller amounts. Apparently, there• fore,, the whole is greater than the sum of the known parts (27, 33, 49). One possible or partial explanation of the discrepancy is that the tar con- tains compounds which, although not themselves carcinogenic, can enhance the cancer-producing properties of the carcinogens. Berenblum and Shubik (3)'„reporting on cocarcinogenesis, described'the potentiating effect of erot'on oil, which itself is noncarcinogenic except in certain strains of mice (4a), on the action of hyd'rocarbon carcinogens. Phenol is reported to have a similar potentiating effect (4, 50) and, as noted above, cigarette smoke contains considerable phenolic material. Long-chain fatty acid esters (39) and free fatty acids (19) have been shown to function as cocarcinogens, and sub- stances of both types occur abundantly in tobacco smoke. It is possible that the potentiating action of croton oil is due to the presence of fatty acids and their esters. A further observation of possible importance is that some poly, cyclic hydrocarbons, though very weak or inactive as carcinogens; are capable of initiating malignant growth under the influence of a promoter. Thus henz(a)ianthracene, identified'in cigarette smoke, is very weak or inactive in initiating malignant' growth by itself, but initiates carcinogenesis under the influence of croton oil as promoter (15). If more were known about the possible cocarcinogenicity of the many inactive components of tobacco smoke, some of the apparent discrepancy between isolation and bioassay data might disappear. It is possible that some of the carcinogenicity of smoke is due to hydroperoxides forme& from un- sat'urated smoke components and destroyed in the isolation procedures. Furthermore both~ sets of data are far from precise; for example, one esti- mate of the amount of the highly potent dibenzo('a,i)'p~~-rene per 1000 cigarettes (Table 2) is 0.02µg. and another is 10pg. However: it is not necessary to wait for an exact balance of the two sets of data to draw a conclusiom from eachL The isolation, experiments, taken 58
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alone, indicate that cigarette smoke contains a number of identified chemicals which are carcinogenic to mice. The bioassays suggest that cigarette smoke probably contains components which, acting in a manner as yet undescribed, are involved in the induction of tumors in mice. Assessment of all conceivable synergistic effects presents a gigantic problem for exploration. Tobacco smoke contains considerable amounts of phenols and fattry acids, bo& of which, as previously mentioned, enhance the activity of known carcinogens: Cellulose acetate filters now in use remove 70-806 percent of acidic constituents of tobacco smoke. MECHANISM OPTHE FORMATION OF' CARCINOGENS Most of the carcinogenic compounds identified in cigarette smoke tar are not present in the native tobacco leaf but are formed by pyrolysis at the high burning temperature of cigarettes. Van Duuren (44) reports formation of benzo(a)pyrene and pyrene on pyrolysis of stigmasterol, a smoke com- CHaCHi Stigmaeterol Benzo(a)pyrene -F Pyrene ponent. Similar pyrolysis of pyridine or of nicotine gives dibenzo (!a,j ) acridine and dibenzo(a,h)acridine, both of which are carcinogenic: (Table 2)~. Pyrolysis of nontobacco cigarettes made from vegetable fibers and spinach resulted in formation of benzo(a)pyrene (50):. Hurd and co-workers (22) by careful experimentation have elaborated plausible mechanisms for the formation of polycyclic aromatics by pyrolysis of materials of lbw molecular weight at temperatures in the range 800-900° C: Posttilated radical intermediates are: (a) CHs=C=CH •*1 CHs-C-=CH (b) CH-CH=CH s-~ CH=CH--CH (c) CH=CH-CH=CH These radicals can arise from propylene, toluene, picoline, or pyridine. A variety of polycyclic hydrocarbons can be generated by reaction of these radicals with themselves or with other small' radicals present in the heating zone. For example„dimerization of (b) should give benzene. 59
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I It thus appears that the pyrolysis of many organic materials can lead to the formation of components carcinogenic to mice. Cigarette paper con- sists essentially of cellulose. Pyrolysis of cellulose has been shown to produce benzti(a) pyrene. The: observation (2)that treatment of tobacco with copper nitrate decreases the benzo (la) pyrene content of the cigarette smoke suggests a possibility for improvement by the use of additives or catalysts. The fact that side-stream smoke contains three times more benzo(a)pyrene. than, main-stream smoke has been cited (50) as evidence that more efficient oxidation could conceivably lower the content of carcinogenic hydrocarbons. THE GAS PHASE The gas phase accounts for 60 percent of total cigarette smoke. Hobbs et aL (34, 35Y found that 98.9 mole percent of the: gas phase is made up of the following seven~ components: N1t'rogen----------------------------- 73 mole percent OxygeR------------------------------ 10 Carbon~dioxide----------------------- 9:5 Carbon-monoxide--------------------- 4:2' Wdrogen---------------------------- 1. Argon------------------------------. 0i6 Methane----------------------------- 0.6. 98.9 The approximately one percent of the gas phase not accounted for by the. seven major constituents contains numerous -compounds, no less than 43 of which have been identified as present ini trace amounts. Some of these are listed in Table 4 (1). TABLE 4. Some gases found in cigarette smoke Compound Carbon Monoxifle--------- _____________ Carbon Dioxide __.____________________ Methane, ethane;,propane,~butane~, etc. A'cetM1lene, ethydene; propylene, etc_____ Formaldrhyde:_________________________ Acetalt3e}lyde--------------------------- Acroleini ------------------------------ Methanol - ----------------------------- Acetmie . - - - - - - - ______- - __________ - Mcthyl ethy~iiketone____________________ Ammonia - ---------------------------- Nitto~en.l)iokide_______________________ 11eth}rl Nitnte __ _ _______ r[cdtogen 8ulfele ______________________ Hy tiogen Cy-anide_____________________ Methy] Chloridc-__-____________________ Concentra- tion (PPm). 42, 000 92,000 87,000 31,000 30 3,200 150 ' 700 ; 1,100 1 500 1 300 250 2~ 40 1,600 1:,200 Sate level for induxtrial I expasure' (PPrn) i 100 -------~--- Toxic action on IunK Unknown \mie None None Itritant~ Irritant IrritanU Irritant Irritant Irritant. Irritant Irr it ant Uhknowni Irritant Rl,spiratory enzyme pocson, Uilknowni 'Thevalues,listed refer.to time-weiqbted average concentrations forr a normal work day. 60 .,..^,- :.
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® 9 EFFECTS ON CILIARY ACTIVITY* An important line of investigation was opened up by the report by Hilding (18) that cigarette smoke is capable of inhibiting the transport activity of ciliated cells such as found in the respiratorytract, It has been suggestedl (10; 17) that failure of ciliary function to provide a constantly moving stream of mucus enables environmental carcinogens to reach the epithelial cells. Kensler and Battista (28) describe development of a method of bioassay for inhibition of ciliary transport activity involving, exposure of the trachea of a rabbit to the test! material. The smoke from a regular cigarette was found to inhibit transport activity by 50 percent after exposure to two or three puffs. Several commercial filter cigarettes gave essentially the same result. The fact that these filters lower the phenol content by 70 to 80'percent and trap about 40~percent of the particulate phase suggested that neither phenolic nor particulate materials are responsible for the inhibi, tion noted. The next trial was with an absolute filter, that is,, one which removes the: entire partSculhte phase and gives nonvisible gas. The obser- vation that such treatment did not significantly alter the inhibitory effect of the puff established that components of the gas phase are responsible for inhibitron~ of ciliary transport activity. Assays ofl known components of the gas phase showed the following compounds to possess such activity: hydFogerc cyanide, formaldehyde. acetaldehyde, acrolein, an& ammonia, al- though no one of these occurs at levels high~ enough to produce the effect noted for smoke. Activated carbons differ markedly in their adsorption characteristics. Carbon filters previously employed in~ cigarettes do not have the specific power to scrub the gas phase. It has been reported that a filter containing special carbon granules removes gaseous constituents which depress ciliary activity (28). PESTICIDES AND ADDITIVES Before 1930 practically the only insecticides used in the growing of to- bacco were lead arsenate and paris green (the mixed acetate-arsenite salt of copper). Analysis of 6 brands of American cigarettes purchased in 11933 showed a range of 7.5-26A parts of As_0,3 per million, wit'h an average value of 13:9' ppm. (6). Coghill and Hobbs (8) found that main-stream smoke per of cigarettes containing 7.1 µg. of arsenic per cigarette contains0:031 ugr puff. This amount would be equivalent to.0.25 µg, of arsenic per cigarette (8 puffs), and hence a smoker consuming 2.5 packs of such cigarettes per day might inhale 12:5 µg. of arsenic per day. By comparison, analysis of the atmosphere of New York City over a 12-year period indicated an~ average contea ofl 100-400µg0 of arsenic per 10 cubic meters, which isan~ approxi- mate daily intake per person (38). Extensive Federal'efforts to discourage the use of arsenicals for the control of tobacco hornworms on the growing tobaeco~ crop resulted! in a sharp de- *Thiss topic is dlscussed morefully, in Chapter 10.. 61 I
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cline: in the arsenic content of cigarettes after 1950. Thus, the average arsenic content of 17 brands of cigarettes analyzed in 1958 was 6.2 ppm. of As20, (14). It seems unlikely that the amount of arsenic derived even f'rom unfiltered cigarettes is sufficient to present a health hazard. Chemicals recommended by the Department of Agriculture for the control of t'obaeco insects are: malathion, parathion„Endosulfan, DDT, TDE, endrin, dieldrin, Guthion, aldrin, heptachlor, Diazinon, Dylox, Sevin, and chlordane (42a). Trace amounts of! TDE and endrin have been ~ detected'in commercial cigarettes and cigarette smoke. Guthion and Sevin residues were detected in main-stream cigarette smoke at level§ approximating 013 percent and 1 percent of that added to cigarettes prior to smoking. Tobacco treated with Guthion and Sevin at the recommended levels showed' no measurable con- tamination of main-stream cigarette smoke (4b). (For discussion of car- cinogenicity of tobacco pesticides, see Chapter 9.) Cigarette manufacture in the United States includes use of additives such as sugars, humectants, synthetic flavors, licorice, menthol~ vanillin, and'rrum. Gl'yceroli and methylglycerol are looked on with disfavor as humectants be- cause on pyrolysis they yield the irritants acrolein and methylyglyoxal. Additives have not'been usedlin the manufacture of domestic~British cicarettessinee the Customs and Excise Act, of 11952, Clause 1176, and probably longer,, inasmuch as Section 5 of the Tobacco Act, ofl 1842' imposed a widespread prohibition on, the use of additives in tobacco manufacture. SUMMARY Of the several hundred compounds isolated from the tobaeco, leaf, two groups are specific to tobacco. One of these groups includes the alkaloid nicotine and related substances. The other includes compounds: described as isoprenoids. Cigarette smoke is an heterogeneous mixture of gases, uncon- densed vapors„and particulate matter. In investigating chemical composition and biologieal'properties, it is necessaryto deal separately with the particulatee phase and gas phase of smoke. Components of the particulate phase other tham the higher polycyclics include aliphatic and alicyclic hydrocarbons,,terpenes and isoprenoid hydro- carbons, alcohols and esters, sterols; aldehydes and ketones, acids, phenols and' polyphenols, alkaloids, nitrogen bases, heterocyclics, amino acids, and inorganic chemicals such as arsenic, potassium, and some metals. Sevem polycyclic compounds isolated from cigarette smoke have been established to be carcinogenic. They are shown in Table 2. The over-all carcinogenic potency of tobacco tar is many times the effect which can be attributed to subst'ancesisolat'ed from it. The difference may be associated! in part with the presence in tobacco smoke of cocarcinogens, several of which have been identified as smoke components. Components of the gas phase of cigarette smoke have, been shown to pro- duce various undesirable effects on test animals or organs, one of which is suppression of ciliary transport activity in trachea and bronchi. 62
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REFERENCES 1. Albert, R. E., Nelsonj N. SpecialI report to the Surgeon General's Ad- visory Committee on Smoking and Health. 2. Alvord, E. T., Cardon, S. Z. The inhibitiomof formation of 3,4-benzpy- rene. Brit J Cancer 10: 498-506, 1956. 3. Berenblum„ L„ Shubik, P. The role of croton oil applications, associated withi a: single painting of a carcinogen, in tumour induction of the mouse skin. Brit J Cancer 1: 379-82„ 1947. -1. Boutwell, R., Bosch, D. K. The tumor-promoting action of! phenol, and related compounds for mouse skin, Cancer Res 19: 413-24, 1959. 4a. Boutwell, R.,, Bosch, D. K., and Rusch, H. P. On the role of croton oil in tumor formation. Cancer, Res 17: 71, 1957. 4b. Bowery, T. G., Guthrie, F. E. Determination of insecticide residues on green and! flue-cured tobacco and in main-streami cigarette smoke. Agriculture and' Food Chem 9(3) : 193-7, 1961. 5. Campbell, J. M.,, Lindsey, A. J. Polycyclic hydrocarbons in cigar smoke. Brit I Cancer 11:1192r5, 1957,. 6. Carey, F. P., Blodgett, G., Satterllee, H. S. Preparation of samples for determination of arsenic: Oxygen-bomb combustioni met'hod. Industr Eng Chem Anal Ed 6, 327-30;,193-1. 7. Clemo, G. R. Some aspects of the chemistry of cigarette smoke. Tetra- hedron 3: 168-74, 1958. 8. Cogbill, E: C., Hobbs, M. E. Transfer of metallic constituents of ciga- rets to t'he main-stream smoke. Tobacco Sci' 1: 68-73, 1957. 9. Dauben, W. G:, Thiessen, W: E.,, Resnick, P. R. Cembrene, A 14-mem- bered! ring diterpene hydrocarbont J Amer Chem Soc 84: 2015-6, 1962.. 10; Falk, H. L.,, Tremer, H. M., Kotin, P. Eflect: of cigarette smoke and its constituents on ciliated mucus-secreting epithelium. J Nat Cancer Inst 23':999-1012, 1959. 11. Fieser, L. F., Fieser, M. Topics in organic chemistry. New York, Reinhold, 1963, p. 43-56. Fieser, L. F., Greene, T. W., Bischoffs F., Lopez, G., Rupp, J. J. [Com- munication to the editor] A carcinogenic oxidation product of choles- terol. J Amer Chem Soc 77: 3928-9;,1955. 13. Grossman, J. D., Deszyck, E. J., Iked'a, R. M., Bavley; A. A study of pyrolysis of solanesol. Chem Industr 1950-1962. 14. Guthrie, F. E., McCants, C. B., Small„ H. G., Jr. Arsenic content of, commercial tobacco, 1917-1958. Tobacco Sci 3: 62-4, 1959. 15. Hadlbr, H. L, Darchun, V., Lee, K. Initiation and promotion activity ofl certain polynuclear hydrocarbons. J N'at Cancer Inst 23: 1383-7, 1959. 16. Hartwell, J. L. Survey of'~ compounds which have been tested for car- cinogenic activity. Fed'erall Security Agency, Public Health Service Pub No. 149, 1951. 583 p. 17. Hilding, A. C. On cigarette smoking, bronchial carcinoma and ciliary action. 3. Accumulation of cigarette tar upon artificially prodirced 12. 714-422 0-64-6 63. ~
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deciliated islands in, the respiratory epithelium. Ann Othol 65: 116- 30, 1956. 18. Hilding; A. C. On cigarette smoking, bronchial carcinoma and ciliary action. 2. Experimental study on the filtering actioni ofl cow's lungs, the deposition of t'ar in the bronchial tree and removaliby ciliary action. New Eng J Med 254: 1155-60; 1956. 19. Holsti, P. Tumor promotfingeffects of somelonachaim fatty acids in experimental skin carcinogenesis in the mouse. Acta Path Microbiol Scand46: 51-8, 1959. 20. Homburger, F., Tregier, A. Modifyina,fact'orsin carcinogenesis. Progr Exp Tumor Res 1: 311-28, 1960. 21. Hurd, C. D., Macon, A. R. Pyrolytic formati'on of arenes. 4'. Pyrolysis of benzene, toluene and radioactive toluene. J Amer Chem Soc 84: 4524A-6, 1962 . 22. Hurd'y C: D., Macon, A. R., Simon, J. I., Levetan, R. V. Pyrolytic forma- tion of arenes. 1. Survey of general principles and findings. J Amer ChemiSoc 84: .1509-L5, 1962. 23. Hurd! C. D., Simon, J. I. Pyrolh-tic formaYioni of arenes. 3: Pyrolysis of pyridine, picolines and methylpyrazine. J Amer Chem Soe84: 4519-24; 1962. 24. Johnstbne,, R. A. W., Plimmer, J. R. The chemical constituents of to- bacco and tobacco smoke. Chemi Rev 59: 885-936, 1959. 25. Keith, C. H., Newsome, J. R. Quantitative studies on cirarette smoke. 1. An automatic smoking machine:Tobacco 144: (113')~ 26-32. Mati~- 29, 1957. 26. Keithy C. H., Newsome, J. R. Quantitatia-e: studies on cigarette smoke. 2. The effect, of physical, variables on the weight of smoke. Tobacco 144 (14): 26-31, Apr 5, 1957. 27. Kennaway, E.,, Lindsey, A. J. Some possible exogenous factors in the causation of lungcancer. Brit '1led~ Bull 14: 124-31, 1958: 28. Kensler, C. J., Battista; S. P. Components of cigarette smoke with ciliary- depressant activity. New Eng, J Med 269: 1161-1166, 1963. 29. Kosak, A. I., Swinehart, J. S., Taber, D., Van Duuren, B. L. Stig- masterol in cigarette smoke. Science 125: 991-2, 1957.. 30. Langer, G., Fisher, N. A. Concentration and particle size of cigarette- smoke particles. AM.V Arch Ifidustr Health 13: 3 72-8; 1956. 31. Liggett & Myers Tobacco Coi Arthur D. Little, Inc. Special repor6 to the Surgeon General's Advisory Committee on Smoking and Health. 32. Lindsey„A. J. Some observations upon the chemistryy of tobacco smoke. In: James, G., Rosenthal, T., eds. Tobacco and health. Springfield,. Ill!, Thomas, 1962. Chapter 2, pi 21-32. 33. Orris, L., Van Duuren, B. L., Kosak, A. I., Nelson, N., Schmitt, F. L. The carcinogenicity for mouse skin and the aromatic hydrocarbon content of cigarette-smoke condensates. J Nat Cancer Inst 21: 557-611, 1958. 34. Osborne, J. S., Adamek, S., Hobbs, M. E. Some components of' gas phase of cigaret smoke. Anal Chem 28: 2111-5, 1956. 64
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35. Philippe, R. J., Hobbs,, M. E. Some components of the gas phase of ciaaret smoke. Anal Chem~ 28,: 2002-6, 1956. 36. Roberts, D. L., Rowland, R. L. Macrecyclic diterpenes a and B-4, 8, 13-Duvatriene -L,3-diolsfrom tobacco. JI Org, Chemi 27: 3989-95, 1962. 37. Row1'andL R. L., Rodgman, A., Schumacher, J. N., Roberts, D. L., Cook, U! . 0., W'alker, W. E. 1963~ I In press)~. 38. Satterlee,, H. S. The problem of arsenic in American cigarette tobacco. New Eng JMed 254: 11-19-5:1, 1956. 39. Setala, H. Tumor promotin=, and co-carcinogenic effects of some non- ionic lhpophilic-hydlrophillc (surface active) agents. _lcta PatL Microbiol Scand f Suppl No. 115) p. 1-93~ 11956. 40. Shubik, P., Hartwell, J. L. Supplement 1, Department of Health, Edu- cationi and Welfare, PHS PubNoI 1k19;1957. 41. Tarbell, D. S., Brooker, E. G., Vanderpooly A., Con«ay, W., Cl'aus, C. J., HalL T. J. A system for paper chromotography of 3,4-benzpyrene, some derivates and other polycyclic aromatic hydrocarbons. J Amer Chem Soc 77: 767-8, 1955. 42. Touev, G. P.. Mumpower, R. C. t1'leasurement of' the eombustion-zone temperature ofcig,arett'es. Tobacco 141: (8Y 18-22, Feb~ 22, 1957. 42a. U.S. Department of Agriculture. Insecticide recommendations of the. Entomology Research Division for the Control of Insects Attacking, Crops andlLivestock for 1963. Handbook No. 120, Agricultural Re- search Service and Federal Est'ensioni Service, 19631 43. Van Duuren, B. L. Identification of! some polynuclear aromatic hydro- carbons in cigarette smoke condensate. J Nat Cancer Inst 21: 1-16, 11958. -1=1. Van Duureny B: L. Some aspectsofl the chemistry of tobacco smoke. In: James, G., Rosenthal. T. eds. Tobacco and health. Sprin,field, I11L, Thomas, 1962. Chapter 3, p. 33-47. 45. Van Duuren, B. L. The polynuclear aromatic hydrocarbons in cig- arctte smoke condensate. 2. J\at Cancer Inst 21: 623-30, 1958'. 46. Van Duuren, B. L,. Schmitt, F. L. Ikolatfiom and identification of some components of cigarette smoke condensate. J Org Chem 2° : 473-5,. 1958. 47. Van Duuren, B. L., Schmitt', F. L. Isolation and identification of squalene f'rom~ cigarette smoke condensate. Chem Industr, 1006-7„ 1958. 48. Williams, J. F., Garmon, R. G. Beryllium in cigaret tobacco. Tobacco Sci 5: 25- 7; 1961. 49. Wynder, E. L., Fritz, L.,, Furth, N. Effect of concentration of benzopy rene in skin carcinobenesis: J Nat Cancer Inst 19': 361-70; 1957. 50. Wynder, E: L., H'offinann, D. Present status of laboratoryy studies on tobacco carcinogenesis. Acta Path .llicrobiol Scand 52: 119-32, 1961. 51. Wynder, E. L.,, Hoffman, D. A study of tobacco carcinogenesis. 7. The role of higher pol~cyclic hn drocarbons. Cancer 12: 1079-86, 1959. 65
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03765F43
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:Y'P`l.e.wi~-i.i4.~-•~_: av... a~..~'-',r4S...r--cs'~-'..l~.nr..4i.:Y-.:J
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Contents Pa~e GE\ ERAL PII AR'~i ACOLOGIC ACTION OF NICOTINE ON NERVE CELLS . . . . . . . . . . . . . . . . . . . . 69 EFFECTS O-.N THE CENTRAL NERVOUS SYSTEM ... 69 CARD IOV'ASCULAR EFFECTS . . . . . . . . . . . . . . 70' GASTROINTESTINAL EFFECTS . . . . . . . . . . . . . 71 DISTRIBUTION AND FATE . . . . . . . . . . . . . . . 71 CHRONIC TOXICITY . . . . . . . . . . . . . . . . . . 73 SUAI MARY . . . . . . . . . . . . . . . . . . . . . . . 74 REFERE\ CES . . . . . . . . . . . . . . . . . . . . . . 75 Figure FicuREL Summary diagram of routes for the metabolism of nicotine in mammals . . . . . . . . . . . . . . . . . 72 68' O W ~ C: C11
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Chapter 7 GENERAL PHARMACOLOGIC ACTION OF NICOTINE ON NERVE CELLS The pharmacology andl chronic toxicity of nicotine, in dosage comparable to the amounts that man may absorb from smoking or other use of tobacco. are pertinent to an evaluation of health hazard. The most notable action ofl nicotine involves a direct effect on sympathetic and parasympathetic ganglion cells (18~):. This~ usually occurs~ as aJransient excitation, follo« ed by depression, or even~ paralysis with effective doses. The: ganglia are rendered more sensitive to acetVlcholine initially and thus make preganglionic impulses more effective. Paralysis is associated with diminished sensitivity of'ganglia to acetylcholine and concomitant reduction in~ the intensity of postganglionic discharges. Similar effects occur at the neuromuscular junction, resulting in a curariform action in skeletal muscle with adequate doses (16). In~ the central nervous system, as in gangli'a, primary stimulation is succeeded bv depression. Furthermore, nicotine like acetylcholinediseharges epinephrine from the adrenal glands andl other chromaffini tissue (20; it also releases, antidiuretic hormone from the posterior pituitary bystimulatingthesupraopticohy.pophyseall system (3'). Nicotine also augments various reflexes by excitation of chemoreceptors in the carotid bod'y (10) . The pharmacological response of the whole organism at any one time therefore, representing as it does the algebraic sum of stimulant! and de- pressant effects resultina, from manM1- direct, reflex,, and chemical'mediaton influences on autonomic nervous transmission and excitability of virtually all or~gan systems, defies accurate description. The wide variation in smoking habits leads to everyy concei'vable pattern of fluctuating bl'ood levels of nico- tine during, the day. This suggests strongly that nieot7ne+sensitive eelk may be shifting continuously from excitation to depression. Such, activity prob- ably accounts for the unpredictable effects observed in different individual5 and in the same individual at different times. Using the classic pharma- cological approach, it is therefore virtually impossible to make reliable state- ment's regarding the effect of smoking on the many organ systerns: In order to characterize the biological effects oflnicotine iniman, it thus becomes neces- sary to place heavy reliance on, symptoms and signs derived from clinical and epidemiological studies. EFFECTS ON THE CENTRAL NERVOUS SYSTEM The action ofi nicotine on central nervous systemi functions has recently, been reviewed (20). Very litt'le of the reported, work involves human 69 l :~,.,>.v, - ~__,.. ._ . . .u.: . .,... : .,, ,..,. ~...~ .,., .... .,.
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experimentation, and most of it is with doses much larger than are asso- ciated with the act of smoking. It suffices to note here that moderate doses of nicotine elicit marked! increases in respiratory, vasomotor, and emetic activity, and still larger doses lead to tremors and convulsions, both in ani- mals and man. The amounts absorbed even in heavy smoking may, produce transient hyperpnea through carotid' and aortic arch reflexes (5). The increase in blood pressure which is commonly observed' is partly central in origin. Nausea and emesis are more pronounced' in~ the novice smoker but may occur even in~heavy smokers with excessive use of tobacco. Electro- encephalographic (EEG) studies in the intact rabbit (21): indicate that nico- tine, in doses of 0.5 to 3:0 milligrams per kilogram, produced an "arousal, reaetion"' involving, the hippocampus. In a later stage of the same reaction there appeared a discharge pattern similar to that noted in convulsions. Lesions ini the septum~ abolished the "arousall reaction," chlorpromazine and evipan abolished' the discharge patterm None of the congeners of nicotine, including lobeline, produced similar patterns. Knapp and Domino (12) found! that concentrations of nicotine ('10 to 20 µg/kg), a levell commonly reached' in man by smoking, prod'uced EEG arousal patterns in four species of animals, the rabbit, cat, dog, and monkey, after neopontine transection. These effects did not appear to be related to fluctuations in blood pressure or to catecholamine or serotonin levels. In a study of electrical activity (as measured by electroencephal'ogram) in 25 human subjects before andl after smoking one cigarette, Lambiase and Serra (15) noted an 80 percent depression~ in~ voltage and an acceleration in frequency of' the alpha rhythm which remained unchanged in form during the recordings. These alterations were more consistent in~ subjects over 35 years of age and were attributed tb carbon monoxide and nicotine resulting in cerebral anoxia and/or release of epinephrine. Hauser et al. (9), who studied the EEG'changeson cigarette smoking, in healthy young, adults, ob, tained highlyy variable: responses usually toward an increase in the dominant alpha frequency of 1 or 2 cycles per second. Some subjects showed sim- ilar changes when puffing a glass cigarette stuffed with cotton and others when puffing specially prepared nicotine-free cigarettes. They concluded that the effects noted were more likely to represent a psycho-physiologic response to the act ofl smoking than to any substances present in cigarette smoking. Bickford (1) arrived at a similar conclusion. Wide gaps of information exist in this area and it is not meaningfull to attempt inferences concerning correlations of electrical events in the central nervous system and subjective effects of smoking from the type of evidence currently available. CARDIOVASCULAR EFFECTS The cardiovascular effects of nicotine are described in Chapter lil, Cardio- vascular Diseases. 70 J
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GASTROINTESTINAL EFFECTS Most but not all experimental and clinical evidence supports the populkr view that smoking reduces appetite (6, 17 p. 27;1). This reduction has been attributed both to direct effects on gastric secretions and motility and! to reflexes arising, from local' effects on thelaste buds and mucous membraness in the mouthi The unpredictable and temporary elevation of blood sugar is probably too small to contribute significantly (17,, p. 326). Nicotine effects on the hypothalamus, comparable to the appetite reduction produeed by other stimulants like amphetamine, and psychological mechanisms may play significant roles (23). Hunger contractions are inhibited but gastric movements of digestion do not appear to be influenced signifieantly by mod'erat'e smoking, (4!). Nausea, often associated with, vomiting, is by f'ar the most common symptom related to thegastrointestinall tract. This effect probably origi- nates centrally in the medull'aryemetic chemoreceptor tTig,aer zone (14). It is now generally agreed that nicotine stimulates peristalsis but the mechanism is a complex one, probably involving local„ central and reflex actions. Schned'orf and Ivy (21)' found wide individual variation in gastro- intestinal passage: time in medicall student smokers and non-smokers but gained the impression that smoking, tends to augment motility of the colon. These effects are probably reltited to actions on the parasympathetic ganglia in the bowel. The summative effects of alll of these pharmacological actions on the whole intestinal tract do not produce a consistent' pattern. Excessive smoking may be associated with diarrhea, constipation, or alternating pat', terns between the two extremes. The only consistency is that symptomss attributable to nicotine effects on the gastrointestinal tract': are very common. DISTRIBUTION AND FATE Nicotine is actively and rapidly metabolized by man and other mammals, the metabolites being in large measure excreted im the urine. If any tissue storage occurs, it is in such small quantity as to elude current analytical r alka- hichi t l l l h t bl i Ni in i h n neu ra o e mo ecu e w er uns a es. sa rat n cot e tec line conditions undergoes a variety of changes. A review•ofthe current concepts of the known and suggested pathways for the metabolism of nicotine is show•n~ in Figure 1 (18). The main intermediate appears to be ( -)-cotenine which yields y-( 3-py.ridyl) -y-methylamino butyric acid. Cotenine has low toxicity and lacks the potent pressor activity of nicotine. Dogs reeeiving, 150 mg/kg"'dayorally for 108 days exhibited no weight loss or other obj'pctive signs (2). Man has ingested 500'mg orally at 8-hour !i intervals for 6 days, without! untoward effects. No evidence has been pre. sented' that the other known metabolites of nicotine carry any significant i systemic toxicity. 71
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~ lV SUMMARY DIAGRAM OF ROUTES FOR THE METABOLISM OF NICOTINE IN MAMMALS (Some hypothetical intermediates are shown in brackets.) Nicptine y-(3-Pyridyl}y-methylnminoGu[yrnlde6yde _1110 y-(3-Pyridyl)-y-rnethyk.minobutyria Acid / ~ I N('11j N - Innmethylnicotinium lon 'Hydrozynicotine' / Hydroxycutinine 'Ketonmidx• FIGORE 1. COOH y-(3-Pyridyl)-y-oco-6utyriq Acid 3-Pyridylacetic Aid Source: n4cKennis, Herbert H., Jr. (18) CHj coo sVyss4eo
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CHRUNIC TOXICITY Evaluation of the chronic: toxicity of tobacco smoke may be considered in several categories: (a) the systemic t'oxiaity, of nicotine or its congeners, (b) the systemic toxicity of other constituents of smoke or tobacco, carbon monoxide andl other compounds, (c) specific organ toxicity incertain~ suse ceptible individuals, such as those with Buerger's disease and allergic re- sponses, (d )! lbcal effect of irritants on mucous and pulmonary membranes by tars, phenols, the oxides of nitrogen, and' others. The latter three types of potentiall toxicity are discussed in Chapter 9; Cancer, and Chapter 10; IWon-Neoplastic Respiratory Diseases. It might appear that! the least difficult problem in this group of variables would be to assess the chronic toxicity, of nicotine since we are deali'ng with a comparatively simple organic compound of known composition and re- actionL Whereas there is a voluminous literature of studies involving chronic exposure to nicotine or tobacco smoke in many animal species (17, pp. 501-5Ud),, most of these are poorly designed and controlled and are of little value for extrapolation to man. For example;, in the best~ nicotine experiments involving life span studies, the daily dose of nicotine was near the: maximal tolerated dose (just subeonvulsive), which is greatly in excess of any human smoking exposure: Even though some authors (11) observed weight loss and degenerative vascular changes in rats under these severe conditions, others (22) noted some weight lbss but no~ histologic change. In life span experimentsim rats, with tobacco smoke in amounts approxi- mating human smoking exposure, very litt'le systemic toxicity was noted (8, 13). Even though animal experimentation is inadequate, especially in lon-term effects of nicotine on large animall species, existing, data permitss a tentative conclusion that the chronic systemic toxicity of nicotine: is quitee low in small to moderate dosage. The clinical literature is devoid of human, datai concerning chronic expo- sure to nicotine albne, and the general statement's regarding the chronic toxicity of nicotine f'or man represent inferences drawn from chronic expo- sure to tobacco in various f'orms, including industrial poisoning. Repeated exposure to tobaecoin excessive amounts is reported to induce amblyopia; arrhythmias, digestive disturbances, cachexia and a wide variety of other signs and symptoms. But the effects of excessive dose are of littleconcern here. The questioni is whether prolonged exposure to nicotine, in the quan- t'ities absorbed systemically fromi smoking or other tobacco use, produces toxic effects which result in unpleasant symptoms, dangerous signs, specific degenerative disease, or shortening of the life spanI. Unfortunately even a tentative answer to this question must be obtained indirectly andl by making certain assumptions. Inasmuch as nicotine is systemically absorbed' from all routes of administration, smoking, chewing, snuffing, or "snuffl dipping," it appears logical tb~ assume that if the amounts of! nicotine absorbed in the various methods ofl use:are of the same order of magnitude, any toxic effects observed should also be in this order of magnitude. There appears to be general, agreement that this is so. Calculations indicate that the nicotine *Asmall amount of snuff is placed in the groove between the tieeth, and the lower lip or beneath thet'onnue and held there from 30~ minutes to severall hours. fll 73 lil 'i
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absorbed (40-60 mg) from 6 cigars uninhaled equals that from 30 eiga- rettes inhaled (19). Chewing tobacco may yield 8 to 87 mg in 6 to 8 hours (244; in chewing snuff, 20-60 mg of nicotine (7). The following, variables play a role in the amount of nicotine absorbed (47,p. 8)1: To sum up, the rate and amount of absorption of nicotine by the smoker depend' to a greater or less extent upon the following factors: 1. Length of time the smoke remains in contact with the mucous membranes ; 2. pH of the body fluids wit'hi which, the smoke comes in contact;, 3. Degree and depth of inhalation; 4. Degree of habituationi of the smoker (?') ~ 5. Nicotine content of the tobacco smoked; 6. Moisture content'~ of the tobacco smoked'; 7. Form in which tobacco is smoked' (cut [cigarettes] or uncut [cigars] )(?); 8. Length of butt; 9. Use of' holder or filter; 10. Alkalinity or acidity of the tobacco smoke (?); 11. Agglbmeration of smoke particles (more important in eigarette- smoking) . There is no,acceptable evidence that! prolonged exposure to nicotine creates either dang-erous functional'i chanbe of an, objective nature or degenerative disease. The minor evidences of toxicity, nausea, digestivedisturbances and the like, are similar in kind and degree with all forms of use. The fact that the over-all death rates of pipe and cigar smokers show little if any increase over non-smokers is very difficult to reconcile with a concept of high nicotine toxicity. Im view of the mortality ratios of pipe and cigar smokers, it follows logically that the apparent increase im morbidity and mortality among cigarette smokers relates to exposure to substances in smoke other than~ nicotine. Unfortunately, there are no useful mortality statistics in those wlio che%v, snuff, or "dip" tobaccoi and! the literature regarding in- dustrial exposure is so~confusing that little help is available here. The type of projection made above, however unsatisfact'ory, is not inconsistent with the animal toxicity data as well as the fact that nicotine undergoes very rapid! metabolism to substances ofl lbw toxicity. The evidence therefore supports a conclusion that the chronic toxieity of nicotine in amounts ordinarily ob- tained in eommomflorms of tobacco use is very low indeed. SUMMARY The pharmacological effects of nicotine at dosage levels absorbed from smoking (il-2 mg per inhaled cigarette) are comparatively small; the response ini any point in time represents the algebraic sum of stimulant and depressant actions from direct, reflex, and chemical mediator influences on the several organ systems. The predominant actions are central stimulation and/or tranquilization which, vary with the individual, transient hyperpnea, 74:
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peripheral vasoconstriction usually associated with a rise in systolic pr~essure, suppression of appetitite, stimulation of' peristalsis andl wit'h larger doses. nausea of central origin whic4 may be associated with vomiting. Nicotine is rapidly metabolized by man and certain other mammals. The primary pathway through (-)-cotenine to y- ( 3-pyridyl )-y,methylamino- butyric acid is described in detaill The known metabolites have very low toxicity. The rapidity of degradation to non-toxic metabolites, the result's from chronic studies on animals, and the low mortality ratios of' pipe and cigar~ smokers when compared with non-smokers indicate that the chronic toxicitv of nicotine in quantities absorbed from smoking and other methods of to- bacco use is very loxv and probablly does not represent a significant health problem. REFERENCES 1. Bickford, R. G. Physiology and drug action: An electroencephalo- graphic analysis. Fed Proc 19: 619-25, 1960. 2. Borzelleca. J. F.. Bowman, E. F., McKennis, H., Sr. Studies on~ the respirator}~- and cardiovascular eff'ect's of (- l~-cotenine: J Pharma- col Exp Ther 137: 313. 1962. 3. Burn, J. H., Tiuelbve, L. H., Burn, I. The antidiuretic action of nico- t7neandlof smoking. Brit Med J 1: 403-6, 1945. 4. Carlsom A. J., Lewis. J. HI. Contributions to the physiology of the stomach. 14. The influence of smoking and of pressure on the abdo- men (constriction of the belt)', on the gastric hunger contractions. Amer J Physiol 34: 149=54, 1914. 5. Comroe. J. H.. N'adel. J. The effect of smoking and nicotine on respira- tion. In: James. G., Rosenthall T. eds. Tobacco and health. Spring- field, Thomas. 1962. Chapter 17, p. 233-43. 6. Eff'ect of smokinr on appetite and on peripheral vascular disease. [Queries and minornotes] JAMA 119: 534, 1912: 7. Gaede. D. Sur wirkung des schnupftahaks. Naunvn Schmicdeberg Archiv Exp Pa& 1'.3O--45, 1944. 3. Haag, H. B:, Weatherby, J. H., Fordham, D., Larson, P. S. The effect on rats of daily-life span exposure to cigarette smoke. Fed Proc 5: 181, 1946. 9. Hauser, M. Schwarz, B. E., Roth. G., Bickford, R. G Electroenceplialo• graphic changes related to smoking. Electroenceph Clin Neuro- physiol 10:57,6, 195& 10. Heymans, C.,, Bouchaert. J. JL, Dautrebande, L. Sinus carotidien et reflexes respiratories. 3. Sensibilite des sinus carotidiens aux sub- stances chimiques. Action stimulante respiratorie reftexe du sulfure de sodium. du cyanure de potassiumi de la nicotine a de la l4beline. Arch Int Pharmacodyn 40: 54-91, 19311. 11. Huepery, W. C. Experimental studies in cardiovascular pathology. 7. Chronic nicotine poisoning in rats and! dogs. Archi Path (;Chicago) 35: 846-56, 11943. 75 r
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12. Knapp, D. E., Domino, E F: Action of nicotine on ascending reticular activating system. Int J Neuropharmacol 1: 333-51, 1962. 13: Kuchle. H. J., Loeser, A,,, Meyer, G., Schmidt, C. G., Strurmer, E. Ta- bakrauch. Ein beitrag zur wirkung von tabakfeuchthaltemittein. Z Ges Exp Med 11$:554-72, 1952, 14. Lal£an, R. J., Borison„ H. L. Emetic action of nicotine andi lobeline. J Pharmacol Exp Ther 121: 468-7~6, 1957. 15. Lambiase, M., Serra, C. Fumo e sistema nervoso. 1. >1'Iiodificazioni dell'attivita elettrica corticale da fumo. Acta Neurol (Napoli) 12: 475-93, 1957. 1'6. Langley; Ji. hi'. 0n the reaction of cells and of nerve-endings t'o certain poisons; chiefly as regards the reaction of striated muscla to nicotine and to curari. J Physiol (London), 33: 374-413, 1905. 17. Larson, P. S., Haag, H. B., Silt~ette, H'. Tobacco. Experimental and clinical~ studies. Baltimore, William & Wilkins, 1961. 932 p. 18. McKennis; H., Jr. Special report to the Surgeon General's Advisory Committee on Smoking and Health. 19. Nicotinecontent of snrokefrom cigarsan&cigarets. [Queries and minor notes] JAMA 130: 825, 1946. 20. Rapela., C. E., Houssay„ B: A. Accian d'e la nicotina sobre la secrecion de adrenalina y nos adrenalina de la sangre venosa suprarrenal del perro. Rev Soc Argent Biol 28: : 219=24,, 1952. 21. Schnedorf, J. G., Ivy, A. C. The elTect' of tobacco smoking on~ the ali- mentary tract. An experimental study of man~ and' animals. JAMA 122: 898-904, 1939. 22. Silvette, H., Hoff, E. C., Larson„ P. S., Haag H. B. The actions of nico- tine on central nervous system f'unction. Pharmacol Rev 14: 1'37-73,, 1962. 23. Stumpf~ C. Die wirkung von nicotin auf die hippocampustatigkeit des kaninchens. Naunyn Schmiedeberg Archiv Exp Path 235: 421-36, 1959. 24. Thienes, C. H. Chronic nicotine poisoning. Ann NY Acad Sci 90: 239, 1960. 76 x_n..
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Chapter 8 Mortality
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Contents Page PROSPECTIVE STUDIES OF MALE POPULATIONS ... 81 Data on Smoking History . . . . . . . . . . . . . . . 82 Adjustment for Differences in Age Distribution ...... 82 RESULTS FOR TOTAL DEATH RATES . . . . . . . . . 85 Mortality Ratios for Current Smokers . . . . . . . . . . 85 Mortality Ratios by Amount Smoked . . . . . . . . . . 85 Mortality Ratios at Different Ages . . . . . . . . . . . 87 Age at Which Smoking was Started . . . . . . . . . . . 89 Mortality Ratios by Duration of Smoking ... ..... 90 Inhalation of Smoke . . . . . . . . . . . . . . . . . . 91 Ex-Cigarette Smokers . . . . . . . . . . . . . . . . . 92 Ex-Cigar and Pipe Smokers . . . . . . . . . . . . . . . 94 EVALUATION OF SOURCES OF' D ATA . . . . . . . . . 94 The Study Populations . . . . . . . . . . . . . . . . . 94 Non-Response Bias . . . . . . . . . . . : . . . . . . 96 Measurement of Smoking History . . . . . . . . . . . . 98 Stability of the Mortality Ratio . . . . . . . . . . . . . 98 OTHER VARIABLES RELATED TO DEATH RATES ... 99 MORTALITY BY CAUSE OF DEATH . . . . . . . . . . 101 Results for Cigarette Smokers . . . . . . . . . . . . . . 102 Mortality Ratios for Cigarette Smokers by Amount Smoked . 106 Cigars and Pipes . . . . . . . . . . . . . . . . . . . 107 The Contribution of Different Causes to Excess Mortality .. 108 SUM MARY . . . . . . . . . . . . . . . . . . . . . . . 108 Total Mortality . . . . . . . . . . . . . . . . . . . . 108 Cigarette Smokers . . . . . . . . . . . . . . . . . . 108 Cigar Smokers . . . . . . . . . . . . . . . . . . . 112 Pipe Smokers . . . . . . . . . . . . . . . . . . . . 112 Mortality by Cause of Death . . . . . . . . . . . . . . 112 APPENDIX I Appraisal of Possible Basis Due to Non-Response .... 113 APPENDIX II Stability of Mortality Ratios . . . . . . . . . . . . . . 117 Assumptions . . . . . . .. . . . . . . . . . . . . . 117 The Binomial, Approximation . . . . . . . . . . . . . 118 The Normal Approximation . . . . . . . . . . . . . . 119 REFERENCES . . . . . . . . . . . . . . . . . . . . . . 120 78 
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i Figure FiGURE 1. Death rates (logarithmic scale) plotted against age for current cigarette smokers and non-smokers, U.S. veterans study . . . . . . . . . . . . . . . . . . . . . . . . . List of Tables Page 88 TABLE 1. Outline of prospective studies of smoking and mortality. 83 TABLE 2. Mortality ratios of current smokers by type of smoking . . . . . . . . . . . . . . . . . . . 85 TABLE 3. Mortality ratios for current smokers of cigarettes only, by amount smoked . . . . . . . . . . . . • • 86 TABLE 4. Mortality ratios for current smokers ofl cigars only, by amount smoked . . . . . . . • • • • • • • . . 86 TABLE 5. Mortality ratios for current smokers of pipes only, by amount smoked . . . . . . . . . . . . . . . . 87 ' '1'AsLE 6: Mortality ratios by age group for current smokers of cigarettes only, men in 25 States . . . . . . . . . 87 TasuE'7. Increase in natural logarithm of death rate per ],000, man-years for each, 5-year increase in age, 6 prospec- tive studies . . . . . . . . . . . . . . . . . . 89. TABLE 8. Mortality ratios by age at which smoking was started and by amount smoked for current, smokers ofl cigarettes only . . . . . . . . . . . . . • • • • 89 TABLE 9. Mortality ratios for current smokers by type of smoking and by length of time smoked . . . . . . . . . • 90 TABLE 10. Mortality ratios for smokers of cigarettes only by inhalation status and amount of smoking ..... 91 TABLE 11. Mortality ratios for ex-smokers and current smokers of cigarettes . . . . . . . • • • • • • • • • • • • 93 TABLE 12. Mortality ratios for ex-smokers of cigarettes only by number of years since smoking was stopped and by amount smoked . . . . . . . . • • • • • • • • 93 TABLE 13. Mortality ratios for ex-cigarette smokers by number of years of smoking, U.S. veterans study ..... 93 TABLE 14. Mortality ratios for ex-smokers of'~ cigars only, and pipes only and for current cigar and pipe smokers . 94 TABLE 15. Age-adjusted death rates per 1,000 man-years for current smokers of cigarettes only (aged 35 and over), by amount smoked, in seven studies and for U.S, white males . . . . . . . • • . • • • • • • • . 95 TABLE 16. Percentages of' usable replies in five studies ..... 96 TABLE 17. Mortality ratios for cigarette smokers by population- size of city . • • • . • • . . • . . . . . . • • 99 TABLE 18. Age-adjusted death rates per 1,000 (over approximately 22 months) for variables that may be related to mortality . . . . . . . . • • • • • • • • . • • 100 714-422 0-64-7 79
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Page TABLE 19. Total numbers of expected and observed deaths and mort'alityy ratios for smokers of cigarettes only in seven prospective studies . . . . . . . . . . . . 102 TABLE 20. Expected and observed deaths and' mortality ratios for current smokers of cigarettes and' other (three studies): and for ex-cigarette smokers (four studies) . 105 TABLE 21. Mortality ratios for coronary artery disease for smokers of cigarettes onlyy by amount smoked ....... 106 TABLF 22. Lung cancer mortality ratios for current smokers of cigarettes only by amount smoked . . . . . . . . 106 TABLE 23. Expected and observed deaths and mortality ratios for current cigarette smokers, for selected causes of death, by amount smoked, in six studies ..... 106 TABLE 24. \ umbers of expected and observed deaths and mortal- ity ratios for cigar and pipe smokers, in five studies . 107, TABLE 25. Percentage of totalinumber of excess deaths of'cigarettee smokers due to different causes . . . . . . . . . 108 TABLE 26. Numbers of'expected and observed d'eaths for smokers of cigarettes only, and mortality ratios, eac6 prospec- tive study and! all studies . . . . . . . . . . . . 109 TaBLE'27. Age-adjusted death rates (per 1,000 person-years) for 1951respondents, 1957 respondents, and non- respondents in L.S: veterans study . . . . . . . . 114 TABLE 28. Illustration of calculation of non-response bias . . .. 115 'hABLE 29. Mort'ality ratios in respondents and computed vahtres for the complete population . . . . . . . . . . . 116 1'ABLE 30. Proportions and death rates for Berkson's example .. 116 80. 1=~
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Chapter 8 PROSPECTIVE STUDTES OF MALE POPULATIONS The principal data on, the death rates of smokers of various types and of nonsmokers come from seven large prospective studies of men. In such studies, information about current and past'~ smoking habits, as well as some supplementary information (e:g., on age), is first obtained from the members of the group to be studied. Provision is also made to obtain death certificates for all members of the group who die during subsequent years. From these data, over-all death rates and death rates by cause are computed for the different types of smokers, usually in five-year age classes. These seven studies comprise all the large prospective studies known to us. The first started in October 1951: the latest, in October 1'959. In brief, the seven~ groups of men are as follows: (11) British doctors, a questionnaire having, been sent to all members of the medical profession in the United Kingdom by Doll and Hill, 1956 (15). (2), White American men in nine states. These men were enrolled by a large number of American Cancer Society volunteers, each of whom was asked to have the questionnaire filled' in by 10 whitee men between the ages of 50 and' 69. Hammond and Horny 1958'. (10). (3)', Policyholders of U.S. Government Life Insurance policies,, available to persons who served' in the armed forces between 1917 and 1940. Dorn, 1958' (6). (4) Men~ aged 35-64 in nine occupations in California who were sus- pected of being,subject to a higher than usual occupational risk of developing lung cancer. Dunn, Linden and Breslbw, 1960 (7). (5) Calif'ornia members of the American Legion and their wives. Dunni Buell and Breslow (8)'. (6) Pensioners of: the Canadian Department! of Veterans Affairs, i.e., vet- erans of World Wars I and II and the Korean War. Best, Josie and Walker, 1961 (2) ~. (7) American men in~ 25 states; enrolled by volunteer researchers of the American. Cancer Society,, each of whom was asked to enroll about 10 families containing, at least one person over 45. Hammond, 1963 (11). ItI will be noted'that the studies cover different types of population groupss in three countries. Study (2), often referred to as the Hammond and Horn study, terminated after 414 months' fo]lowup, and the data discussed here for this study are essentially the same as those already published (10). All other studies have accumulke& substantial' amounts of' data beyond that which has been publishedL The authors and agencies responsible for 81 O C.~ ~ ~ CR OD
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the studies supplied' their latest available data for this report. The tables in' this Chapter are based on the new compilations. Table I shows for each study the approximate number of subjects from whom usable replies about smoking habits were obtained, the date of en- rolllnent, age range, number of' months followed~ total number of deaths, and the number of' person-years of exposure. The number of subjects studied (usabie replies) ranged from around 34,000' in the Britisll doctors study to 448,000 in the nLw American Cancer Society study. The number of months of follbw-up varied from' about22 to 120. Although several' of the studies obtained some data on women, only the California Legion study' (8)' and the new American Cancer Society study (Ill) includ'e large numbers of women. No tabulations on women are as yet available from these prospective studies. The exact description of the type of smoking and the amounU smoked at all times throughout a man's past life would necessitate an amount of detail and an accuracy of inemory that was not considered practicable in these studies: While the information' collected on smoking habits varied' from study, to study, all studies asked for data on the current amount and type of smoking as of the date ofl answering the questionnaire. These amounts were usually expressed as the number of cigarettes, cigars or pipes per day. In' the case of subjects who had stopped smoking previous to the date of enrollment (ex-smokers /, most studies obtained data on the maximum amount previously smoked'per day. The category described as non-smoli;ers sometimes included also those men who had smoked an insigpificant total amount during their whole previous lifetime. As regards type of smoking; cigarettes, cigars and pipes appear in all seven combinations. Since results for the "mixed" categories are diflieult to interpret and sometimes involve relatively small numbers of subjects, the analysis here concentrates on the following types: Cigarettes only Cigarettes and other Cigars only Pipes only In some instances the lhst two categories have been combined' when the num- bers of subjects are too small to give reliable dhta for the separate types. ADJUSTMENT FOR DIFFERENCES IN' AGE DISTRIBUR'IoN Since the death rate of any group of inen is markedly affected by their age distribution, it is essential, when comparing tbe death rates of two groups of men, to ensure that theio• age distributions are comparable. A standard meas- ure for this purpose is the age-specific death rate, in which the rate is com puted for a group of inen wliose ages all lie within'a relatively narrow span, say 50-54 years. This measure is particulariy appropriate when it is desired to examine how the relative death rates in two groups change with age. 82
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TABLE I.-Outline of prospective studies of smoking and mortality Authors --- Doll & Hill (5) - -- - - llammon l & Horn (10) -- Dorn (6) - Dunn, Linden, Bmslow (7) . . . Dunn, Buell, Breslow (8) . . _ _ . Best, Josie, Walker (2) . Hammond (11) 8ubjects British doctors -- i Wbite men in 9 States -- - U.$. veterans Californix occu- pationul groups ~ - California Ameri- can Legion mcm- bers - Canadian pensioners (veterans and de-. penilonts)-- Men in 25 States Number of usnble replies 34,000 188,000 248,000 fi7,0(10 Ofi,0(10 78,000 448,000 Date of enrolllnent Oct. 1951 Jan.-Mar. 1952 Jan. 1954 nand Jan. 1957. Nov. 1953 and May 1957. May-Nov. 1957 Sept. 1955-July, 1950) Oct. 1959-Feb. 19fi0. Age range 3,4-7,5{- 50-fi0 3tF75_-f- 35-1i9 35-75+ 35-75+ 35-89 Mont.hs followed 120 4-4 78 About 46 About 24 72 About 22 Number of deaths 4,534 11,870 24,519 1,714 1,704 9,070 11,612 Person-years of exposure 269,000 61'~i,pW 1,312,0110 222,000 119,000 383,000 620,000 099S9LE0
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Several methods of adjustment for differences in age distribution are available for populations that have a wide range of ages. For comparing the death rate of a group of smokers with that of the non-smokers in the study, the measure most frequently used in previous publications is a type of mortality ratio, obtained as follows: In each five-year age class, the age- specific death rate for non-smokers is multiplied by the number of person- years in the group of smokers. This product gives an expected number of deaths, which represents the number of deaths of smokers that would be expected to occur if! the age-specific death rate were the same as for non- smokers. These expected numbers of deaths are added over all age classes, and their total is compared with the total! number of observed deaths in the smokers. The mortality ratio is the ratio (total observed deaths in the smokers)/(total expected deaths)~. A mortality ratio of 1 implies that the over-all deatL rates are the same in smokers and non,smokers after this adjustment for differences in age distribution. It does not imply that: the death rates of smokers and non•smokers were the same at each specific age. A mortality ratio higher thani 1 implies that the group of smokers has a higher over-all death rate than the non-smokers. Another common method of adjustment: for age is to use some age- distribution as a standard, for instance the combined age-distribution of all' persons in the study or the age-distribution of the ULS. male population as of a certain Census year. The age-specific death rates for a certain group: (e.g., smokers) are multiplied by the number of persons of that age in the standard distribution. These products are added and finally divided by the total standar& population to obtain, an age-adjusted rate for the group. A mortality ratio of smokers to non-smokers is then computed as the ratio of the age-adjusted rates for smokers and non-smokers: Mortality ratios com- puted in different ways will of course give somewhat different results an& experts in this field do not regard any one method as uniformly best. In this report we have used the ratio of observed: to expected deaths, as described in, the previous paragraph, primarily because this measure is the most'common~ one in previous publications from these studies. Both methods of adjust- ment run the risk of concealing a change in the relative death rate with age:. For instance, the over-all mortality ratio might be unity if smokers hadlhigher death rates than non-smokers prior to age 60,,but lower death rates thereafter. Smokers and! non•smokers may differ with regard to variables other than age that are knowni or suspected to influence death rates, such as economic level, residence, hereditary factors, exposure t'o occupational hazards, weight„ marital status, and' eating and drinking habits. In the summary results to be presented in subsequent sections, as in: most results previously pub- lished, the death rates of! smokers and non-smokers have not been adjusted so as to equalize the effects of' these disthirbing variables. This issue will be discussed later in this chapter. A further compllexity in interpreting the results comes from interrela- tionships among the variables that describe the habit of smoking, As will be seen, the death rates of a group of cigarette smokers vary with the amount smoked; the age at which smoking was started, the duration of smoking, and the amount of' inhalation. In trying, to: measure the "net"' effect of one of these variables, such as the number of cigarettes smoked' per day, we 84
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should make adjustments so that the different groups of smokers being compared are equalized on all other relevant aspects of the practice. This can be done at best only partially. Most', studies measured only some of the variables on which adjustment is desirable: When the data are subclassi- fied in order to make the adjustments, the numbers of d'eaths per subclass are small, witL the consequence that the adjusted d'eat'h rates are somewhat unstable. Consequently, like previous reporters om these studies, we have used our judgment as to the amount of subclassification and adjustment to: present. The possibility that part of the differences in~ death rates may be associated with smoking variables other than the one under discussion cannot be excluded, RESULTS FOR TOTAL DEATH RATES. MORTALITY RATIOS FOR CURRENT' SMOKERS Table 2'showsthe mortality ratios to non-smokers for men who were smok- ing regularly at the time of enrollmentL For males smoking cigarettes only, the over-all d'eath~ rate is higher than that for non-smokers in all sthdies, the increase ranging from 44 percent for the British doctors to 83 percent in the men in 25 states. For smokers of other forms of tobacco as well as cigarettes t'he increases in death rates are in all cases Ibwer than for the smokers of cigarettes only. For smokers of cigars only, or of pipes only, three of the studies show small increases in over-all death rates; ranging from 5 percent to 111 percent. The study of inen in 25 states, however, gives slight decreases for both types, as does the British stYldy for the two types combined. TABLE 2-1Vlortal'ity ratios of current smokers by type of smoking Study g roup I ~ Type of smoking Briti doct sri ~ ors Men Stat in 9 es U.S, era vet- ns Canad veter ian 34en in ans State 25 s Ci arettes onl 44 1 1.70 1179 1.65 1183 ' y ________________________ g Cigarettes and other . 1.05 I 1. 45 1i 46' 1. 73 1'. 54'. . _ _______ Ci ars only' r 1. 10 110i 1.11 0.97 g ------------------------ Pipes only.--------------------------------- I 0.95 t 1. 05 1.06 1.10 i 0. 8e I The California occupational and Legion sttrdies give mortality ratios of 1.78 and 1i58 respectively, forr all cigarette smokers (current and ex-smokers). MORTALITY RATIOS BY An1OUNT SMOKED For smokers of cigarettes only who were smoking at the time of entry, the mortality ratio increases consistently witL the amount smoked im each of the seven studies, with one exception4 or the California occupational st'udy, which includes ex-cigarette smokers as well as current smokers (Table 3)~. 85
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For smokers of cigars only who were smoking at the time of entry,, four of the studies give a breakdown int'o two amounts of smoking (Table 4). Mem smoking less than five cigars per day have death rates about the same as non-smokers. For men smoking higher amounts there is some elevation of the death rate. When the results are combined by adding the observed and expected deaths over all four studies, an over-all mortality ratio of 1.20 is obtained for the five-or-more group. This over-all increase is statistically significant at the 5 percent level.* I TABLE 3'.-lblortality ratios for current smokers of cigarettes only, by amount smoked Cigarettes per British Men in 9 U.S. California California Canadian Men in 25 day doctors States veterans ' occupa- Legion•' veterans States tional' I Less.than 10---.-- 10-20------------- 21-39--- 40 and over -- --- - '1.06 1.31. s1.62 11.50 . 1133 . 1168. 1193 2:.20 1..35 1.70 1.99. 2.22 L 44 l' 2,1,. ~. / 1. 55 1.79 J } 1.88 2.27°'1.~I`.. s1.84 1. 83 ~ .85 J 1:45 l 1.75 ( 1.90 l 2.20 *Current and ex=ciRarette smokers combined. ~"Less than 10" is "lessthan 5" plus"9bout yJ"; "10-20" is "about 1"; "21-39" is "about 13¢"t 3 Less than 1 pack. 3 20-34':. + 35 plus: , 5 More thanil pack., 6 About 1 pack. T More thani 1 pack... TABLE 4.-Mortality ratios for current smokers of cigars only, by amount smoked Number per dag 1 H---------------------------------------- 5 or more--------------------------------- s 1-2. ~ 3 or more. Men in 9 States 1. 00 1.20 U.S: vet- erans 0. 99'. 1,24 Canadian veterans s 1.12 21.26 Men in 25 States 0.93 1.10 o ver-an results 1.00 1.20 I For current pipe smokers (Table:5), men smoking less than 10 pipefuls per day have death rates very close to those of non-smokers. For heavy pipe smokers (10 or more per dgy)' two studies show increases of 15 and 12 per- cent in deathi rates, but the other two studies show little or no increase. The over-all mortality ratio of 1.05 does not differ statistically f'rom, unity. The *Statistical significance throughout this report' refers to the 5 percent llvel, un- less otherwise specified. In testing whether an observed mortality ratio of smokers, relative to non-smokers is greater than unity, the probability is calculated that a ratio as large as or larger than the observed ratio would occur, by chance if the smokers and non-smokers were drawn from two popullitions having the same deathirate. If this proba- bility is less than 0.05 (5 percent)' the observed increase in the death rate of smokerss relative to non-smokers is said to be statistically significant at the 5 percent level. The results of significance tests willl be quoted only for mortality ratios in whichithe numherof deaths raises a doubt as to whether the difference from unity could be due to sampling errors. 86
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British~doctors study gives a mortality ratio of 0!91 for cigar and pipe smokers together (presumably mostly pipe smokers) who consume more than 14 gms. of tobacco daily. TABLE 5.-1llortality ratios for current' smokers of pipes only, by amcuntt smoked Pipes per day. 1-9----- ----------------------------------- 10or more--------------------------------- Mmin 9 States 1.00 1.15 Study U.S. veterans Canadiann veterans 1.03 1.12 Men in 25 States. 0.92 0.76' O cer-all ratio MORTALITY RATIOS AT DIFFERENT AGES 1.01 1.05 As indicated previously, the mortality ratios presented in previous tabless for different! groups of smokers represent' a kind of' average over the age- distribution of the smokers concernedy and do not necessarily apply to smokers ofl any specific age. For cigarette smokers, the studies show that the mortality ratio declines with increasing age, being higher for men aged 40-50 than for men over 70i This effect is illustrated in Table 6 from the study of men in '25 states, which gives the mortality ratio computed separately for five age classes. The drop in mortality ratio with each increase in age appears fairly con- sistentlyy for every amount of smoking. For smokers of cigarettes only as a whole, the death rate is more than double that for non-smokers in the agee range 40-49, but only about 20 percent higher for men over 80: The. pic- ture is, of course, different if we look at the absolute excess in death rates at different! ages. Owing to the marked increase in~ death rates with age, thee absolute excess also increases steadily with increasing age. A more thoroug)1 investigation of the relation between death rates and age for different groups of smokers has been made by Ipsen and Pfaelzer (14). If the logarithm of the age-specific death rate is plotted against age, the resulting points lie reasonably close to a straight line. For the U.S. TABLE 6.-IYlortality ratios by age group for current smokers of cigarettes only, men in 25 States Number of cigarettes per day Age at start of st udy 40-49 50-59' 60'-69 70-79 80-89 1-9---------------------------------------- 2. 27 1.44 1.40 1.40 1.08 10-19 - - ------------------------------ 2.12 1.94 1.60 1.50 1.65 20-a9-------------------------------------- 2,22 2.05 1.78 1.48 1.16 40i---------------------------------------- 3.06 ' 2.37 1.68 1.28 0.~58 All amountk------------------------------- 2.33 106 . 1.70 1.47 1.22 87 I
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veterans study, Figure 1 shows the points and fitted lines for non-smokerss and' for current smokers of cigarettes only. (The lines were fitted by the standard method of least squares, weighting each point' by the number of deaths involved.) If the lines for cigarette smokers and non-smokers were parallel, thiss would imply that the mortality ratio of the smokers to the non-smokers wass constant at all ages, because the vertical distance between the two lines at any age is the log of the mortality ratio for that age. In Figure 1, however, DEATH RATE (logarithmic scale) PLOTTED AGAINST AGE, PROSPECTIVE STUDY OF MORTALITY IN U.S. VETERANS CURRENTICIGARETTE SMCKERS AGE IN YEARS 88 FIGURE 1.
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the. slope is slightly less. steep for theeigarette smokers than for the non- smokers. This indicates that the mortality ratio is declining with increased age. Table 7 shows these slopes (increase in the natural logarithm of the death rate for each 5-year increase in age) computed f!rom~ six of the studies. The salient features are as f'ollows: (1) In each study the slope for cigarette: smokers is smaller than the slope for non-smokers; (2)~ Within the cigarette smokers the slope tends to decline, with some inconsistencies, as the amounts smoked become greater; (3) for cigar or pipe smokers theslopes are closer to those for non-smokers. TABLE 7-lncrease in nadurallogaritkm of deathrateper I;00© man-years f or each 5-year increase in age, 6 prospective studies, British Men~in 9, U.S. Calitornia California ' Men in 25 Type of smoking doctors States veterans occupa I-egion I States r tional I Non-smokers----------------- .593~ .474 ' .499. .489. .502 ~ .490 Cigarettes by arnount per day-, .492 ' .427 ~ .448 .436 '. .476 . . 438 1-$ --------------------------- .536: .484 '' .490 .401 .567 .445 10-20'------------------------- .551 .457 ' .454 I .461 . .471 .441 21-39!-.----------------------- .477 .420 .46i~ .447~ .449~. .401 40+--------------------------- .401 .345 ------------ ------- - .~401 Cigars Pipes-------------- ------- 598 } { .466~ ~ I 521 .483 .458 ------ i-------- ~----------- ----------- ------------ .457 I .458 I "CigareEtes" includes "cigarettesand otrier^an&currenti and ez-smokers. 2 First.10 months'experience. AGE AT WHICH SMOKING WAS STARTED The study of U.S. veterans and the study of men in 25 states provide dataa on the d'eathi rates of current smokers of cigarettes only,, classified by the age at which, the person started'' to smoke. Since in bothi studies the. men, who start, to smoke early tend to smoke greater amounts per day thani men' who start later in life, the mortality ratiosto non-smokers are preonted separately for different amounts of smoking (Table 8). TASIlE' 8.-Mortality ratios by age at whichsmoking was started and by amount smokedtor currentsmokers of,cigarettes only Age started to smoke Number of cigarettes per day Over- all 1-9 10-20 21-39 40+ ratio U:S. veterans: Under 20------------------------------ 1.,60~ 1.89 2.16 2.45 1.98 20-24'------------- -------- 1.40, 1.72 1.87~ 2.23 1.72 25 or over-- --------------------------- 1,15 1.50 1.47 1. 11, 1.39 Men in 25 States: Under15____________ ___ 1179 1 2.23 2 2.! 21 2.15 2.17 15-19__________________________________ 1.75 1 1.83 22.101 2.38 1.99 20-24---------------------------------- 1.25 1 1.52 ' ~ 1.62 1. 93 1. 59 25~or over------------------------------ 1.03' 1 I.36 ~ 1.45 1.56 1.34 1 10-19 cigarettes per day. I 20i39 cigarettes per day:. 89
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For a fixed amount of smoking, the mortality ratios (with one exception) exhibit a consistent and rather striking,increase as the age at which smoking was started decreases. This increase appears in all smoking groups of Table 8. For men who started smoking cigarettes under the age of 20,, the over-all death rate was about twice that for non.smokers, whereas for those who did not start until they were over 25 the death rate was only about 35 percent higher. MORTALITY RATIOS BY DURATION OF SMOKING Three studies have some data available on the number of years during, which the subjects had smoked. The comparison of mortality' ratios for difl'erent! lengths of time smoked is of interest in relation to two questionss raised by Dorn (6) in an earlier analysis of'~ the U.S. veterans' data. Is theree a minimum period of use during' which no effect on the death rate is notice- able? Is there a maximum period after which no increase in the relative death rate is perceptible?' For current cigarette smokers the results (Table 9) are not clear-cut. In the U.S: veterans study, men smoking for less than 15 years had death rates about the same as non-smokers. There is a rise of about 50~ percent in the mortality ratio for those who had! smoked! 15-35 yeare, with a further rise for those smoking ]bnger than 35 years. The study of men in nine states shows a rise from under 25 years to 25-34 years duration, but no further rise thereafter. In the Canadian~ study the mortality ratio with cigarette smokers is just': as high for d'urations less than 15 years as for durations of 15-29' years, though there is a rise (to 1.73) for smokers of cigarettes only who have been smoking more tham 30 years. TABLE 9:-Rlortality ratios for current smokers by type of smoking and by length' of time smoked Number of years smoked Type of smoking Cigarettcs only____ C igarettes an d oUier ----------- Cigars only __----_ Pipes.only-------_- ti . S: , veterans Canadian veterans Men in 9 States <15 15-24 2.5-34'. 35+}- <15 15-29 ~30+ <25. 25-34 i 35-f- 0.92 1.52 1.50 . 1. 8s 1.52 1.41 li L 73'. 1.46 i 1,74 1.78 1.07 1.41 1. 33'. 1.49 1l 24 1.27 1i22 0.92 0!94 0.95. 1. 12 1i06' 0.81 1i 31 1.01 1.34 0.97 1. 07. 1i36', 0l93 1109: Thus, all three studies show some increase in the mortality ratios with longer duration of smoking, but the pattern is irregular. In a further break- down of' the data by amount smoked, Hammond'andl Horn (10)' found no trend with duration for men smoking, more than a pack a day, but the other two studies show an upward trend for this group of smokers. For cigar smokers the only groups showing, an increase in death rates over non•smokers are those smoking for the longest period (Table 9). The in- creases of 12 percent, for the 35 years or over group in the U.S. study and of 90
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r: 31 percent for the 30 years or over group in the Canadian~study are both statistically significant. For pipe smokers no trend with duration of smoking is discernible. The two figures which stand out (1.34 in the U.S. study and! 1.36 in the Canadian study) are both based on relatively small numbers of deaths. INHALATION OF SMOKE In two: of the studies the subjects were questioned as to whether they inhaled. In the stud!y of men in 25 states each subject was asked to place himself in one of the four classes: do not inhale, inhale slightliy, inhale moderately, inhale deeply. In the Canadian veterans study the subjjecUsimpUy classified himself as an inhaler or non-inhaler. For current smokers of cigarettes only in the UIS. study, 6 percent of the subjects stated that they did not inhale, 14 percent inhaled slightly, 56 percent moderately and 24 percent deeply. In the Canadiam study 11 percent classified themselves as non-inhalers. Since inhalation practices may vary with the amount smoked, the resultss for cigarette smokers (Table 10) are given separately for different amounts. For the men in 25 states ani increase in the degree of inhaling for a fixed amount of smoking is in general accompanied by an increase in the mortality ratio. Therelation of inhalation to mortality appears quite marked: for instance, non-inhalers who smoke 20-39 cigarettes daily have mortality rathos no higher than moderate or deep inhalers who smoke 1-9 cigarettes d'aily. With the very heavy smokers (40+ ) the figures in Table 10 suggest that the mortality ratio~ may remain the same for non~, slight4 and moderate inhAers. The ratios of 2.05 (non-) and 1.97 (slig)it)! are, however~, based on only 26 and 411 deaths, respectively. TABLE 10: Mortality ratios for smok'ersof cigarettes only byinhalation status and amount of smoking Degree ol inhalation 1-9 Cigarettes per day. 10-19 20-39 Overall ratio 40+ Men in 25 States: None-----'---------------------------- 1.29 1.46 1.56 ' 2.05 1149 . Slight--------------------------------- 1.29 1.fi8 1. 54 1.97 1168' Moderate - -------------------------- 1.61 1.82 1'. 84 2.01 1183 Deep----------- ----------------------- 1.88 1.76 2.18 2.50 2,20 Canadian veterans:~ None------ ----------------- 1.05 2 1.11 1 1.03' 1.08 8ome---------------------------------- 1.35 21.50 31.71 1:52 I Aanountsare lifetime maximumamounts smoked. 7 10-20 cigarettes per day. 3 Over 200 cigarettes per day:. Looking, along the rows of the U.S. veterans study it will be seen that for each degree of' inhalation the mortality ratio increases with the amount smoked. Ipsen and Pfaelzer (14) have shown that the logarithms of the 16 death rates at age 61, (approximately the average age), can be adequately rep- 91
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resented as an additive function of the amount of smoking and the degree of inhalation (although other types of mathematical relationship would also fit the data). In their analysis, the average change in logarithm of death rate from "no inhalation" to "deep inhalation" is as great as the difference be- tween consumption of less than 10 cigarettes and consumption of more than 40 cigarettes daily. In the Canadian data the inhalers have higher mortality ratios than the non-inhalers for each amount of smoking. No trend with amount of smok- ing appears for the non-inhalers, but the ratios in this row are based on rather small numbers of deaths. For cigar smokers (current and ex-smokers) in the 25-state study 19 per- cent stated that they inhaled to some extent. The mortality ratio is 0.89 for non-inhalers and 1.37 for inhalers. The latter increase of 37'percent (based on 91 deaths) is statistically significant, but as the data have not been sub- classified by amount of'. smoking the result may be partially a reflection of the increase in death rates noted in~ Table 4 for heavy cigar smokers. In the Canadian study, 13 percent of the cigar smokers classified themseNves as in- halers; but the number of deaths is insufficient to present a breakdown of the mortality ratio by inhalation status. Among, the pipe smokers there were 28 percent who inhaled in the U.S: study and 18 percent in the Canadian study. The U.S: mortality ratios are 0:8' for non-inhalers and 11.0 for inhalers; the Canadian data contain too few deaths to allow a breakdown, by inhalation. EX-CIGARETTE SMOKERS For men, who had stopped smoking prior to the date of enrollment, Table 11 gives the mortality ratios f'romi five studies for "cigarette only" smokers and "cigarette and other" smokers. The corresponding, results for current cigarette smokers (from Table 2) are given for comparison. The distinc- tion between current and ex-smokers is not of course clear cut, since some current smokers may have stopped after enrolling in the study and some ex- smokers may have later resumed smoking. With one exception, the mortality ratios for ex-smokers lie consistently be- low those for current smokers and above those for non-smokers. In inter- preting comparisons of ex-smokers and current smokers there are at least three rellevant factors. If smoking is injurious to health, cessation of smok• ing would be expected to reduce the mortality ratio. Secondly, some men stop smoking, because of illhess: In the 25-State study, over 60 percent of the men who had stopped smoking within a year prior to entry stated that a disease or physical complaint was one of the reasons for st'opping (12). This factor would tend to make mortality ratios for ex-smokers higher than those for current smokers. Finally, ex-smokers may have previously smoked smaller amounts than current smokers. This factor is not the explanation of the drops in mortality ratios in~ Table 11. In a further breakdown by amount of smoking, made for the three largest studies, the mortality ratio for ex-smokers is consistently below that for current smokers for each amount smoked. 92
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TABLE 1L-Mortality ratios for ex-smokers and current smokers of cigarettes British doctors Men in 9 UIS. I States veterans i Canadian veterans Men in 25 States Ex-cigarettes ------------------------------ 1.04 1.40 1.41 1,42 1.50 Current cigarettes_________________________ 1.44 1.70 1.79 1165 1.83 ~ Ex-cigarettes and other_ _____ _ _______ ______ 1: 21 1.29 1. 211 1'. 18 1.511 Current cigarettes and other______________ 1.05 1.45 1.46 1.23 1.54 TABLE 12.-Mortality ratios f or ex-smokers o f cigarettes only by number o f years since smoking was stopped and by amount smoked Study Ciearettes Number of years stopped Current per dayI <1 1+-4 1-9 5-9 10+ smokers <19 2 04 1.30 1. 08 1.61 Men in 9 Stetes I ---------- l 20+ . 2,69 . 1.82 1.50 2:02' <19 1 60 62 1 1i 46 0 81 3 1. 13 Men in 25 States________-__ l 20+ . 2.80 . 2.01 1151 . 1.22 2.01 I These data are from Hammond and Horn, 1958: TABLE 1'3.-Mortality ratios f or ex-cigarette smokers by number o f years o f smoking, U.S. veterans study Cigarettes per day 1 Number of,years of smoking 1-20 ---------------------------------------------------- 20 - ---------------------------------------------------- 1-20 ---------------------------------------------------- 20+---------------------------------------------------- <15 I, 1&24! . 25-34 35+ 1.05 1.08 1125 1.58 1.12 1.18 1.41 I 00 2.00 Age at which smoking was stbppe& <45 45-54 55+ ~ 1.09 1i 24 1. 51 1.12 1'. 59 1.86 Some supplementary analyses throw a little further light on this topic. In the two American Cancer Society studies (Table 12) a breakdown is given by the number of years since smoking was stopped. Except for the smokers of'~ under one pack a day in the 25-State study, the mortality ratio for men who had stopped less than a year is higher tham that for current smokers. Thereafter the ratio drops steadily as the intervall since smoking was stopped increases. In the UIS. veterans study, further breakdowns are available by the numbers of' years during which the ex-smokers were smoking an& by the age at which smoking was stopped (Table 13), as well as by the amount of' smoking. The mortality ratios are about the same for those smoking less than 15 years as for those smoking 15-24 years. Thereafter the ratios rise with longer durations of smoking. Table 13 also shows that mortality ratios were higher for those who stopped smoking,at later ages. 93
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I. Ex-CIGAR AND PIPE SMOKERS Mortality ratios for smokers of cigars only and pipes only who had stopped smoking prior to the date of entry are given in Table 14, the cor- responding ratios for current smokers being included for comparison. For ex-cigar smokers the mortality ratios are higher than those for non- smokers and higher than those for current smokers in all four studies pre- sented. The same is true for ex-pipe smokers wi& the exception of the Canadian study. The interpretation of this result is not clear to us. According, to Ham- mond and Horn (10) and Dorni (6), the explanation may be that a sub- stantial number of cigar and pipe smokers give up because they become ill: some data from cigarette smokers that support this explanation~ have re- cently been analyzed by Hammond (12). Further analysis of the U.S. veterans data indicates that mortality ratios run highest in ex-smokers who smoked~ heavily and for a long time. TABLE 14.-Mortality ratios for ex-smokers o`, cigars only and pipes only and for current cigar and pipe smokers Type of smoker British Men in U.S. Canadian ' Men in doctors 9 States veterans veterans 25 States ]yx-cigar----------------------------------- ------------ 1.65 1.30: 1.17 i 1.24 Current ciKar- ---------------------------- ------------ 1.10 1.07 1.11 0.97 Fx-pipe----------------------------------- 11.12 i 1.29 1.,38' 1.01 L 23 Current pipe------------------------------ 10.95 I 1.05 1.06 1.10 0.86 I Pipe andicigar combined. EVALUATION OF SOURCES OF DATA THE STUDY POPULATIONS Various reasons dictated the particular choices made of the seven study populations, considerations of feasibility playing an important role. None of' the populations was designed, in particular, to be representative of the U.S, male population. Any answer to the question "to what general popula- tions of men can the results be applied?", must involve alr element of un- verifiable judgment. However, three of the studies have populations with widespread geographic distribution within the United States, as do the British and Canadian studies within their respective countries. Taken as a whole, the seven populations offer a substantial breadth of sampling of the type of men and environmentali exposures to be found in North America and Britain, as well as providing some variation in methodological approach, although the basic plan was similar in al11 studies. The seven studies differ considerably in size. They vary also in the extent to which they are free from methodological weakness. The studies of men in nine states and men in 25 States, for instance, suffer from the difficulties 94 d
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that the populations studied are hard to define, that the smokers and non- smokers were recruited by a large number of volunteer workers, and that completeness in the reporting, of deaths was hard to achieve, since this de- pends on reports from the volunteers. On the other hand these studieshave the advantage of being large and of having a broad geographic representa- tion of the U.S. male population, while the second study is the only one that attempts to investigate many other relevant variables in which smokers and non-smokers may differ. In the California occupationall study the focus of interest is occupational differences in lung cancer mortality, smoking history being recorded primarily in order to be able to adjust comparisons among different occupational groups for differences in amount smoked. In the analysis we.have not attempted to rate the studies as to over-all quality or to assign differential weights to their results, except'that in the smaller studies it is recognized that mortality ratios are subject to larger sampling errors. Our attitude is to attach importance: only to results that appear to be generally confirmed by the studies. Some idea of the relative death rates in~ these studies as compared with the 1960 white male population of the United States is given in Table 15, which shows the age-adjusted death rates for ages 35 and over, using the age dis- tribution of the U.S. white male population as a standard. (The choice of ] 960 for the comparisoni is arbitrary, but the white male rate clianged! little between 1955 and 1960:)'. In all studies the death rates for non~smokers are markedly below thosee of U.S. white males in 1960. Even, the smokers of one pack of cigarettes or more daily have death rates that average slightly belbw the U.S: white male figure. To some extent this is to be expected, since hospitalized and other seriously ill persons are not recruite& in such studies. The sizes of the differ- ences appear, however, surprising for the studies with United States popula- tions. Hammond and Horn (10)1, in a special' investigation on this ques- tion, concluded that the discrepancy in their study was due to the screening out of sick persons in recruiting, plus probably a selection towards men, of higher economic levels. They point out that their death rates are substantially above those for males who had held ordinary life insurance policies for from TABLE 15.-Age-adjusted death rates per 1,000 man-years /or current smokers o f cigarettes only (aged 35 and over) i, by amount smoked, in seven studies and f or U.S. white males Study 1Con- Current smokers of cigarettes only U.S. white smokers Less than 1 pack 1 pack or more males, 1960 British doctors---------------------------------------.-- 15.8 19.2 23.2 22. 9 Men in~,9~States------------------------------------ ---- 1 14.4 122.4 127:1. 122,6 U.S. veterans----------------------------------------- 1220 18.1 23:9 22.9 California~~.occupational---------- ______________________ 110.51 i 14.2 1 18.0 122,6 Cahfornia legion ------------------------------------ -- 11. 3 16.4 16:3 219 Canadian veterans------------------------------------- 14.1 22.1 242 72.9 Men in~25.States__________________ - 2 12.9 ~ 18. 5 3 19:2 22.9 I Ages 50-69; ' These figures may be too low by about 1.7 percent, since the person•years used' in the computation included some contribution by men who ~bad not been fully traced. 95 7 f 4-422 0-64-8
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5 to 15 years. The U.S. veterans' study population also: came mainly from the middle and upper socio-economic classes (6). Another reason might be a failure to trace all d'eaths: In mass studies it is almost impossible to devise infallible provisions for recording every death. The study directors were, however, experienced in handling this problem~ and it seems unlikely that more than, say, 5 percent of the deaths would be missed. (Moreover, in~ the studies of veterans it is to the family's advantage to report the death.) Another contribution, probably came from the failure to obtain data for „ some members of the population. Evidence on this point is available from the British doctors and the U.S, veterans' studies, in which deathi rates for the complete population (respondents and' non-respondents) are available. In these studies the death rate for the whole population exceeded that in the respondents, but by only 5 percentl to 10 percent, so that non«response appears unlikely to be a major cause of the discrepancy. So far as interpretation of results is concerned~ the discrepancy raises two points. It is clear that the seven~ prospective studies involve popula- tions which are healthier than U.S. males as a whole. Secondly, the low death rates for non-smokers suggest the possibility, that the studies recruited! unusuallyy healthy groups of non-smokers. In the case ofi the five studies which had clearly defined populations, this selection would arise only if the non-smokers who refused to enter the study had death rates much higher than~ those who were enrolled. This point is discussed in the next section. NON-RESPONSE BIAS In all five studies that had! a clearly defined target population, sizeable pro- portions of the population~ were omitted. The maj or reason was failure to answer the questionnaire; in addition, certain replies were rejected as too incomplete. The percentages of the populations for which usable replies were obtained were approximately as shown in Table 16. TABLE 16.-Percentages o f usable replies in five studies Britisti ~ doctors 68 LT.S. veterans. Californi a occupa- tional 68,95 1 85 California Legion 56 Canadian veterans 57 In the ULS. veterans study, 68' percent'~ replies were obtained from the 1954 questionnaire. A second questionnaire, sent in 1957, enrolled an addi- tional 17 percent, for whom data are available during the period 1957-60. In the two Americani Cancer Society studies it is not possible to present meaningful percentages, since each research volunteer selected her own small part of the study population from among her acquaintances. The possible effects of these amounts of non-response on the mortality ratios have received little discussion. Some pieces of information about 96 I
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non-respondents are available in two studies. From a recent sample, Doll (4) states that'. (a)~ the death rate of non-respondents in the British doctors study is higher than that of respondents; (b) consequently the death rate for respondents is lower than that of British doctors as a whole, perhaps by as much as 5 percent to 10 percent; (c) there are relatively more smokers among the non-respondents than among the respondents. In the U.S. vet- erans' study, the death rate for the whole study population exceeded t'hat for the original! 68 percent responders by 7 percent in 1958'& and' 5 percent in 1959. From~ this study one can also calculate mortality ratios separately, during,1957=60; for the 1954 respondents and the: 1957 respondents. The results forr smokers oflcigarettes are as follows: 1954 1957 Non- respondents respondents: respondents(6$ percent) (17 pereent)(~15 percent)i Current cigarettes only_____________ 1.87 1.71 ? Current cigarettes and other________ 1.56 1.33 ? Those who did not respond in 1954 but did respond in 1957 show lower mortality ratios than the: original set of men giving usable replies. By making guesses about the mortality ratios in the 15 percent of' non-responders, one can compare the resulting mortalit'y ratio in the whole population with that found in the original 68 percent. To consider how much of an over- est'imate the ratios of 1.87 and 1.56 might be, we might suppose, to illustrate the method, that! the mortality ratio is unity for the non.respondents. The mortality ratio for the whole population then turns out to be 1.71 for cig- arettes only andl 1.44 f'or cigarettes and other. Thus, with a non-response rate of 30 percent, the computed mortality ratio might overestimate by 0.1 or 0:2. Berkson (1) produced a set of assumptions under which, with a mortality ratio of 1 in the whole population and a. response rate of 71 percent, the mortality ratio in the respondents is found to be 1.5. Non-respondents are assumed to be of two types. One group, destined to have a high~ death rate, refuses because they d'on't feeL well. This group has a high refusal rate (50 percent) for both smokers and non-smokers, since the reason for refusal is illness and not smoking. In the remainder of the non-respond'ents, the refusal rate is higher among smokers than non-smokers. Qualitatively, these assumptions are not unreasonable and agree in direction with the results quoted previously for the British doctors and' U.S, veterans' studies. Korteweg (15 )' worked further examples of Berkson's model as applied to individual causes of death in the first report of the study of men in nine states. He concluded that the response bias im the mortality ratio might be as high as 0.3. Both Berkson and Korteweg, had, of course, to make some arbitrary assumptions about the sizes of biases from different sources. Further discussion of the non~response bias and computations as to its magnitude are given in Appendix I. The computations indicate that re- ported mortality ratios lying between 1 and 2 might overestimate by ass much as 0.3; a mortality ratio of 5.0' might overestimate by 1.0, and one of 10.0 might overestimate by 3.0. Thus, under assumptions that are rather extreme, although consistent with the available data about non-respondents, 97
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the mortality ratios of cigarette smokers would still remain substantially higher than unity after adjustments for these amounts of over-estimation. MEASUREMENT OF SMOKING HISTORY Measurement of the type and amount of smoking, being based on a single mail questionnaire, was admittedly crude. Consider men recorded as cur- rent smokers of cigarettes only. Subsequent to enrollment, some of these presumably stopped smoking, at least temporarily, and some took up other forms, with orwit'hout cigarettes. Similarly, some men recorded as non-smokers may have begun to smoke cigarettes subsequently. Consequently, the group designated as "current smokers of cigarettes only" presumably contained men who were, for somee period of time "ex-smokers" or "cigarette and other" sanokers, while men designated as "non-smokers" contained' some who smoked cigarettes for a time. It seems likely that this dilution of the contrast between the two groups would make the mortality ratio of cigarette smokers, as reported in previous tables, underestimate the mortality ratio of unchanging cigarette smokers relative to unchanging non-smokers, particularly when we note that the groups labeled "ex-smokers of cigarettes" and "cigarette and other" smokers both had mortality ratios lower than the group labeled "current smokers of cigarettes only". As regards number of ciprettes per day, two types of errors of measure- nient may occur. There will be "random" errors of measurement (some men overestimate the amount and others underestimate it) that tend to cancel out over all men in the study. The efEect' of such errors is that the reported data underestimate the increase in the mortality ratio per additional cigarette smoked daily, the computed increase being an estimate of B/(1'+ h), where B is the true increase and h is the ratio of the variance due to errors of' measurement in the amount smoked to its total variance, Yates (17). There may also, however, be systematic errors in reporting the amount smoked. Heavy smokers may tend! to underestimate the amount smoked. If'. this happens, the reported increase in mortality ratio per additional cigarette smoke& will be an overestimate of the true increase,. although the upward trend of mortality ratio with increasing amount smoked will remain. On balance, we are inclined to agree with the opinion expressed by the authors of several'i of the studies to t'he effect'that the general result of errors in reporting smoking, history is t'o depress the mortality ratios of smokers relative to non-smokers, so that reported' ratios willl tend to be underestimates so far as this source of error is concernedl STABILITY OF THE MORTALITY RATIO The sampling distriliution of the mortality ratio has not to our knowledge been at all thoroughly investigated and appears to be complicated. As a rough approximation (Appendix II ), the ratio of smoker deaths to smoker 98 60-
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plus non.smoker deaths may be regarded as a binomial' proportion with mean .kR/(1+hR)i where R is the true mortality ratio, X is the ratio of the expected smoker deaths to the observed non.smoker deaths and the samplee size is the number of smoker plus non-smoker deaths. From this approxima- tion, confidence limits for R may be derived. This approximation requires that (1) the age distributions of smokers and' non-smokers do not differ greatly and (2) all age-specific death rates are small. An alternative normal' approximation that avoids assumption (1) is also giveni in Appendix II. The sampling variation of the estimate of R is seldom of major import in, this part of the report, since the ratios for total mortality are mostly based on relatively large number~s of deaths. The estimate has a: positive mathe- matical bias, negligible with large but not with smalll numbers of deaths. In another sense the particular mortality ratio used in this report has a: different kind of bias. Since the standard age-distribution used in this ratio is the age-distribution of the smokers, who are somewhat younger than the non-smokers, the mortality ratios apply to populations slightl!y younger than the combined population of the st'udy. This is not in~ our opinion a seri- ous objection, but may sometimes be relevant ini questions of interpretation. OTHER VARIABLES RELATED TO DEATH RATES. As mentioned previously, the smokers and' non-smokers in these studies may differ with respect to other variables that might influence the death rate. Except in the new 25-State study, no attempt was made to measure these variables apart from urban,r~ural residence, and previous reports on thesee studies give little discussion of this problem. For urban-rural residence, Doll and Hilll (5) found that the proportions of smokers of different amounts in the study population were about the same in rurall areas, small cities and large cities. In~ three studies the mortality ratios of cigarette smokers weree computed separately by size of city (6, 10, 11). In the study of men in 25 States, the data refer to men who smoked 20 or more cigarettes a day and said that they inhaled moderately or deeply. In all three studies the mortality ratios show little:change with size of community (Table 17). In the 25-State study, over 20 other variables that may be associated with death rates were recorded. The study population was broken down int'o: subgroups for many of these variables separately: for instance, into smokers who have long-lived parents an& grandparents and those: whose parents and TABLE 17.-Mortality ratios f or cigarette smokers by population-size o f city Population-size Study. O ver 50,000~ 10;000- 50;000 Small towns Rural Men.in 9~States---------------------------------------- 1.48 1i62 1.50 1.152 iP.S. veterans ------------------------------------------ 1. 54'. 1151 1.42 1.59 Menlin 25 States--------------------------------------- 1.89 12,02 ------------ 1.74 I Includes towns of less tban 10,000. 99
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grandparents were short-lived. Inclhlded among these variables were reli- gion„ educational levely native or foreign birth, residence: by size: of town and occupational exposure, use of aleohol, use of fried food, amount of nervous tension, use of tranquilizers, and presence or absence of prior serious disease. For cigarette smokers who smoked more than a pack a day and inhaled moderately, or deeply, the mortality ratio was computed within each subgroup. For example, the mortality ratio was 1.99: for men with long-lived' parents and 2.30 for men with short-lived parents: In every subgroup the mortality ratio was well above unity, the lowest among 71 computed ratios being 1.57 (for men with a history of previous serious disease):. These data provide information on the association of the other variables with mortality as well as on, the association of smoking with mortality. For six of the most relevant variables, Table 18' gives age-adjusted death rates, using the combined' populations of non-smokers and cigarette: smokers as the standard population. The death rates apply to a period of roughly 22-months follow-up. As already mentioned, the: cigarette smokers (of more than a pack per d'ay who inhaled moderately or deeply)~ have higher deathi rates thani the non-smokers in, every cell of Table 18. Since not all respondents answered these supplementary questions, the results may be subject to some additional non-response bias. As would be expected, death rates are relatively high for men with previ• ous serious disease and for meni from short-lived families, and are somewhat TABLE 18!-Age-adjusted death rales per 1,000' men (over approximately 22months)f or i•ariablesthatmay be relatedto' mortality Type of smoking None ------------------------------------- Cigarettes '-------------------------------- None-------------------------------------- Cigarettes '- ------------------------------ :rione----------- --------------------------- Cigarettes,V `------------------------------- None-------------------------------------- Cigarettes I -------------------------------- Long4ived parents and grandparents 14i S 27.1 Single 2fi. 0 ~ 50.1 No high school 22.7 35.2 None Shortdived~ parents and grandparents 21.1 44.8 Married 18. 9 33.0 No previous serious disease 11.5 22.3 Use tran- quilizers Educational level Some high !IIiRh school I school I gradhate. 20. 0 34.5 16: 9 35.5 Degree of eaceroi'se2 Slight 23.8 34.1 14.7 25.5 Previous serious disease 42:5 65:0 Do not use tranquilizers 29.1 !' 18.2 52.4 1 31.8 Some college College graduate 18.3 34. 2' ' 15.8 29:4. IIeavy 11.0 20.8 9,5 19.7 I Smokers of~morethania.pack per day«-ho,inlialed rnoderatelyor deeply. , Confined to men with no history of heart disease, stroke, high blood pressure or cancer (except skin) who: were not sick at the time of entry. Moderate: r t 100
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higher for single: than for married men. The size of the excess death rate for users of tranquilizers compared to men who d'o noti use them is perhaps surprising (29.1 against 18.2 and 52.4 against 31.8). However, the tran- quilizers in question~ required a doctor's prescription, so that some mem in this group are presumably under medical attention for illness. The group of users is small, comprising only about 10 percent of those who answered this question. Death rates tend to decrease slightly as the educational level increases; this associationi may represent, some facet of the association of death rates with socio-economic level. Degree of' exercise displays an inter- esting association with mortality, the deathi rate declining, steadily with additional degrees of exercise. In particular, the two "no exercise" groups show marked elevations in death rates. These groups, however, amouM to only 2 percent of'. the respondents to this question. From the same data; Ipsen and Pfaelzer (14)~ made a further analysis of seven variables that appeared to be related to mortality, in order to see whether any of the variables had a stronger association with mortality than did cigarette smoking. They concluded that apart from previous serious disease, none of the other variables examined had as high a correlation with mortality as smoking of cigarettes. Further, the correlatiom of any of these other variables with cigarette smoking, was too weak to reduce markedly the correlation of cigarette smoking with mortality after adjustment for the other variable. In the analyses above, smoking was matched against each variable sep- arately. In additiony Hammondl (1'1) carried out a "matched pair" analysis,, in which pairs of cigarette smokers and non,smokers were matched on height, education, religion, drinking habits„ urban-rural residence and' occupational exposure. The percentage who had died in the 22 months was 1.64 for smokers and 0.88 for non-smokers. These informative analyses are available, unfortunately, for only one of the studies: However, in~ order that the association of cigarette smoking with mortality should disappear when we adjust for another variable, the correlations of this variable with smoking and with the death rate must both be higher than the correlation between smoking and the death rate. Except for the breakdowns by longevity of parents and grandparents, the analyses throw little light, however, on the objection that a part of the differences in death rates may be constitutfional; psychological or behavioral; i.e., that regular cigarette smokers are the kind of men who would' have higher death rates even if they did not smoke. Further discussiom of this point appears in the next section. MORTALITY BY CAUSE OFDEATH In all seven studies the underlying cause of deaths as specified in, the Inter- nationall StatisticaU Classification of Diseases, Injuries and Causes of Death, was abstracted from the death certificate. In the two American Cancer So- ciety studies, further confirmation of the cause of death, including,histological evidence, was sought from the certifying physiciamfor all cancer deaths; this 101
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procedure was also follbwed' in the British doctors' study for all certificatess in which lung cancer was mentioned as a direct or contributory cause. With these exceptions the data presented here represent the results of routine death certification. For current smokers of cigarettes the total mortality, after adjustment for differences in age composition, was found previously (Table 2) to be about 70 percent higher than that of non-smokers in these studies. The primary objective in this section is to examine whether this percentage increase ap- pears to apply about equally to all principal causes of death, or whether the relative increase is concentrated in certain specific causes or groups of causes. RESULTS FOR CIGARETTE SMOKERS I For 24 causes of death, plus the "alllot'her causes" category, Table 19 shows summary data over all seven studies.* In~ four of the studies the data are those for current smokers of cigarettes only, but in the two California studies and the 25-State study the cause-of-death breakdown was available only for all cigarette smokers including "cigarette and other" smokers and current and ex-smokers. For each listed cause, Table 19 shows the total numbers of expected and observed deaths of cigarette smokers summed over all seven studies; and TnsLE19,-Totalnumbers of ' expected and observeddeatJisand mortality ratios f or smokers of'cigarettes only 1 inseven prospective studies Underlping cause of death Expect'ed~ i Observed, Mortality ratio Median mortality ratio Non-smoker deaths - Cancer of lun¢~(162-3) ~--_---____ 170.3 1;R33 I 10.,8' 11.7 123 _ Bronchitis and emphysena (502: 527.1) }__ 89.5 546 6. 1 7.5 59 Cancer of larynx (161) _------------------- 14.0 75 5 4 5.8 8 Cancer~~oforaloavity(140-.-8). ______________ 37.0: 152~ 4.1 ~ ~ 3.9 27 Cancer~of esophaeus(d50) .-- -------------- 33:7~ 113 3:4. I 3.3 Stomach and duodenal ulcers(540-1)------ 105.1 ~, 294 2:8 5.10 67 ~ Other circulatoryy diseases (451-f68)~-------- 254.0 ~ 649: 2:6 2:3~ '~. 170 Cirrtiosisofliver(581)------------------ ___ 169.2 379 2.2 2.1 96 Cancer of bladder (181) -------------------- 111.6 216 1.~9 2.2 92 Coronary artery disease (420)-------------- 6;430:7 11,177 1,7 1.7 4,731 Other heart diseases (421-2, 430~)--------- j 526.0 868 li 7, 1.5 398 Ilypertensive~heart disease,(444-3)._------- 409.2 631. 115 1.5 334 (7enerallarteriosclerosis (450)--------------- 210.7 310 115 1.7 201 Cancer of kidneyy k180)--------------------- 79.0. 120 P.5 1.~4 59 All other caneer--------------------------- 11061.4 1,524 I 1.4 1.4 742 Cancer of stomach (151)-------------------- 285.2 I 413 1.4 L 3 203 Influenza, pneumonia (480-493)_----------- 303.2 415. 1.4 1.6 169 AB otiiercauses--------------------------- 1,.508. 7 1j 946 1.3 1.3 1,036 Cerebral vascular lesions (330-4) ---------- 1,461.8 1j 844 1.3 1.3 11 ~9 Cancer ofiprostate (177)'_------------------ 253.01 318 1.3 1.0 198 Accidents,suioides, violence (800-999)_---- 1,063.2 1,310 1.2 1.3 627 Npphritis (592-4)-------------------------- 156.~4 173 1.1 ' 1.51 ~ 98 Rheumatio~~heart~disease (490+416)--------- 290;6'. 309~ 1.1 1.1 185 Cancerofreetum(154)-__----------------- 20Z8' 218~ 1.0 ! 0.~9~ 150 II intestines (152-3) 422:6 395 0.9 ~ 0!9'~ 307 Allcausen---------------- I 15;653:9 2fi;223' 1.68~ 1.65 ,I I Currenti cigarettes only for four studies:i all cigarettes (current and ex-) for the two California studies and the study of men in 25 Btates. 2 "Bronchitis and empriysema'."includes "other bronchopulmonary dlscasesl"for men in nine States and Canadian veterans. *The individual resultsfor the seven studies are shown for reference purposes Table 26, 102 im
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the resulting mortality ratios, arrange& in order of decreasing ratios. The combination~of the results of the seven studies in this way is open to criticism, since it gives more weight to the larger studies than may be thought adavis- able, and since the true mortality ratios for specific causes presumably differ somewhat from study to study. However, for some causes of death that are of particular interest the numbers of deaths are small in all! studies, so that some procedure for combining the results is hibhly desirable. As an~ alternative measure of the combined mortality ratio, the median of thee seven mortality ratios (obtained by arranging the seven ratios in~ increasing order and selecting the middle one) is also shown for each cause in Table 19. The mediany of course, gives equall weight to small and! large studies. AlthougK there are some changes in the ordering of the causes when~medians are used instead of the ratios of' the combined deaths, the general pattern in Table 19 is the same for both, criteria. Table 19 also presents the total numbers of non-smoker deaths on which the combined! mortality ratios are based. Lung cancer shows the highest mortality ratio in every one of the seven studies, the combined ratio being 10.8. Other causes that exhibit sub- stantially higher mortality ratios than the ratio 1.68 for alll causes of death in Table 19 are bronchitis and emphysema, cancer of the larynx, cancer of the oral cavity and pharynx, cancer of the esophagus, stomach and duodenal ulcers, and a rather mixed category labeled "other circulatory diseases," which incliides aortic aneurysm, phlebitis of the lower extremities, and pulmonary embolism. For three of these causes-cancer of the larynx, oral cancer and cancer of the esophagus-the numbers of non,smoker deaths are small, so that the over-all mortality ratio~ cannot be regarded as accurately determined. The U.S. veterans' study and the 25-State study provide an additionall breakdown for two of the causes listed in Table 19. For the rubric 527.1 (emphysema without mention of bronchitis), these sthrdies give mortality ratios of 13.1 and 7.5, respectively. For ulcer of the stomach they give 5.11 and 4:3, whereas for ulcer of' the dtiod'enum their mortality ratios are 2.3 and! 1.1. Bronchitis and emphysema also show a high, rate, 12.5, in the British doctors' study. There follows a list of 14• causes whose mortality ratios are not'~ greatly different from the ratio of 1.68 for all causes in, Table 19. These causes range from cirrhosis of the liverr„ with a ratio of 2.2, down to a ratio of 1.2 for the miscellaneous class which; contains accidents, suicides and violent deaths. This group includes the leading cause of death, coronary artery disease, with a ratio of 1.7, cerebral vascular lesions with a ratio of 1.3, and the "all other causes" group with a ratio, of 1.3. For each of these 14 causes the mortality ratio differs from unity, by the approximate statistical test of significance. Finally, there are four causes-nephritis, rheumatic heart disease, cancer of' the rectum and cancer of the, intestines-whose mortality ratios are close to unity. For smokers of cigarettes and other, the data from four studies agree in general with the ordering of' causes in Table 19, although the mortality ratios for most causes are slightly lower than with smokers of cigarettes 103
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only. These and the corresponding data for ex-cigarette smokers are shown in Table 20. Data on ex-cigarette smokers can be obtained from four studies. The causes of death with mortality ratios of 2.0 or higher are, in~ decreasing order, bronchitis and emphysema (~7.6), cancer of the larynx (5.4), cancer of! the lung (4.8)~, stomach and duodenal ulcers (3.1), oral cancer (2.0), and othercirculat'ory diseases (;2:0)~. The group of 17 causes with mortality ratios below 2 in Table 19'requires discussion. If cancer of the bladder (mortality ratio 1.9) and coronary artery disease (mortality ratio 1.7) are omitted, since they receive d'etaile& consideration~ elsewhere in this report, the numbers of expected and observed deaths for this group as al whole are as follows: Expected Observed Mortality Ratio 8,241.3 10,789 1.31 If we exclude from this total the four causes at the foot of Table: 19, for which the mortality ratios are 1 and smaller, the corresponding totals become: Expected Observed Mortality Ratio 7,164.01 9,699 1.35 In either case the excess of observed over expected' deaths is close to 2,500 or about 25 percent of~the totaliexcess in observed deaths ini Table 19. Thus, although the mortality ratios for these groups are:only moderately over 1, the group as a whole contributes substantially to the total number of excess oh- served deaths. The group consists mainly of a miscellaneous collection of chronic diseases. Several tentative explanations of this excess mortality ratio can be put for- ward. Part may be due to the sources of bias previously discussed. It was indicated in the section on "Non-Response: Bias" that the bias arising flrom~ non-response might account for a mortality ratio of 1.3. Relatively high mortality ratios in certaini causes of death that have not yet been examined' individually may also be a contributor, although as these causes are likely to be rare, the contribution from this source can hardly be large. Part may be due to constitutional and genetic differences between cigarette smokers and non-smokers. Except for the breakdown mentioned previouslyy by longevity of parents and grandparents in the men in 25 States study, there is no body of data available that provides a comparison of cigarette smokers and non-smokers on these factors as they affect longevity. But it! is not un- reasonable to speculate that the kind of men who become regular cigarette smokers are, to a.moderate degree, less inherently able to survive to a ripe old age than non-smokers. We know of no way to make & quantitative estimate of the difference in d'eath~ rates that might be attributable to such constitu- tional and genetic factors. Studies reporte& ini Chapters 14 and 15 indicate that some average differ- ences can be detected' between smokers and non-smokers on behavioral, psychological and morphological characteristics. Nevertheless, the same com- parisons show considerable overlap between the individual men in a: group of smokers and a group of non-smokers: For what they are worth, these com- 104. ..<
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TABLE 2O.-Expected and observed deaths and mortality ratios for current smokers of' cigar'ettesand other (threes'tudies)1 and for ex,cigarette smokers, ( fburstudies) 2 Underlying cause of death Cigarettes and other Ex-cigarette Cancer of lung (162-3)'.-_____-_ Bronchitis and emphysema (502,.527:1) 3 ----------------- Cancer of larynx (161), ._ Cancer of oral cavity (140+8) _ - Cancer oCesophaeus (150) i _ _ _ _ Stomaoh and duodenal ulcers (540-1) --------------------- Other circulatory diseases (451-468)'- ----------------- Cirrliosis of liver (581)--------- Cancer of bladder (181),___-___ Coronary artery disease (420)_ Other heart diseases (421-2, 430-'k)----------------------- Hypertensive heart disease (440~3) --------------------- General arteriosclerosis (450)-_ Cancer of kidney (180)________ All other cancer _ ------------ Cancer of stomach (151) _ ____ Influenza, pn un:onia (480+493)_ All other causes _____________ Cerebral vascular lesions (330- 4)'-------------------------- Cancer of prostate (177) __ A'ccidents, suicides, violence (800-999) ------------------- Nephritis~(59211). -._____-____ Rheumaticheart disease (400- 416): ------------------------- Cancer of'.rectum (154)-_ _ C9ncer ofiintestines (152-53)-.. All oauses,--__________________ Number of deaths : Mortality Number ofideaths Mortality Expected Observed ratio E'xpectad Observed ratio 60.9 ' 510 9.4 30.4 ' 145' 4.8 53.2 191 3.6 17.4 133' 7.6 1.6 20, 12.5 1.3 7 5.4 11.1 42' 3.8 5.9 12 2.0 111 57 4.4 5.4 6 1.1 23.0 99 4.3 13.0 40 3.11 99.0 227 2.3 45.8 93 2: 0 57.3 85 1.5 22.4 271 1.2 58. 2 73' 1.3 29.8 311 1.0 2; 335. 0 3,262 1.4 1j 245 0 1, 731' 1.4' 225.9 321 1.4 124.1 178 1.4 144.4 174 1.2 93.0 133 1.4 106.8 146 1.4 63.7 75 li 2 25. 0 37 1.5 13. 9' 25 118 2719 339 1.2 199.3 239 II2 101.0 139 1.4 ' 51.4 66 1.3 199.2 '. 153 0: 8 55: 1 55 1.0 769:3 790 1.0 308.1 357 1.2 634. 0 ~ 605 1.0 300:1 321 1.1 97.1 118 12 52.0 57 1. 1 287.1 316 111: 169.6 159 0.9 30.17 44 114 21.7 23' 1. 1 96.~ 0. 86 0,9 47.9 59 1.2' 89:7 64 0,7 . 43.3 38 0.9' 149.6 ' 164 1.1 85.8 97 1.1 5,~ 941. 1 8,062 ' 1.4 3; 045. 5 4,107 1.35 1 British doctors, U.S, veterans and Canadian veterans. 2 British doctors„men in nine States, U.S. veterans, and Canadian veterans. '"Bronchitis and'emphysema" includes "ottier broachopulmonary diseases" for men in nine States and Canadian veterans, parisons suggest by analogy that the differences in death rates from constitu- tional or genetic factors may be moderate or small rather than large.* Fur- ther, it seems unlikely that constitutional or genetic differences between cigar and! pipe smokers and! between~ these groups and non-smokers can have any substantiali effect on their death rates, since the over-all death rates of these three groups differ only slightly. Finally, part of the difference may represent a general debilitating effect of cigarette smoking, ini addition to marked! effects on a few diseases. Pearl's hypothesis that smoking increases the "rate of living" is of this type, though there are difficulties in making' this hypothesis precise enough to he subject to medical investsaation. Hammond! (13) has suggested that the explana- tionimiglit lie in the effect of cigarette smoking inidecreasing the quantity of oxygen per unit volume ofblaod, but there are numerous medical objections to this hypothesis. This Committee has no information that would'' lead it to favor one or another of the possible explanations put forward above. •This question is discussed more fully in Chapter 9, p. 190. 105
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MORTALITY RATIOS FOR CIGARETTE SMOKERS BY AMOUNT SMOKED For coronary artery disease and lung,cancer, the mortality ratios are given j 11 smokers (~current and ex-smokers combined) show a less marked trend. studies. The two California studies, in which the data are for all cigarette In Table 21 an increasing trend with amount smoked appears in all five by amount smoked in Tables 21 and 22 for current smokers of cigarettes only: TABLE: 21. Mortality ratios f or coronary artery disease f or smokers o f cigarettes only by amount smoked Number oUpacks per day British doctors < --------------------------------------- 1.0 1.2 3~t`1--------------------------------------- 1.5 1.9 1-2`--------------------------------------- 1 7 2:1 Ocer 2 ---------------------------------- 2.4 I More than one pack. TABLE 22.-Lung cancer mortality ratios for current smokers of cigarettesonly by amount smoked Number of packs per day E 3!i ° ------------- -------------------------------------- Sz-1---------------------------------------------------- 1 -2 ----------------------------------------------------- Over 2------------------------------------------------- I Over one pack. The trends in lung cancer mortality ratio with amount smoked are steep in all four studies. The two California studies also show marked trendss for all cigarette smokers combined. For the six causes of death (other than lung, cancer) ~ that were pointed out in Table 19 as having unusually high mortality ratios„ the numbers of deaths permit a breakdown~ only into two amounts smoked. The results from six studies are shown~ in Table 23. Data were not available from the TABLE 23.-Expected and observed deaths and mortality ratios for current cigarette smokers, for selected causes of death, by amount smoked, in six stud zes Causes of death i Bronchitis and emphysema:-- Cancer ufilaryna-------------- Canccr oforal cavity-----_--- Cance~r ofiesopfiagus.--------- Stomach and duodenalulc.^rs- Other circulatory-----_------ Caneer of4hee bladder---_---- 106 One pack or less More than one pack Number of deaths Mortality Number of deaths Expected Observed ratio 11 E apccted O hserved 44.6 225 5.0 17.2 147 3:8 19 5 3 4 1' 31 18: 8 53 . 3.2 . . 14. 8 60 13.2 401 3.0 9.7, 48 32:5 110 3. 4 31i2 91, 98.5 253 2.8' 60.4 175 57:3 80 1.4 23.7 73 Mortality ratio
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men in the 25-State study. Cancer of the bladder is included in Table 23 as background data for Chapter 9. All causes except' stomach and' duodenal ulcers show some increase in the mortality ratio for the heavier smokers. The rate of increase cannot be regarded as accurately determined in view of the small' numbers of deaths. CIGARS AND PIPES In view of the small numbers of deaths involved, the data for cigar and pipe smokers were combined in7ablb 24, which lists the totatexpected deaths,, total observed deaths and mortality ratios from five studies (British~ doctors, U.S. Veterans, Canadian Veterans, and men in~ 9 an& 25 States). Causes of death with relatively high mortality ratios are oraI cancer (13.4) , cancer of the esophagus (3'.2)1, cancer of the larynx (2.8)1„ cancer of the lung (L7),, cirrhosis of the liver (1.6),, and stomach and duodenal ulcers (1.6). It should be noted that all these ratios are based on modest numbers of deaths. TABLE 24.-Numbers of'expected and'observed deaths and mortality ratios for cigar and pipe smokers, in five studies " UnderlyinK cause of death Number of deaths Mortality Expected Observed ratio Cancer of oral cavity (140-8)L_______________________________________ 13.5 46'. 3.4 Cancer ofesophagus (150)_______________ _-_____________ 10:2 33 3.2' Canceroflarynx (1F1)----------------------------------------------- 3:2 9 2.8 Cancer oflunQ (162-3) ----------------------------------------------- 65.2 113 1.7 Cirrhosis of liver (581)______________________________________________ 47.5 77 1.6 Stomach and duodenal ulcers (540-1)________________________________ 35.2 56 1.6 Cancer of kidney (180)----------------------------- °--------------- 30!8 39 1.3 Cancer of intestines (152-3)_________________________________________ 174.6 219 1.3 Other circulatory diseases (451-168)_________________________________ 89.1 105. 1.2: Allothercancer_____ _________________ ___ 396. 7 456'. 1. 1 Cancer of prostate (177)---------------------------------- ___________ 127.2 144 1.1 Cancer of stomach (151)_____________________________________________ 116.8 ' 132 1.1 Cancer of rectum (154)----------------------------------- ___________ 78.2 ' 88 1. 1 Hypertensive heart disease(440-3)__________________________________ 194. 5 218 1.1 Other heart diseases (421-2;,430+4)_ ___________________ 272. 6 303 1.1 Bronchitis and emphysema (502; 527.1)______________________________ 33.7 37 1.1 Cerebral vascular lesions (330-4)____________________________________ 685. 3 720' 1.1 Coronary artery disease (420)__--_-_____°__________________________ 2,721.5 2,842 A1l other causes----------------------------------------------------- 612. 9 587 1.01 Influenaa andlpneumonla (480-493):_________________________________ 93.8 88 0.9 Accidents. suicides..violence (806-999)____________________________-_ 347.1 318 0.9 Cancer of bladder(181)---------------- _____________________________ 63.1 56'. 0.9 Oenerallarteriosclerosis (450)________________________________________ 124.1 109 0.9 Nephritls (592~)~------------ --------------------------------------- 63.6 55 0.9 Rheumatic heart disease (400-416)___________________________________ 100.5 69 0.7 A11 causes----------------------------------------------------------- 6,500.9 6,910 i 1.06 i Ineludes British doctors, men ini 9 States, U.S. veterans, Canadian veterans, and men in 25 States; includes ex-smokers for men in 9 States;,excdudes pipe smokers for Canadian veterans. Separate breakdowns by cause of death for cigar-only smokers and for pipe:only smokers are available in only three studies. The numbers of deaths are too few to throw any light on the question whether there are differences between cigar and pipe smokers in the causes of death for which~ mortality ratios are elevated. 107 As.% 11~. ,, l tl
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TIIE CONTRIBUTION OF DIFFERENT CAUSES TO EXCESS MORTALITY Several of the reports previously published on these studies have included a table showing how the excess number of deaths of cigarette smokers over non-smokers is distributed among the principal causes ofi death. For each cause, the difference between the observed and the expected number of deaths f'or cigarette. smokers is divided by the total excess for all causes, and multipliedl by 100 to express the figures on a percentage basis. Table 25 presents these percentages for the sevem studies for 13 groups, of causes. A negative percentage, which occurs in a few places in the table, implies that for this cause the observed smoker deaths were smaller than the expected deaths. TABLE 25.-Percentage of total number of, excessdeatlts, of'cigarette smokers due to dijfereat causes1 Underlying cause British ~Mcndu dbctors. 9'States II.S. veterans California~California occupa- Legion i tiona3 i Canadianj veterans. MIetrin 25 States ~ Coronary arterv disease_ ------ 32.9 51.9J 38.6 ! 43.5 43. 5 44.2 51.7 Otherheartd.isease------------- 9.9 3A ' 6.8 ! 1.4 ' 4..5 5.9 5.5 Cerebral.vascularlesimu------- 6.11 4..5, 4.9. '5.3 6.,5: -1.8 3:3 Other circulatbrp,diseases------ 1.9 2J7 7.1 1.71 0.2 5.6 4.4 Cancer of lung_ _______________ 24.0 13.5 14.9 20.2 16.8 18.3 1ti:6 Cancer of oral cavity, esopha- gus,dhrynz__--------------- 3.3 2:9 2.7 0.2 3.0 2.2 2.2 Othercaneer----------------- _ Bronchitisand emphyscma___ -0.2 9.6 9:8 I 1.1 , 8.9 4.0 6.3 1i.3 -2.2 5.6 7.2 8.2 7.6 3.8 Influenza and' pneumoni:i _ _ 2.4 1. 6. j 0.4 2.4 I ! 1.5 1..5. 1.5 Stomach and duodenaliuleers _ 2.7 3.1i 1.4 -1:7 2.2 2'9 1.3 Cirrhosisotliver_ _____________ 2.9 1:6 2:5 6.9 2.2 0.8 0.9 Accidents, suicides, violence__ 0.2 1i 2 i 2.0 0 8.3 3.7 4.6 0.8 All.othercatLVes:---------------- 9.2 3.0 5.8 4.2 12:,5 0:4 3.4 All causes_____________________ I 100.0 100.0 100.0 I 100:0 100.0 100.0 100.0 I All cigarette smokers, (current and' es-) for the two California and men in 25 States studies;: current cigarette smokers only for the remainder. As previous writers have noted, all studies agree inshow~ing, coronaryartery disease as the prime contributor to excess mortality, with lung cancer in second place. Other rubricsthat show a substantial contribution in some studies, though not in all, are bronchitis and emphysema, cancers other than those ofe the mouth and lungs, and heart'disease other tham coronary. SUMMARY This report summarizes the results of the seven major prospective studies of the relative death rates of male smokers' and non-smokers. TOTAL MORTALITY Cigarette Smokers The d'eathi rate for smokers. of! cigzrettes only who were smoking at the time of entry is about 70 percent higher than that for non•smokers. 108
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11 989S911c0 TABLE 26.-Numbers o f expected and observed deaths f or smokers o f cigarettes only, and mortality ratios, each prospective study and all studies Cause of death Cancer of lung-------------------------- (162-3) Bronchitis, emphysema_____________ (502, 527.1) Cancer of larynx-------------------------- (161) Cancer of oral cavity-------------------- (140-8) Cancer of esophagus----------------------- (h50) 9tomach-and duodrnal uic_ers_________(5_40,541) Other circulatory diseases--------------- (451-fi8) Cirrhosis ofliver-------------------------- (581) Cancer of bladder------------------------- (181) Coronary artery disease _______ _________(420) Other heart disea.ses-------------- (421-2, 430-4) Hypertensive heart diseaso ___ __ ___(440-3) General artericsclerosis ___ ____ ______(450) CanceCof kidney------------------------- (180) All other cancer----------------------------- ---- Cancwr ofstomach------------------------ (151)Influcnza, pneumonia------------------ (480-93) All other causes--------------------------------- Cerebral vascular lesions---------------- (330-4) Cancer of prostate________________________ (177) Accidents, suicides, violence_====______(800-999) Nephritis------------------------------- (592-4) Rheumatic heart disease--------------- (400-16) Cancer of rectum .-------------------------(154) Cancer of intestines--------------------- (152-3) All causes-------------------------- ---- British doctors Men in 9(3tates U.S. veterans California occupational Deaths Deaths Deaths Deaths Mortalit Mortality Mortality Mortality y ratio ratio ratio ratio Expected Observed Expected Observed Expected Observed Expected Observed 6.4 129 20.2 23.4 233 10.0 43.3 519 12.0 8.7 138 15.9 -- 4.2 --53 12.5 12.8 30 2.3 14.4 141 9.8 2.8 11 4:3 .0 7 --------- 1.3 17 13.1 2.4 14 5.8 .0 3 __________ .0 6 _ 7.8 22 2.8 8.1 54 6.0 7.2 7 1.0 3.3 7 2.1 2.7 18 6.6 5.2 33 6.4 5.5 4 .7 .0 14 __________ - 2.2 61 5.0 21:5 67 3.1 23.1 12 .5 17.2 27 - 1.6 - 19.7 53 2.7 66.4 228 3.4 11.5 18 1.6 .0 15 ---------- 23.5 49 2.1 31.2 11l 3.6 14.7 59 4.0 13.9 12 ----:9 17.2 41 2.4 31.4 55 1.8 2.2 13 6.0 366.9 535 1: 5 9 27: 7 1,734 1.9 1, f300. 3 3,037 1.7 273.9 551 2.0 78.8 115 1.5 _ 72: 5 108 1.5 122.2 244 2.0 23.8 24 1.0 21.0 32 1.5 89.7 107 1.2 138.7 223 1.6 27.2 28 1.0 21.2 21 1.0 9.1 18 2.0 97.0 1Fi.1 1.7 .0 5 __________ ,0 8 ---------- 14.0 21 1.5 23.1 34 1.5 .0 10 - - 81. 7 73 .9 132.9 230 1.7 315.8 457 1:4 72:1 105 1.5 2Fd:3 31 1. 1 33.7 76 2.3 f11.5 90 1.5 31:4 24 - .8 47.0 35 . 7 15.6 41 2.6 22.6 36 1. 6 10.3 25 2.4 144.0 182 1.3 209:5 263 1.3 354.8 530 1.5 69.9 101 1:5 161.1 192 1.2 208:8 279 1.3 309.1 467 1.5 42.2 76 1.8 29.0 15 . 5 32.4 51 1: 6 53. 7 106 2. 0 8.6 4 . 5 89. 2 90 1.0 174.1 192 1.1 241.5 306 1.3 108.4 161 1.5 8.1 17 2.1 43.3 34 .8 18.6 30 1.6 16.0 10 .6 10.2 13 1.3 48.4 43 .9 67.4 77 1.1 22.9 31 1.4 --4.2 15 3. 6 29.8 25 . 8 68. 7 62 . 9 13.6 14 1.0 26.1 28 1:1 65.6 35 .5 121.2 152 1.3 217 22 .9 1,161.8 1,672 1.44 2,227.7 3,781 1.70 4,043. 1 7,236 1.79 818.5 1,456 1.78
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TABLE 26.-Numbers of expected and observed deaths for smokers of cigarettes only, and mortality ratios, each prospective study and all studies-Continued Cancer of IunK____ (162-3) Bronchitis, emphy sema_:(502,5?7.1) Cancerof7arynz__ (161) Cancer of oral cavi ty_________(140-8) Cancer of esopha8 us____________(150) Stomach and duodenal ulcers 541) Other circulatory diseases_ __(431 _!i8) Cirrhosis of liver__ ______________(581) Cancer of lladdeF= -------_---___(181) (540, as __(421-2, 430-4) Coronary artery di sease___:____(420) Other heart disens 7Iypertensive hear t disease___(440-;i) General arterioscle rosis_________(450) Cancer of kidney_ ______________(180) -------------- -- All other cancer_ _-------------------_ Cancer of stomach _ ------------ (151) Influenza, pneumo nia_______(480-93 ) All other causes___ ___________________ Cerebral vascular 1 esion8 _____(330~t) Cancer of prostate (177) Accidents, suicid~, vlolonce (800 999) i~lephritis _.______ (692 4) Rheumatic heart d isease_____(406-16) Cancer of rectuxn_ ______________(154) Cancer of intestin s___________(152~) e All causes--_------ Caus death e of California Legion Canadian veterans Men in 25 States Total, all studies Median Deaths Deaths Deaths Deaths mortality Mortality Mortality Mortality Mortality ratio ratio ratio ratio ratio Expected Observed Expected Observed Expected Observed Expected Observed 19.9 98 4.9 27.1 317 11.7 41.5 399 9.6 170.3 1,833 10.8 11.7 3:6 30 8:4 36:5 166 4:6 15:4 115 7.5 89:5 546 6.1 7.5 4.0 6 1.5 .0 5 ------ ____ 6.3 23 3.7 14.0 75 6.4 5.8 5.2 10 1.9 6.1 20 3.9 3.6 33 9.2 37.0 152 4.1 3.9 1.8 9 6.1 6.8 22 3.3 8.4 20 2.4 33.7 113 3.4 3.3 1.8 12 6.8 7.9 54 6.9 38.6 74 1.9 105.1 294 2.8 6.0 16.7 37 2.2 41.5 96 2.3 81.0 190 2: 5 2.54: 0 649 2: 6 2.3 13:1 73 1:8 37:6 50 1:3 49:1 72 1:5 169.2 379 2.2 2.1 7:8 -7 4:0 22:3 38 1.7 22.8 50 2.2 111.6 216 1.9 2.2 312.8 515 1.7 882.5 1,582 1.8 1,863.6 3,223 1.7 6,430.7 11,177 1.7 1.7 13.1 26 2.0 75.3 156 2.1 140.3 195 1.4 526.0 868 1.7 1. 6 24.9 29 1.2 36.2 bt3 1.6 71.5 154 2.2 409.2 6:31 1.5 1.5 39.1 20 .5 14.7 48 3.3 29.6 35 1.2 210.7 310 1.5 I:7 8.3 6 .7 9.5 13 1.4 24.1 28 1.2 79:0 120 1.5 1.4 75:4 84 1:1 104:1 149 1:4 279:4 426 1:5 1,061.4 1,524 1.4 1.4 20.5 25 1:2 41.2 76 1.9 68.6 01 1.3 285.2 413 1.4 1.3 14.7 22 1.5 135.0 159 1.2 58.0 97 1.7 303.2 415 1.4 1.6 39.1 94 2.4 361.5 360 1.0 330.9 416 1.3 1,508.7 1,946 1.3 1.3 57. 1 87 1.5 2~34. 1 266 . 9 389.4 477 1.2 1,461.8 1,844 1.3 1.3 22.1 19 .9 32.3 48 1.5 74.9 75 1.0 253.0 318 1.3 1.0 46.0 62 1.4 101.3 174 1.7 303.7 325 1.1 1,063.2 1,310 1.2 1.3 :0 3 _______:__ 11:6 17 1.5 58.8 62 1.1 156.4 173 1.1 1.5 14.2 18 1.3 48.1 39 .8 79.4 88 1.1 290.6 309 1.1 1.1 12.0 9 .8 41.3 24 .6 38.2 64 1.7 207.8 213 1.0 .9 33.2 13 .4 48.6 64 1.4 106,2 - 81 .8 422.6 395 -.9 :9 -- - 799. 4 1,264 1. 58 - 2,. 420. 1 4, 001 ---- 1.65 4,183. 8 - -- - 6, 813 1.63 15,653.9 26,223 1.68 1.65 ,o: 4 e9S9GE0
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The death rates increase with the amount smoked. For groups of men smoking less than 10, 10-19,, 20-39, an& 40 cigarettes and over per day, respectively, the death rates are about 40 percent, 70 percent, 90 percent and 120 percent higher than for non-smokers. The ratio of the death rates of smokers to that of non-smokers is highest at the earlier ages (40-50) represented im these studies, and declines with increasing age. The same effect appears to hold for the: ratio of the death rate of heavy smokers to that of' light smokers. In the studies that provided this information, the mortality ratio was substantially higher fbr men who started to smoke under age.20 than for men who starte& after age 25. In general~ the mortality ratio was increased as the number of years of smoking increased'y although the pattern of in- crease was irregular fromi study to study. In two studles which recorded the degree of inhalation; the mortality ratio for a given amount of smoking was greater for inhalers than for non-inhalers. Cigarette smokers who had stopped smoking prior to enrollment in the study had mortality ratios about 1.4 as against 1.7 for current cigarette smokers. Two studies reported the number of years since smoking, was stopped~ In these, the mortality ratio declined in general as the number of' y.ears ofl cessation increased. The mortalfityy ratio of ex-cigarette smokers increased with the number of years of smoking and was higher for those who stoppe& after age 55 than for those who stopped at an earlier age. (These results «•ere available in one study only..). Taken as a whole tlhe seven studies offer a substantial breadth of sampling, of the type of men and environmental exposures to be found in NortL America an& Britain, although none of the groups st'udie& was planned as a random, sample of the U.S. male populationL All the studies had death rates below those of the U.S. white male population in 1960. To some extent this is to be expected, since men in poor health were likely to beunder-recruitedl in these studies. Only a, minor part of these differences in death rates can be attributed to a failure to trace all deaths or to higher death rates among non-respondents in these studies. The data; on~ smoking status and' on amount smoked were subject to errors of measurement, particularly since smoking, status was measured only once and some: men, presumably changed their status after entry into thee study. For men designate& as current smokers of cigarettes only; our judgment is that the net effect of such errors of! measurement is to make the observed mortality ratios relative to non-smokers underestimates of the true mortalityy ratios. The studies suffered from a failure to obtain substantial portions of thee study populations selected for investigation. For a non-response rate of 32 percent in the prospective studies, calculations based on the available informatiom about the non-respondents indicate that reported mortality ratios lying between 1 and 2 might overestimate the corresponding figure for the complete study population by 0.2 or 0.31 In our judgment these biases can account for only a part of the elevation in mortality ratios found for cigarette smokers (see Appendix I). In three studies in which the data could be subdivide& by size of city, the mortality ratios differed little in the four sizes of communities studied. 714-422 0-64-9 111
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In one study numerous other variables that might influence the death rate, such as longevity of parents and grandparents, use of alcohol, occupational exposure and educational level, were recorded. Adjustment for each of these variables individually produced little change in the mortality ratios. Although similar information from other studies would have been~ wel- come, it is our judgment that the mortality ratios are unlikely to be explaine& by such environmental, social class, or ethnic differences between cigarette smokers and non-smokers. Except for the analyses reported above by longevity of parents and grand- parents and by previous serious disease, no direct information is available on whether there are basic constitutional differences between cigarette smokers and non-smokers that would! affect their longevity. As described elsewheree in this reporty differences have been~ found between cigarette smokers and non-smokers on certain psychological'i andl behaviorall variables. However,, even for these variables the distributions for cigarette smokers and non- smokers show considerable overlap. It seems a reasonable opinion that the same situation would apply to the constitutional hardiness of cigarette smokers and non-smoker~s, if it were possible to measure such a variable. This implies that constitutional differences, if they exist, are likely to express themselves in only a moderate difference in death rates. Cigar Smokers Death rates are about the same as those of non-smokers for men smoking less than~ five cigars daily. For men smoking five or more cigars daily, death rates were slightly higher (i9 percent to 27 percent) than for non- smokers in, the four studies that gave this information, There is some indi- eation, that this higher death rate occurs primarily in men who have been smoking for more than 30 years and in men who stated they inhaled the smoke to some degree. Death rates for ex-cigar smokers were higher than those for current smokers in alll four studies in which this comparison coul& be made. Pipe Smokers Death rates for current pipe smokers were little if; at! all higher than for non-smokers, even with men smoking 10 or more pipefuls per day and with men who: had smoked pipes for more than 30 years. Ex-pipe smokers, on the other hand, showed higher death rates than both non-smokers and current smokers in four out of five studies. The epi- demiological studies on ex-cigar and ex-pipe smokers are inadequate to explain this puzzling phenomenon. According to Hammond and Horn (10) and Dorn (6), the explanation may be that a substantial number of cigar andlpipe smokers st'op smoking because of illhess: MORTALITY BY CAUSE OF' DEATH In the combined results from these seven studies, the mortality ratio of cigarette smokers was particularly high for a number of~ diseases: cancer of 112 i
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the lung (10.8), bronchitis and emphysema (6.1)', cancer of the larynx (5.4), oral cancer (4:1), cancer of the esophagus (3.4), stomach, and duodenal ulcers (2.8), and the rubric, 451-468, "other circulatory diseases" (2.6). For coronary artery disease, the mortality ratio was 11.7. There is a further group of diseases, including some of the most important chronic diseases, for which the mortality ratio for cigarette smokers lay between 1.2 and 2. The explanation of the moderate elevations in mor- tality ratios in this large group of causes is not clear. Pan may be due to the sources of bias previouslly mentioned or to some constitutional and genetic difference between cigarette smokers and non-smokers. There is the possibility that cigarette smoking has some general debilitating effect, although no medicali evidence that clearly supports this hypothesis can be citedl The substantiatnumber of possibly injiurious agents in tobacco and its smoke also may explain the wide diversity in diseases associated with smoking. In alli seven studies, coronary artery disease is the chiefl contributor to the excess number of deaths of cigarette smokers over non-smokers, with lung cancer uniformly in second place. For cigar and pipe smokers combined, the data suggest relatively high mortality ratios for cancers of the mouth, esophagus, larynx and lung, and for cirrhosis of the liver and stomach~ and duodenall ulcers. These ratios are, however, based on small'numbers of deaths. APPENDIX I APPRAISAL OF POSSIBLE BIASES DUE TO NO11I'-RESPONSE The non-response rates in the prospective studies were approximately as follows: 15 percent! for the California occupational study; 15 percent for the U.S: veterans' study during the 3-year period 195 7-1959 and 32 percent during the 3-year period 1i954-L956: 32 percent for the British doctors' study; and about 44 percent for the Calif'ornia Legion study and the Canadian veterans' study. Ini forming ai jud'gment about the size of the bias that may be due to non-response, we have concentrated! on a non-response rate of 32 percent, since this represents roughly an average figure for these five studies. The objective is to estimate by how much the mortality ratio for the whole populationi might differ from that found in the respondents. The only useful informationlin any detaiL about the non, respondents comes from the U.S. veterans' study. Table 27 shows data on d'eathi rates ini 1958 and 1959 (16)'. For the present purpose the 1957 respondents will be regarded as a; part of'~ the 32 percent': of non-respondents to the original questionnaire for wliom, we are fortunate to have some data. Table 27 indicates that, the non-respondents in 1954 have higher death rates than respondents for both non-smokers and smokers. For non-smokers the ratio: of the death rate of 1957 respondents to 1954 respondents was 1.35 in 113
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TABLE 27.-Age-adjusted death rates (per 1,000 person,years)' for 1954 respondents, 1957 respondents, and non-respondents in U:S. veterans study (3roups. 1954 respondents--------------------------- J~ lnn$znokers; liAll smokers_---------- 1957 respondents_-------------------------- V on-smokers----_ ---- All smokers------- _ -- AFon-respondents--------------------------- A11----------------- 19.84 1958 and 1.27 in 1959. For smokers the corresponding figures are 1.18 in 1958' and 1.14 in 1959. If the adjusted death rates in Table 27 are weighted by the proportions of men in the population, it is found that the over-all 1958 death rate for 1954 respondents was 17.77 as compared with 19.05 for the complete study popula- tion. The ratio 19.05/17.77 is 1.07, so that in 1958' the deatL rate for the study population was 7 percent higher than for the 1954 respondents. In 1959 the corresponding death rates were 1!7.46 for 1954' respondents and 18.31 for the complete population, the ratio being 1.05. These ratios agree wit'h, Doll's judgment (4) ' that in the Brit'ish doctors' study the death rate in the complete population may exceed that in his 68 percent of respondents by from 5 percent to 10 percent. Comparison of the 1954 and 1957 respondents also suggests that the non- respondents in 1954 contain a higher proportion of smokers than the re- spondents. In the 1954 respondents, non-smokers contributed 183,094 person-years of experience dilring 1957-1959 as compared with 179,750 person-years for current smokers ofl cigarettes only, non-smokers represent- ing 506 percent of the total of the two groups. Among the 1957 respondents the corresponding figure was 46.8' percent. A further decline may have oc- curred in the non~respondents to the 1957, questionnaire. From these data the following assumptions were made in investigating the non-response bias as it affects the mortalit'y ratio of current smokers of ciga- rettes only. 1. The proportions of the relevant groups in the complete population are as follows: Groups Tw on- smokers Cigarette smokers . Total V on-res pondents------- _-_- _ ----- 0.14 0.18 0.32 Bes p onde nts------------------------ .34 .34 CompVete populat8on--------- .52 1.00 This assumes that in the 68' percent of respondents, non-smokers consti- tute 50 percent of non-smokers plus cigarette smokers, but in the non.res spond'ents this figure has dropped to 44 percent. Death rates
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2. The death rate in the complete population is 10 percent higher than in the respondents. 3. One further numerical relationship is needed in order to obtain con- crete results. For this, the computations were made under two different sets of assumptions. The more extreme (3a) is that cigarette smokers have no higher death rates among non-respondents than among, respondents. The alternative (3b) is that the death rate of cigarette smokers was 10 percent higher among, non-respondents than among respondents. Both sets of assumptions seem more extreme than the indications from the U.S. vet- erans' study in which, as alteady noted, the smoker death rates were 18 percent and 14 percent higher among 1957 respondents than among 1954! respondents. For total mortality, the calculations of most interest are those for a mortality ratio of 1.7 among the respondents, since this is the average ratio found in, the prospective studies for smokers of cigarettes only. For indi- vidual causes of death, however, the mortality ratios among respondents range from 1 to 10, so that calculations were made for a series of different mortality ratios among respondents. Table 28 illustrates the caleulations made on assumptions (3a) and (3b) for a mortality ratio of 1.7 among respondents. f, TABLE 28. Illustration of calculation of non-response bias Assumption (3a) Assumption (3b) Mort6lity ratios Non-respon dents _-__- H e s po n ue n t s_..- --- --- ~ Non- 6Ismokers I+ (1i865) 11000 Cigarette smokers ll 700 11 700 Complete populatton- M. H'----- s (1:252)11° (ll700) , I (1i 36), ' (1.772) Non-respondents_.-_- 1 (}.350) Heeponde.nts____-_- Mortality ratios Non- smokers Cigarette smokers 4 (1'646) 1.000 1.870 1.700 2 (11485) Compl&Le.population_ diL188). ^ M.H----------------- 7 (1. 48) I e' (1.772) . 1 (1.350) 2 ' (1.4S5) ~ The figures without parentheses in the mortality ratio tables represent the start of the computations. The indexes (1 2 etc.) show the order in which other figures are computed. For assumption (3a); (1.350) '=[(0.34)(1.000),+(0.34)(1.700)U,(0.68) (1.485) 2 =(1.1) (1.350) ~ (1.772) e=[(1.485)-(0.6'8).(1.350)]/(0:32)', (1-865) 4=[(0:32)(1.772)-(0:18)(1.700) /(0.14) (1.252) a-[(0:14)(1.8tV5);+(0.34)(1A00)1l(0.48) (1.700) 5=[(0:18)(1.700)+(0.34)(1.700)1/(0.52) (ll36) 7=1.700/1.252 Thus, the mortality ratio drops from 1.7 to 1.36 in the complete population under assumption (13a ) and to 1.48 under assumption (3b). One conse- quence of assumption (3a) is that the mortality ratio of cigarette smokers among the non-respondents is less than 1. Table 29 shows the results obtained for a range of mortality ratios in the respondent population. For the high mortality ratios the assumptions may appear unduly extreme. For instance, under assumption (3a) with mortality ratio 10.0 in the respond- ents, the non,smoker death rate in the non-respondents has to be 3.6 times 115
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that in the respondents, although the smoker death rates are assumed the same in~ respondents and non-respondents. It may be of interest to quote Berkson's (11), example in the same form (Table 301). TABLE 29.-Mortality ratios in respondents and computed values f or the complete population In complete.population~~ In respondents (68 percent) Assump- tion (3a) Assump- tion (3b) 1.2`---------------------------------------------- 1.00 1.06 1.4----------------------------------------------- 1.14 1,23 ---------------------------------------------- 1.28 1.40 1.8----------------------------------------------- 1.43 ' 1.56 2:0----------------------------------------------- 1.57 1.73 5:0----------------------------------------------- 3.43 4.07 10,0---------------------------------------------- 5.65 7.41 TASLe 30.-Proportions and death rates for Berkson's example Proportions D eath rates Group Non- Smokers Total Non• Smokers Total smokers smoke rs Blon-respondents.------------- 0. 0049t 0, 28360 0.28 854 60: 121 4.217 ' 5.174 Res po nclents--- --------------- .1951N'i. . 51f:k0 .71 140 1. 553 2.:332 2:1d8 Total!------------------ .20000. .80000 1 1.00 000 3. 000 3: 000 3.000 In their general direction, Berkson's assumptions are similar to those made in this Appendix, but the differences in death rates between respondents and non-respondents were more extreme in his example. The d'eatL rate in thee complete population (3.000)' was 42 percent higher than the respondent death rate. The non~smoker death rate was over 38 times as high among' non- respondents as among respondents (60.1211/1.553), whereas among' the smokers it was only 1.8 times as high. His calculations referred to the early years of a study, in which the effects of differential entry of ill persons among' smokers an& non-smokers are likely to be most marked. Further, as we in- terpret his writing, the example was intend'ed as a warning' against the type of subtle bias that can arise whenever a': study' has a high proportion of non- respondents, rather than a claim that this numerical estimate of the bias ac- tually applied to these studies. To summarize, the amounts of non-response in the prospective studies could have produced sizable biases in the estimated mortality ratios. Taking assumption 3b in Table 29;, as representing fairly extreme conditions, it appears that a reported mortality ratio between 1 and 2 might overestimate by 0.3, a ratio of 5.0 by 1.0 and a ratio of 10.0 by 3.0. 116
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APPENDIX II STABILITY OF MORTALITY RATIOS In computing,the mortality ratio: of a group of smokers to a group of non- smokers, each group is subdivided into age-classes (usually 5-year). For the ith agp-class let yi denote the number of smoker deaths and' x, the num- ber of non-smoker deaths. The "expected" number of smoker deaths in the f ith class (expected on the assumption that srnokers have the same age-specific death rates as non-smokers)' is ~ (Person-years for smokers in class i) (Person-years for non-smokers in class i),x,=X~x, (sayl The estimated mortality ratio R is defined as Iy' 1 R=Y.?LJx (i ) summed over the age-classes. In, the interpretation of the values of R found in the seven studies, much ~ weight has been given to the consistency of the values from one study to another, on the grounds that if the values of R for a particular cause of death f are highi in, alli seven studies, this evidence is more impressive than R values t that are high in say, three studies but show no elevation in the remaining four studies. As a: consequence, the question whether the value of R in an individual study is significantly above unity, in the technical sense of this term; becomes less important. Nevertheless, an answer to this question is occasionally useful in the analysis. Moreover, for some causes of death the total numbers of deaths, even when all seven studies are combined, are small enough so that ai measure of the stability of the combined R is need'edl ~ Assumptions In attempting to get some idea of the stability of R without too much com- plexity, the following assumptions will be made. 1. The numbers of deaths yt and x, are distributed as Poisson variables. As Chiang (3) has shown, a more accurate assumption is to regard yt and x„ as binomial numbers of successes. But with causes of death for which the probability of dying in a 5•year age span is very small the Poissom assump- ;, tion, which is slightly conservative, is reasonable. 2. The qNantities A, can be regarded as known constants. This is not qµite correct. Initially, the Ai are the ratios of the numbers of smokers to non-smokers in the age-classes, which cani reasonably be regarded as given: In subsequent-years, however, the numbers are depleted by deaths, and the number of deaths is' a random variable. When death rates are small, how- ever, this assumption should introduce little error. 3. The variates y; and yi are uncorrelated. An error in the age assigned to a death, putting it ini the wrong age-class, induces a negative correlation between, yj and yj. The existence of such errors should have no effect on 117
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the variance ascribed to Y,y,, on the assumption of independence. The same remarks apply to the assumption that xt and xi , are uncorrelated. variates, and numerator and denominator are independent of one another. The exact distribution of a ratio of'this type has not been worked out. Twoo approximate methods of obtaining confidence limits for the true mortality ratio R will be given. Confidence limits are presented rather than the standard error of R because the distribution of R is skew when the numbers of deaths are moderate or small, so that the standard! error is harder too interpret. xl and y,. Such errors should of course not be allowed to happen, since they vitiate the comparison of the death rates that is the main point! of the study, but occasional errors of this type may have_occurred. With these assumptions the numerator ly, of R follows a Poisson distri- bution. The denominat'or Y,,Clxi, is a linear function of independent Poisson 4. The variates xl and yl are uncorrelated. An error in assigning a death~ to the correct smoking,category would induce a negative correlation between~ The Binomial Approximation Ifl the, A;, can be regarde& as approximately constant ('=,1, say)' then R becomes of the form y/Xx, where y and x are independent Poisson variates. Since Xx then represent_s the expected number of deaths of the smokers, the quantity A is estimated as the ratio of the expected number of smoker d'eaths to the number of non-smoker deaths. By a well-known~ result it follows that' x/(y+x), the ratio: of non-smoker deaths to smoker plus non-smoker deaths, is distributed as a binomial proportion with n=number of'. trials=y+ x p=probability of success=l/(1-'~ XR)' where R' is the true mortality ratio. Confidence limits for R are found' from those for p. Example. For the study of men in 25 States; the figures for lung cancer for cigar and pipe smol.ersare as follows: Non- smokers Number otAe.nths- ----------------- Observed 16(%). Smokers Observed 15(y) Expected 9:71(xx) Hence, X=9.71/16=0.607 and the binomial ratio is 16/31=0.516. Hald's. (9) table of the 95 percent two-tailed confidence limits of the binomial distribution gives 0.331 and 0.698 as the confidence limits for p. Those for R are given by the relation R=(L-p)/,k'p This yields 0.7 and 3.3 as the 95 percent limits for R. Since the lower limit, 0.7, is less than unity, the estimated R, 1.5, is not significantly above unity. 1'18 1 Oak
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U2lfortunatell- the assumption thatX] is constant is not true in these studies. For instance, in~ the study of inem in 25 States A] has the value 3.85 for cigarette smokers aged 45-49 and declines steadily with increasing age to a value of 0.96 for men aged 75-79. For cigar and pipe smokers the fluctuation in~ yj with age is less drastic but is still~ noticeable. The Narmal, ApproximertionThis approach avoids the assumption that the Ai are constant„ but makes other assumptions that are shaky with smalli numbers of, deaths. If Risthe true mortality ratio, the quantity y- Re where e=1a;xi is the expected' number of smoker deaths, will follow a; distribution that has mean zero. If µi, m; denote the true means of y; and xi, respectively, the variance of (y-Re) is Y.(µ„+R'h;my) The basis of this approximation is to regard the quantity ~ y- Re ( µ;+R2k;m,) (2) as normally distributed with zero mean, since y, and x; are regarded, ass previously, as independent Poisson variates. The 95 percent confidence: limits for R are then obtained, by a, standard device, by setting the absolutevahle of this quant2ty, equat to 1.96 and solving the resulting quadratic equationi for R. Since the µ, and the mi are unknown, a further approximation is to substitute y as an estimate of :~µi and ~~;xi as an estimate: of, t Example. For the example previously discusse& the data are as follows: i y=15: e=9.71: :~k2.1=6:059 On squaring, (2), the quadratic equationi becomes (15-9.71R)z=3.84(15+6:059R'). The roots are found to be 0!7 and 3.4, in goodi agreementl with, the: limits 0:7 and 3.3 given by the binomial approximation. This agreement is better than will usually be found withi small numbers of deaths. The following are 4 comparisons of the confidence limits for cigarette smokers in the same study. Number of deaths 95 percent limits Cause oGdeath, Non- smoker s Cigarette smok ers Mortal ratio ity Binomial N ormal observe d Observ ed! Exp ected Cancer of lung---------------- 16 399 41120 9.7 (5'.0, 14.:5) (5.0.21.4) . ~ EmphFsema ----------------- 7 115 15.31 7.5 ' (3. 5~, 18-.1) : (4! :0, 40: 0)'. Canoer of rectum---- -------- 16 641 38.42 1.7 (1.0.3.3'); (1.0;3;6) Influenza and pneumonia__- 29 97 58. 01 1.7 (1. 1, 2. 6) ~~ (1. 1, 2.9)~. 119
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The lower confidence limits agree well; but the upper limit'1 runs higher for the normal approximation. For cigarette smokers the normal method is perhaps more accurate. The binomial method has some advantage in simplicity. _ REFERENCES 1'. Berkson, J. The statistical study of association between smoking and lung cancer. Proc Staff Meeting,, Mayo Clin 30: 319-48, 1955. 2. Best, E: W. R., Josie,, G. H.,, Walker, C. B. A Canadian study of mor- t'alfity in relation to smoking habits, a preliminary report. Canad J Pub Health 52 : 99-106. 1961. 3. Chiang, C: L. Standard error of the age-adjusted death rate. Vital statistics. U.S. Department of Health, Education and Welfare. SpeciallReports No 47, 275-85, 1961. 4. Doll, R. Personal'i communication to the Surgeon General's Advisory Committee on Smoking and Health. j 5. Dolh R., Hill, A. B. Lungcaneerandlothercauses of! death in relation to smoking. Brit Med J 2: 1071-81, 1956. 6. Dorn, H. F. The mortality of smokers and~ non-smokers. Proc Soc Stat Sect Amer Stat Assn~ 34-71, 1958. 7. Dunn; J. E., Jr., Linden, G., Breslow, L. Lung cancer mortality ex- perience of men in certain occupations in California. Amer J PubHealth50~: 1475-87, 1960; 8. Dunn, J. E., Jr., Buell, P., Breslow, L. California State Department ofi Public Health. Special report to the Surgeon General's Advisory Committee on Smoking and HealthL 9. Hald, A. Statistical tables and formulas: Wiley, New York, 1952. 10. Hammond, E. C., Horn, D, Smoking and' death rates-report on forty- four months offollbw-uponi 187,783 men. Part I. Total mortality. Part II. Death rates by cause. JAMA 166: 1159-72, 1294-1308, 1958. 11. Hammond, E. C. Special report to tihe Surgeon Generalrs Advisory Committee on Sinoking, and Health. 12. Hammond, E. C. Special report to the Surgeon~ General's Advisory Committee on Smokingand Health. 13. Hammond, E. C. The effects of' smoking. Sci Amer 207: 3-15, 1962. 14. Ipsen, J., Pfaelzer, A. Special report to the Surgeon General's Advisory Committee on Smoking and Health. 115. Korteweg, R. The significance of selection in prospective investiga- tions into an association between smoking and lung cancer. Brit J Cancer 10: 282-91, 11956. 16. Krueger, D. Personal communication tothe S'urgeoni General's Advis- ory Committee on Smoking andl Health. 17. Yates, F: Sanipling methods for censuses and surveys. Griffin, Lon- don, (Section 9.4), 1'960. 120
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Chapter 9 -.. Cancer I
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Contents Page CANCER MORBIDITY AND MORTALITY ....... 127 Sources of Information . . . . . . . . . . . . . . . . 127 ~ Sex Ratio . . . . . . . . . . . . . . . . . . . . . . 133 I! Geographic Variation . . . . . . . . . . . . . . . . . r 133 , Urban-Rural Gradients . . . . . . . . . . . . . . . . . ]33 Income Class . . . . . . . . . . . . . . . . . . . . . 133 Occupation . . . . . . . . . . . . . . . . . . . . . . 134 Ethnic Group . . . . . . . . . . . . . . . . . . . . . 134 Trends . . . . . . . . . . . . . . . . . . . . . . . . 135 Age-Specific Mortality From Lung Cancer . . . . . . . . 136 Effects of Changes in Lung Cancer Diagnosis on Time Trend s . . . . . . . . . . . . . . . . . . . . . . . 139 CARCINOGENESIS . . . . . . . . . . . . . . . . . . . 141 Fundamental Problems in Carcinogenesis in Relation to Induction of Neoplastic Changes in Man by Tobacco Smoke ..................... 141 Threshold . . . . . . . . . . . . . . . . . . . . . 143 Carcinogenicity of Tobacco and Tobacco Smoke in Animala.. 143 Skin ........................ 143 Subcutaneous Tissue . . . . . . . . . . . . . . . . . 144 Mechanism of the Carcinogenicity of Tobacco Smoke Condensate . . . . . . . . . . . . . . . . . . . . 144 Other Materials of Possible Importance in Carcinogen- icity . . . . . . . . . . . . . . . . . . . . . . 145 Pesticides . . . . . . . . . . . . . . . . . . . . . 145 i Lactones . . . . . . . . . . . . . . . . . . . . 145 Radioactive Components 145 . . . . . . . . . . . ~ . . . ~. Summary . . . . . . . . . . . . . . . . . . . . . . 146 Carcinogenesis in Man . . . . . . . . . . . . . . . . . 146 Polycyclic Aromatic Hydrocarbons . . . . . . . . . . 146 Industrial Products . . . . . . . . . . . . . . . . . 147 Soot . . . . . . . . . . . . . . . . . . . . . . 147 Coal Tar and Pitch . . . . . . . . . . . . . . . . . 147 Mineral Oils . . . . . . . . . . . . . . . . . . . 147 Summary . . . . . . . . . . . . . . . . . . . . . 148 CANCER BY SITE . . . . . . . . . . . . . . . . . . . 148 Lung Cancer . . . . . . . . . . . . . . . . . . . . . 149 Historical . . . . . . . . . . . . . . . . . . 149 Retrospective Studies . . . . . . . . . . . . . . . 150 Methodologic Variables . . . . . . . . . . . . . . . 151 Form of Tobacco Use . . . . . . . . . . . . . . . . 155 122
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k t t !i CANCER BY SITE-Continued Lung Cancer-Continued Retrospective Studies-Continued Page Amount Smoked . . . . . . . . . . . . . . . . . 155 Duration of Smoking . . . . . . . . . . . . . . . . 158 Age Started Smoking, . . . . . . . . . . . . . . . 158 Inhalation . . . . . . . . . . . . . . . . . . . . . 159 H istologic Type . . . . . . . . . . . . . . . . . . 159 Relative Risk Ratios from Retrospective Studies . . . . 160 Prospective Studic s . . . . . . . . . . . . . . . . . 161 Experimental Pulmonary Carcinogenesis . . . . . . . . 165 Attempts to Induce Lung Cancer with Tobacco and Tobacco Smoke . . . . . . . . . . . . . . . . 165 S ummary . . . . . . . . . . . . . . . . . . . . 165 Susceptibility of Lung of Laboratory Animals to Carcin- ogens . . . . . . . . . . . . . . . . . . . . 166 Polycyclic Aromatic Hydrocarbons . . . . . . . . 166 Viruses . . . . . . . . . . . . . . . . . . . . . 166 Possible Industrial Carcinogens . . . . . . . . . . 166 Summary . . . . . . . . . . . . . . . . . . . . 167 Role of Genetic Factors in Cancer of the Lung. . . .. 167 Summary . . . . . . . . . . . . . . . . . . . . 167 Pathology-Morphology. . . . . . . . . . . . . . . . . 167 Relationship of Smoking to Histopatliological Changes in the Tracheobronchial Tree . . . . . . . . . . . 167 Summary . . . . . . . . . . ... . . . . . . . . 172 Conclusion . . . . . . . . . . . . . . . . . . . 173 Typing of Lung Tumors . . . . . . . . . . . . . . 173 Conclusions . . . . . . . . . . . . . . . . . . . 174 Evaluation of the Association between Smoking and Lung C ancer . . . . . . . . . . . . . . . . . . . . . 175 Indirect Measure of the Association . . . . . . . . . 175 Direct Measure of the Association . . . . . . . . . 179 Establishment of Association . . . . . . . . . . . 179 Causal Significance of the Association ....... 182 The Consistency of the Association. . . . . . . . . 182 The Strength of the Association . . . . . . . . . . 183 The Specificity of' the Association . . . . . . I . . . 183 Temporal Relationship of Associated Variables ... 185 Coherence of Association . . . . . . . . . . . . . 185 (1.) Rise in Lung Cancer Mortality . . . . . . . 185 (2.) Sex Differential in Mortality . . . . . . . . 185 (3.)' Urban-Rural' Differences in Lung Cancer Mor- tality . . . . . . . . . . . . . . . . . . 186 (4.) Socio-Economic Differentials in Lung Cancer Mortality . . . . . . . . . . . . . . . 186 (5.)' The Dose-Response Relationship. . . . . . . 187 (6.) Localization of Cancer in Relation to Ty pe of Smoking . . . . . . . . . . . . . . . . 188 Histopathologie Evidence . . . . . . . . . . . . . . 189 123 W 0
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CANCER BY SITE-Continued Lung Cancer-Continued Constitutional IIypothesis . . . . . . . . . . . . . . Genetic Considerations . . . . . . . . . . . . . . . E pidemiological Considerations . . . . . . . . . . . (1.) Lung Cancer Mortality . . . . . . . . . . . (2.)' Tobacco Tars . . . . . . . . . . . . . . . . (3.)' Pipe and Cigar Smoking . . . . . . . . . . . (4.) Ex-Cigarette Smokers . . . . . . . . . . . . Other Etiologic Factors and Confounding Variables ... (1.)' Occupational Hazards . . . . . . . . . . . . (2.) Urbanization, Industralization, and Air Pollution . (3.)' Previous Respiratory Infections . . . . . . . . (4.) Other Factors . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . Oral Cancer . . . . . . . . . . . . . . . . . . . . . . Epidemiological Evidence . . . . . . . . . . . . . . . Carcinogenesis . . . . . . . . . . . . . . . . . . . Pathology . . . . . . . . . . . . . . . . . . . . . Evaluation . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . Laryngeal Cancer . . . . . . . . . . . . . . . . . . . . Epidemiological Evidence . . . . . . . . . . . . . . . Retrospective Studies . . . . . . . . . . . . . . . Prospective Studies . . . . . . . . . . . . . . . . Carcinogenesis . . . . . . . . . . . . . . . . . . . Pathology . . . . . . . . . . . . . . . . . . . . . Evaluation of the Evidence . . . . . . . . . . . . . . Time Trends . . . . . . . . . . . . . . . . . . . Sex Differential in Mortality . . . . . . . . . . . . Localization of Lesions . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . Esophageal Cancer . . . . . . . . . . . . . . . . . . E pidemiological Evidence . . . . . . . . . . . . . . . Retrospective Studies . . . . . . . . . . . . . . . Prospective Studies . . . . . . . . . . . . . . . . Carcinogenesis . . . . . . . . . . . . . . . . . . . Evaluation of Evidence . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . Urinary Bladder Cancer . . . . . . . . . . . . . . . . . Epidemiological Evidence . . . . . . . . . . . . . . . Retrospective Studies . . . . . . . . . . . . . . . Prospective Studies . . . . . . . . . . . . . . . . Carcinogenesis . . . . . . . . . . . . . . . . . . . Evaluation of the Evidence . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . Stomach Cancer . . . . . . . . . . . . . . . . . . . . Epidemiological Evid'ence . . . . . . . . . . . . . . . Retrospective Studies . . . . . . . . . . . . . . . Prospective Studies . . . . . . . . . . . . . . . . 124' Page 190 190. 192 192 192 192 192 193 193 194 195 196 196 196 196 202 203 203 204 205 205 205 209 210 210 210 210 211 211 212 212 212 212 217 217 217 218 218 218 218 222 223 223 225 225 225 225 228 ,
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CANCER BY SITE-Continued Stomach Cancer-Continued Page Carcinogenesis . . . . . . . . . . . . . . . . . . . 228'. Evaluation of the Evidence . . . . . . . . . . . . . . 228. Conclusion . . . . . . . . . . . . . . . . . . . . . 229 SUMMARIES AND CONCLUSIONS'. . . . . . . . . . . . 229 Lung . . . . . . . . . . . . . . . . . . . . . . . . . 229. Oral Cancer . . . . . . . . . . . . . . . . . . . . . . 233 Larynx . . . . . . . . . . . . . . . . . . . . . . . . 233 Esophagus . . . . . . . . . . . . . . . . . . . . . . 234. Urinary Bladder . . . . . . . . . . . . . . . . . . . . 234 S tomach . . . . . . . . . . . . . . . . . . . . . . . 235 Figures f 1. Mortality from cancer (:all sites), U.S. Death Registration I I Area of 1900, 1900: -1960 . . . . . . . . . . . . . . . 128 2. Age-adjusted mortality rates for cancer-all sites, in 17 countries, 1958-1959 . . . . . . . . . . . . . . . . 129 3A. Age-adjusted mortality rates for cancer of six sites in~ six selected countries-males . . . . . . . . . . . . . . 130 ` 3B. Age-adjusted mortalityy rates for cancer of six sites in six selected countries-females . . . . . . . . . . . . . 1311 4: Comparison of age-adjusted mortality rates by sex, United States, 1959-1961, with incidence rates from State regis- tries of New York and Connecticut . . . . . . . . . . 132 5. Trends in age-adjusted mortality rates for cancer by sex- all sites and respiratory sy stem in the United States, 1930-1960 . . . . . . . . . . . . . . . . . . . . . 136 6. Trends in age-adjusted mortality rates for selected cancer sites by sex in the United States, 1930-1960 ...... 137 7. Age-adjusted mortality rates for cancer of the lung an& bronchus by birth cohort and age at death for males, United States, 1914, 1930-1932, 1939-1941, 1949-1950, ' 1959-1961 . . . . . . . . . . . . . . . . . . . . . 138 8. Age-adjusted mortality rates for cancer of the lung and bronchus by birth cohort and age at death for females, United States, 1914, 1930-1932, 1939-1941, 1949-1950, 1959-1961 . . . . . . . . . . . . . . . . . . . . . 139 i 9. Crude male death rate for lung cancer in 1950 and per capita consumption of cigarettes in 1930 in various countries .. 176 10. Percentage of persons who have never smoked, by sex and ; age, Uhited States, 1955 . . . . . . . . . . . . . . . 178' iV 125
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Illustration Page 1. Examples of normal and abnormal bronchial epithelium . 168-9 List of Tables 1. Expected and observed deaths and mortality ratios of cur- rent smokers of cigarettes only, for selected! cancer sites, all sites, an& all causes of death; each prospective study and all studies . . . . . . . . . . . . . . . . . . . . . 149 2. Outline of! methods use& in retrospective studies of' smoking in relation to lung cancer . . . . . . . . . . . . . . 152 3. Group characteristics in retrospective studies on lung cancer and tobacco use . . . . . . . . . . . . . . . . . . 156 4. Relative risks of lung cancer for smokers from retrospective studies . . . . . . . . . . . . . . . . . . . . . . 161 5. Mortality ratios for lung cancer by smoking status, type of smoking, and amount smoked, from seven prospective stud ies . . . . . . . . . . . . . . . . . . . . . . 161 6. Percent of slides with selected lesions, by smoking status and presence of lung cancer . . . . . . . . . . . . . . . 168 7. Changes in bronchial epithelium in matched triads of male non-smokers and smokers of different types of tobacco .. 171 8. Relation between W'HO and Kreyberg classifications of lung tumors . . . . . . . . . . . . . . . . . . . . . . 174 9. Mortality ratios for cancer of the lung by smoking class and by ty pe of tumor, U.S. Veterans Study ...... .. 175 10. Outline of retrospective studies of tobacco use and! cancer of the oral cavity . . . . . . . . . . . . . . . . . . 198 10A. Summary of results of retrospective studies of smoking and detailed sites of the oral cavit'y by type of smoking ... 201 11. Oiutline of retrospective studies of tobacco use and cancer of the larynx . . . . . . . . . . . . . . . . . . . . . 206 12. Summary of methods used in retrospective studies of tobacco use and cancer of the esophagus ..... ... 13. Summary of results of retrospective studies of tobacco use 214 and cancer of the esophagus . . . . . . . . . . . . . 216 14. Summary of methods used in retrospective studies of smoking and cancer of the bladder . . . . . . . . . . . . . . 220 15. Summary of results of retrospective studies of smoking and cancer of the bladder . . . . . . . . . . . . . . . . 221 15A. Summary of results of retrospective studies of cigarette smoking and cancer of the bladder in males ...... 222 16. Summary of methods used! in retrospective studies of smoking and cancer of the stomach . . . . . . . . . . 226 17. Summary of results of retrospective studies of smoking and cancer of'the stomach . . . . . . . . . . . . . . 227 126
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a Chapter 9 CANCER MORBIDITY AND MORTALITY Cancer has been the second ranking cause of'~ death in the United States since 1937. Reviewing the mortality statistics of'~ those parts of the United States which began relatively accurate reporting in 1900, (District of Colum- bia and 10 states-the so-called Death Registration Area of 1900) it can~ be seen that the number of cancer deaths per year has increased markedly (Figure 1). After subtracting the part of the increase due to growtL of the population and the part due to increase in life expectancy or aging of the population, there is still a residual increase of sigpificant proportions. While a part of this is undoubtedly due to improvement in~ diagnosis, most observers agree that a true increase in the cancer death rate has occurred during this time. As general background inf'ormation, it is useful to review the pattern of cancer risks found in the population of the United States as compared with, the patterns in other countries. Segi has prepared systematic international compilations of cancer mortality (317). These show that the United States occupies an intermediate position in comparisons of death rates for all sites combined: the age-adjusted rates for U.S. males and females are lower than those in Austria and higher than in Norway and Japan (Figure 2). The point to be stressed, however, is not the rank order of countries according to over-all, cancer mortality, but the differences in, ranking for individual sites (Figures 3A and 3B)s Mortality statistics, cancer register data, and collected series of pathological specimens are in general agreement in identi- fying individual countries as having, their own characteristic site patterns of risk (146). Some of the more striking features in the United States are very low risks for esophagus and stomach and moderately high rates for urinary bladder; lung cancer mortality for males, while below the rates in England and Finland, is well above those in Canada, Norway and Japan. SOURCES OF' INFORMATION Information on morbidity and mortality from cancer in the Uhited States comes from three principal' sources: mortality statistics prepared by the National Vital Statistics Division of the U.S'. Public Health Service, the large central registries receiving reports omdiagnosed cases in Connecticut (136)~ upstate New York (112) and California (37), and the morbidity surveys conducted in ten metropolitan areas in 1937-39 and 1947-48 (91) and in Iowa in 1950 (148). Each body of material has its virtues and weaknesses. Mortality statistics report on the national experience and cover longer time spans than the specialized sources, but the diagnostic information in the death certifications is less reliable and complete. Recent studies of medical certifications have demonstrated that the quality of information for most 714-422 0-64-10 127
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MORTALITY FROM CANCER (All sites), U.S. DEATH REGISTRATION AREA 111 OF 1900, 1900-1960 sa 70 60 50 40 30 20 RESIDUAL INCREASE INCREASE DUE TO AGING INCREASE DUE TO GROWTH OF POPULATION CANCER', DEATHSIN 1900 1900 1910 1920 1930 1940 1950 1960 i FIGURE1. Includes Maine, New Hampshire, Vermonts Massachusetts, Rhode Island, Connecticut, New York„New Jersey, Michigan, Indiana, District of'Columbia. Sources: a. United States Census of Population: 1940, 1950, 1960. 1 b. Vital Statistics of the United States, Part 1, 1940; Voll 111, 1950;, Vol. II, Part B, 1960. i c. Cover, Mary. Cancer Mortality in the United States, Part I, Public Health Bulletin 248, 1939: cancer sites can be regarde& as good (91, 247), so that the problems in~ interpretation are less formidable than those arising in studies of cardio- vascular disease. Completeness of reporting to the major registries is satisfactory and the accuracy of diagnostic information is excellent, but the registers cover only a limited number of: areas. Fortunately, the registers in Connecticut 128
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AGE-ADJUSTED MORTALITY RATES FOR CANCER - ALL SITES, IN 17 COUNTRIES 1958-1959.111' RATE PER 100,000 / AUSTRIA I} FIINLAND ~ EN'GLAN'D & WALES SWITZERLAND FRANCE GERMANY FR DENMARK NETiNERLANDS UNIITED STATES AUSTRALIA CANADA JAPAN ITiALY IRELAND NORWAY SWEDEN ISRAEL DENMARK AUSTRIA GERMANY FR NETHERLANDS SWITZERLAND ISRAEL ENGLAND 8. WAL ES CANADA FINLAND IRELAND SWEDENI UNITED STATES FRANCE NORWAY, AUSTRALIA ITALY, JAPAN 5 0 10 0 15 0 200 I MA LE I FiGURE 2. ILS: data age-adjusted to total population o/ the continental United States, 1950. Source: Calculated from Segi„M, and Kurihara, M. (317). and New York have been in operation long enough to provide reliable data on incidence trends over the past two decades. The morbidity surveys for 1947-48 produced a comprehensive report on cancer incidence in large cities with very good medical care facilflties; but this information has not been updated by resurveys. 129 , 250 . FEMALE V- - ____
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AGE-ADJUSTED MORTALITY RATES FOR CANCER OF 6 SITES IN 6 SELECTED COUNTRIES - MALES (4 RATE PER 100,000 POPULATION! ! ENGLAND FINLAND UNITED STATES CANADA NORWAY JAPAN JAPAN FINLAND NORWAY ENGLAND CANADA UNITEDSTATES UNITED STATES ENGLAND CANADA FINLAND NORWAY, JAPAN' 20 40 60 80 100 I I FINLAND JAPAN ENGLAND UNITEDSTAT~ES CANADA NORWAY I STOMACH I ESOPHAGUS IE ENGLAND I II UNITEDSTAT!ES M M M M MMEENNNEI CANADA FINLAND BLADDER & URINARY NORWAY JAPAN FINLAND ENGLAND UNITED STiATES CANADA. JAPANI NORWAY EF TRACTI (excludiing Kidnely) LARYNX FicLee, 3A. U.S: data age-adjusted to the total' population of, the continental Uhited States, 1950. Source: Calbulatod from Segii M.,,and Kurihara, M. (317). The deficiencies in, any single set of data; should not be overstressed. Com- parisons of the various sources indicate good internal consistency among them and they usually lead to the same inferences on, patterns of risk for 130
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AGE-ADJUSTED MORTALITY RATES FOR CANCER OF 6 SITES IN 6 SELECTED COUNTRIES - FEMALES IN RATE PER 100;000 POPULATION ENLLAND UNITEDSTAT~ESFINLAND CANADA' JAPANI NORWAY JAPAN FINLAND NORWAY ENGLAND CANADA, UNITED STATES FINLAND ENGLAND NORWAY UNITED STATES CANADA JAPAN FINLAND JAPAN ENGLAND CANADA UNI TED STATiES NDRWAY ENGLAND UNI TED STATESCANADA NORWAY FINLAND JAPAN ENGLAND, JAPAN FINLAND CANADA UNITEDSTATESNORWAY MM r BUCCAL CAVITY & PHARYNX ~I II ESOPHAGUS I I I BLADDER & URINARY TRACT (excluding Kidney) I I I LARYNX I FiGUxE 3B. U.S. data age-adjusted to the total population of the continental United States 1950. Source: Calculated' from Segi, M., and Kurihara, M, (3ll7)_ individual sites„ particularly those for which~ the five-year survival rates are very low. Figure 4, which contrasts recent mortality and incidence rates, demonstrates that these rates differ markedly only for sites with more favor- able progtlosis-oral cavity, prostate, and urinary bladder. These differ• ences are compatible wit'h~ existing, information on the survival experience of cancer patients. 131 I
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COMPARISON OF AGE-ADJUSTED MORTALITY RATES BY SEX IN THE UNITED STATES 1959-1961 WITH INCIDENCE RATES FROM STATE REGISTRIES - UPPER NEW YORK STATE 1958-1960 AND CONNECTICUT 1959. MALES FEMALES / :.;,~~~ ~: .; 0 20 - 40 60 0 20 _ MORTAIIITY, UNiTED ST'~ATES WHITE POPULATION„1959-1961 ~ INCIDENCE, UPPER NEWYORK STATE, 1958-1960 ~ INCIDENCE, CONNECTICUT, 1959 Lung and bronchus Esophagus Stomach Buccal cavity and pharynx Bladder and other urinary organs, excluding kidney Larynx Fccvta 4. Sources: Vital Statistics of the United States, annual volumes; Ferber, B. eUal (112). Eisenberg, H.,, personal communication to the Surgeon General's Advisory Committee oniSmoking and Health. The next sections describe some aspects of incidence or mortality for eight sites-lung and bronchus, larynx, oral cavity, esophagus, urinary bladder, kidney, stomach and prostate. Of these, six were selected for spe- 132
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cial consideration because they are the ones most often reported by the prospective studies to have the highest mortality ratios of tobacco-users to non-users, and stomach was included because the trend in cancer of this organ in recent years has been in such marked contrast to that for cancer of the lung and bronchus. SEX RATIO The male-female ratios of age-adjusted death rates (US., 1959-61) (252) from cancer for the six sites common to both sexes are given belbw: Male/Female Ratio Whites Male/Female Ratio Nonwhites. Larynx ------------------------- 10.8 7.6 Lung and bronchus--------------- 6.7 6.2 Oral cavity---------------------- 3.8' 3.3 Esophagus----------------------- 4.1 4.2 Stomach ------------------------ 2.0 2.3 Urinary bladder------------------ 1.3 1.6 The ratios of male/female death rates vary with site: ranging from about 10 to 1 for larynx to much less than 2 to 1 for urinary bladder, the findings for white and nonwhite populations being in substantial accord. The male- female ratios for five of the six sites have remained quite stable over the past 30 years, lung cancer providing the important exception. The lung cancer sex ratio was 1.5 to 1 in 1930 and! has steadily, increased during the inter- vening period to the current value of over 6 to 1. Mortality, register and survey data yield consistent information on~ sex ratios, and material from the latter sources need not be reproduced here. GEOGRAPHIC VARIATION Cancers of the oral cavity, larynx, lung and bronchus, prostate, and urinary bladder do not exhibit any consistent marked regional departures from the over-all U.S, incidence and mortality experience (91, 130). Cancer of the esophagus is higher in the Northeast and North Central regions, an& gastrie cancer is encountered less frequently in the South thani ini other parts of the country. Within regions, some cities are known to display exceptionali incidence of certain types of cancer (91). URBAN-RURAL GRADIENTS I I The excess risk for residents of urban areas is most pronounced for cancer of the lung and bronchus, oral cavity, and esophagus. This urban excess is not characteristic of the data for stomach,, prostate, or bladder (208). INCOME CLASS Information on income class gradients in cancer risks by site was secured in the morbidity surveys of ten U.S. metropolitani areas in 1947-48 (91). 133 8
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According to this source, incidence was inversely related to income class for five sites under review-oral cavity, esophagus, stomach, larynx,, lung. The rates for males in the lowest income class for esophagus and ltrng were about double those for high income males;, the range for the remaining sites was not quite so pronounced, the excess in low income risks being, on the order of 60-80 percent, For one site within the oral cavity, salivary glands, no: relationship was found between incid'ence and income class. The inverse gradient by income class, while present,, was much weaker among females for esophagus, stomach, and lung. The female risks for cancer of the oral cavity and the larynx were too small to permit meaningful state- ments on this t'opic. Incidence of bladder cancer was not relate& to income class for either males or females. OCCUPATION From unpublished'tabulations of deaths for 1950 according to occupation and indYrst'ry prepared by the National Vital Statistics Division of the Public Health Service (252), it is possible to select cert'ain occupations with un- usually high mortality for specific sites. One of the more striking results is the liability of bartenders, waiters, and others engaged in the alcoholic beverage trade to oral and esophageal cancers, the: mortality ratios beingg about double those for all males of comparable age. Similar findings have been reported by the Registr~ar-Generall of England and Wales (135)'. Review of the distribution of~ lung cancer risks by occupation indicates a large variety of occupational groups in metal working trades, such as mold- ers, boilermakers, plumbers, coppersmiths, sheet metal workers, etc., who are subject to a 70-90 percent excess risk for this site. One feature which does not come through clearly in the rather crude occu- pational mortality data is the high risk of bladder cancer among, workers exposed to aromatic amines, as established by observations on workers in individual plants ('179, 336)~. The 50 percent excess of bladder cancer mor- tality of workers in chemical and allied industries, reported in vital statistics, must represent a dilution of' higher risks in specific occupations in which the hazards are mu& greater. This dilution occurs because data from a number of industries and occupations, including many in which no partfie- ular bladder cancer hazard's are present, are pooled in~broad categories. ETHNIC GROUP Foreign.born migrants to the United States as a group have age-adjusted death rates for cancer of the esophagus and stomach about twice those re- corded for native-born white males and females. Lung, cancer mortality is about one-third higher among the foreign-born, again for both sexes. No important differential between native- and! foreign~born has been~ observed for oraP cancers (both sexes)' or for bladder (males) ; the rates for bladder cancer are about 30 percent lower for women born abroad than for women born in the Uhited States. Laryngeal cancer has not been systematically studied from this point of view (144). 134
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The several ethnic groups in the United States display their own charac- teristic patterns of excesses and deficits in risk by site. Men and women born in~ Ireland have high death rates for oraI and esophageal cancers. The Polish-born Americans have pronounced excess mortality for esophageall and gastric cancers for both sexes, and Polish males rank first in lung cancer. The Russian-born, a large proportion of whom are Jews, show high death, rates for stomach (both sexes) an& a striking excess risk for esophageal cancer among women. The English-born American men and women, have above-average lung cancer risks. TftENDS Figure 5 describes the divergent behavior in mortality trends for cancer,, all sites, among men and women since 1930. The age.adjpsted death rate has been declining slightly in females, but increasing in males; most of the rise for males is obviously attributable to the sustained upturn in lung cancer certifications. The succeeding logarithmic graph (Figure 6)' portrays trends in mortality among whites for individual sites; nonwhites have been excluded because the comparability of data over time for this group would be affected more seriously by recent improvements in quality of death certifications. Lung cancer mortality among males has risen at a fairly constant rate since 1930; . for females the trend has also been consistently upward, but at a much slower pace. This form of cancer was responsible for the deaths of approxi- mately 5,700 women and 33,200 men in the United States in 1961. As recently as 1955, the corresponding, totals were 4,100 women~ and 22,700 men (252). The register and survey data: also have reported a marked rise in lung cancer incidence. No other cancer site has exhibited in recent history a rate of increase, absolute or relative, approaching that recorded! for lung cancer in males. Inspection of age-adjusted mortality rates for oral cavity, esophagus, larynx, prostate, and urinary bladder cancers pinpoints no dramatic shdflt in risk. The rates for stomach cancer, however, have been declining steadily. This has led some observers to conjecture that the rise in lung cancer and the decline in stomach cancer may represent two aspects of the same phenomenon, a progressive transfer of deaths to lung, cancer which might formerly have been certified as stomach cancer. Detailed examination of the data on possible compensatory effects by country, sex, age and other variables con- clusively rules out diagnostic artifacts of this type as a possible explanation. The Connectieut, and New York State registers (112, 136) an& t'he ten-city surveys (91) confirm the decline in gastric cancer and the absence of impor- tant changes over time for oral cavity, esophagus, urinary bladder, and kidney, and show a small increase for larynx. The registers also indicate a small rise in incidence of prostatic carcinoma; the age-adjusted rate in upstate New York increased from 21'.4 in 1941-43 to 24.9 in~ 1958-60, and the Connecticut experience revealed a similar displacement. A possible reason for this increase in case reports of prostatic cancer to registers may be found in more careful examination by pathologists of prostates removed 135 L
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TRENDS IN AGE-ADJUSTED MORTALITY RATES FOR CANCER BY SEX - ALL SITES AND RESPIRATORY SYSTEM IN THE UNITED STATES, 1930•1960. Cl) 0 150 MALE 19601930 1940 FEMAL ® 1930 1940 1950 1950 1960 CANCER, ALL SITES ~ CANCER, EXCLUDING RESPIRATORY SYSTEM --- CANCER, RESPIRATORY SYSTEM ONLY F9CURE S. Age-adjusted to the total population o/'the continental United States, 1950. Source: Vital Statistics of tlie United States,,annual volumes: surgically, which would result in discovery and' reporting of more asympto- matic prostatic carcinomas. The mortality data relate to clinically active prostatic carcinomas and in this instance probably give a more accurate assessment of changes over time than the registry data: AGE-SPECIFIC MORTALITY FROM LUNG CANCER The schedules of age-specific lung cancer mortality rates for males studied in five suecessive time periods from 1914 to 1960 are shown in Figure 7 (dotted lines). It ean be seen that the rate rises to a maximum at age 70 and then declines gradiially thereafter. Incidence data from cancer registers provide a close parallel (112). 136 ~ - Ca
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TRENDS IN AGE-ADJUSTED MORTALITY RATES FOR SELECTED CANCER SITES BY SEX IN THE UNITED STATES, 1930-1960. ('Y ~ - F EMAL ES 0 -- _ 0-- i ~ I . 5- ~ . . .. ~ E _- - 4.; . . I , Z ~ • i tt 1 I 5 I MALE S ~ • 0 0 0 0 0 0 • 0 0 LUNG AND BRONCHUS STOMACH BLADDER AND OTiHER URINARY ORGANS (EXCLUDING KIDNEY) PROSTATE ESOPHAGUS BUCCAL CAVITY'AND PHARYNX. LARYNX KIDNEY FtGVttE 6. Data are for the white,population,,age-adjusted to the total population o/, the continental United States, 1950: Sources: Gordon T., et al. (130) ; and unpublished calculations of the Biometry Branch, National Cancer Institute, UIS. Puhlic Health Service. However, when any separate cohort (a group of persons born dtrring the same ten-year period) is scrutinized over successive decades, the seeming downturn of mortality rates after age 70 can be seen to bean artifact due. 137
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AGE-ADJUSTED MORTALITY RATES FOR CANCER OF THE LUNG AND BRONCHUS BY BIRTH COHORT AND AGE AT DEATH FOR MALES, UNITED STATES 1914, 1930-32 , 1939-41, 1949-50, 1959-61. f 200 100 50 o. a LU a. a ; q0 I a~- 9 , ~--- _ -- ~- -- - - ~~ - - - . r / ~ I I i / / /' \ , . -~ -- --- --__..- -- - ---- ~.~~~- - --- _._ --.~-.---- ~ / __ 0 0 0 00 0 . 0 i : 0 9 30 20 3 .3 AGE FIGUAE'7: Data are for the white population. Sources: Dorn, H. F., and Cutler, S. J. (91). Unpubli'shed calEulations of the Biometry Btanch, National Cancer Institute, U.S. Public Health Service. to the admixture of cohorts with differing mortality experiences. When the points representing mortality rates among members of the same cohort group are connected, from each~ dotted'•line curve to the next, the new curve (each of the bold lines) represents the mortality rates over time for the members of a cohort. Thus, to cite the cohort born around 1880 as an example, the bolde llne curve shows the mortality, rates of the cohort in 1911 when its members were about 34 years old, in 1930-32 when they were about 51 years old, in 1939-41 when they were about 60 years old, im 1949-50 when they were about 70years old, and in 1959-61 when they were about 80 years old. The new, series of curves,, representing, the mortality' experience of the individuall cohorts, reveall two important facts :(a ) Within each cohort, lung cancer mortality increases unabated to the end of the life span;, and (b)) successively younger cohorts of males are at higher risks throughout life 138 ~939-41 1930-32 1914 0
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AGE-ADJUSTED MORTALITY RATES FOR CANCER OF THE LUNG AND BRONCHUS BY BIRTH COHORT AND AGE AT DEATH FOR FEMALES, UNITED STATES 1914, 1930-32, 1939-41, 1949-50, 1959-61. 0), 0 m 20 F" 40 AGE m 60 m tE 90 FIGURE 8. Sources: Dorn, H. F., and Cutler,, S. J. (9L)_ Unpublished calculations of the Biometry Branch, National Cancer Institute;, UiS. Public Health Service. than their predecessors. The increasing steepness of the slope of the cohort mortality curves, beginning with the 1850~ cohort, and~ examining the cohort curves from right to left, shows that the rise in lung cancer mortality is much more rapid in the recent cohorts. The pattern would suggest that the effects noted may be attributable to differences in exposure to one or more factors or to a progressive change in populhtion composition among the several cohorts. For women, incidence and mortality increase up to the older ages, when the rates fluctuate irregularly (Figure 8). A cohort approach to the female experience reveals only small displacements in rates between successive cohorts, the effects being smaller than those noted for males. EFFECTS OF' CIIANGES IN! LUNG CANCER DIAGNOSIS ON TIME TRENDS The cause of death is at times difficult to establish accurately from~ clin- ica1 findings alone, and the incidence and mortality rates recorded fbr lung 139 J
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cancer vary with the diagnostic criteria adopted (147, 148). A pathologic anatomic diagnosis provides the most reliable evidence for the classification of lung cancer deaths. Shifts in diagnostic standards or in diagnostic errors must be considered in evaluating the trends in lung cancer mortality shown in tabulations pre- pared! by the offices of vital statistics. In recent years, about two-thirds of the certifications of lunn cancer deaths have been based on microscopic examination of tissue from the primary site and the percentage is even higher for deaths under 75 years (146, 247)1, The proportion of lung cancer certifications in the 1920's and 1930's based on comparable diagnostic evi- dence is unknown, but the figure was certainly much lower. Gilliam (128) has attempted to evaluate the possible effects of diagnostic changes onn the published lung cancer mortality statistics: He caleulated that if two percent of the deaths certified to tuberculosis in 1914 were really due to lung cancer, the observed increase in bronchogenic carcinoma between 1914 and' 1950 could be scaled downi from 26- to 8-fold for males and from 7-fold to L3-fold fbr females. If 1930 or a later year had been used as the point of departure to estimate the effects of continued misdiagnoses of tuberculosis on this scale, the downward revision in the slope of the lung-cancer rates would' have been much smaller. The improved accuracy of lung cancer diagnoses must be concededy so that the issue remains a quantitative one: what part of the recorded increase can be accounted for by control of diagnostic variation? Retrospective adjustment of vital statis- tics from past years can yield only rough qualitative judgments (267), and we must re1W on the: composite evidence from several sources. The f'ollowing points have been advanced to support the thesis of a real increase in lung cancer (62) : (a) The rising ratio of male to female deaths (b), The increasing mortality among successively younger cohorts (e)The magnitudeof the increase in mortality in recent years To this we would add that the question can be resolved by referrence to the contemporary experience of large,, population-based cancer registers for which, a high percentage of the cases reported have microscopic confirma- tion. Sufficient time has now elapsed to permit the tumor registries in Connecticut (136). and New York (112) to supply convincing, evidence for a true increase in lung, cancer. Diagnostic comparability is a far less im- portant consideration in the review of data collected by cancer registries. Between~ 1947 and 1960 there were no significant advances in diagnostic methods (exfoliative cytology studies of the sputum have been used for diagnostic purposes since 1945)'. In upstate New York the age-adjusted incidence of lung cancer per 100,000 males rose from 17.8 in 1947 to 41.0 in 1960 and for females from 3.2 to 4.9. These figures imply an average annuall rate of increase of about 7 percent! for males and' 3-3.5 percent for females during this interval. For earlier years the relative frequency data from necropsy series con- tribute valuable information:. The records of large general' hospitals where diagnostic accuracy of lung cancer has been uniform and excellent~ for many years also support the thesis of a reall increase in lung cancer. Institutions such as the Universit'y of Minnesota Hospitals (Minneapolis) (350), Presby- 140.
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terian HospitaP (New York City) (323)~, and the Massachusetts General Hospital (Boston) (54), now find many more lung cancers than in the past. In the Massachusetts General Hospital, for example, only 17 cases of brorn- chogenic carcinoma, 11 males and 6 females, were diagnosed in 5,3000 autopsies from 1892 to 1929 (autopsy rate of 33 percent), compared to 172 cases, 140 males and 32 females, in 5,000 autopsies from 1956 tb, 1961 (autopsy rate of 68 percent)1. This American experience is consistent with that reported abroad, where virtually all patients dying in certain hospital services have been subjected to autopsy for many years. Steiner (328)i summarized several such series and' Cornfield et, al. (62) returned to the original sources and found' the collective evidence to affirm a rise, in the percent of lung, cancers found at necropsy fromi 1900 om The Copenhagen Tuberculosis Station data, reviewed by Clemmeseni et al. (56), present an unusual opportunity for evalnating the effect of improve- ment in diagnosis on the time trend. In the Copenhagen tuberculosis referral service, used extensively by local physicians, where diagnostic standards and procedures including,systematic bronchoscopy remained virtually unchanged between 1941 and 1950, the lung cancer prevalence rate among male examinees increased at a rate comparable to that recorded by, the Danish cancer registry for the total male population. The rising trend for lung cancer during the past 15 years thus is welll documented. The increasing frequency of lung cancer found at necropsy from 1930 onwards while of itself not decisive, when considere& in the light of recent events reported' by cancer registers, would support the conclusion that the rise in lung cancer did not begin in the 1940 decade, but was a continuation of a trend begun earlier. CARCINOGENESIS Tobacco and tobacco smoke contaim a complex mixture of hundreds of different chemical components among which are (a) numerous polycyclic aromatic hydrocarbons and (b) inorganic compounds. Many of these:com- pounds have been shown to be carcinogenic in animals. For information on other components of' tobacco and tobacco smoke see Chapter 6. Before considering the biological evidence available for the carcinogenic eflect of these components of tobacco and tobacco: smoke, it may be helpful to review briefly some basic principles of carcinogenesis. FUNDAMENTAL PROBLEMS IN CARCINOGENESIS IN RELATION TO INDUCTION OF NEOPLA'STIC CHANGES IN MAN BY' TOBACCO SMOKE Carcinogenesis is a complex process. Many factors are involved. Some are related to the host, others to the agents. The host factors include genetic,, strain, and organ differences in sensitivity to: given agents; hormonal and other factors which modify sensitiivity, of cells; and nutritional state (123). The character of the agents involved in carcinogenesis varies greatly. Some agents by themselves cause irreversible alterations in cells which may 141
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lead to the production of cancer; others promote the carcinogenic process. (21, 33). The former are called initiators, the latter promoters. Some subst'ances,such as urethan, can be both. Several classes of chemicals are known to be capable of inducing cancers (143). The chemical properties, the physical state of a substance, and the vehicle in which the substance is introdueedl into the body can influence the carcinogenic potency of environmental agents, e.g., insertion of! a plastic membrane into tissues can cause a cancer (2, 261, 347), but a fine powder of the same plastic has not done so (257). Carcinogens vary with respect to organ affinity and mechanism of inducing a neoplastic change. There is mounting evidence that viruses may also play an important role in the induction of tumors (137, 140; 345). It follows from these considerations that failure to produce cancer in a given test, by a given mat'erial, does not rule out the carcinogenic capacity of the same material in another species or in the: same species when applied under different circumstances. Conversely, induction of cancer by a com- pound in one species does not prove that the test compound would be carcinogenic in another species under simil'ar~ circumstances. Therefbre, tests for carcinogenicity in animals can provide only supporting, evidence for the carcinogenicity of a given compound or material in man. Neverthe- less; any agent that can produce cancer in an~ animal is suspected of being carcinogenic in man also. The types of cancers produced by the polycyclic aromatic hydrocarbons and other carcinogens depend on the tissues with which they make contact. Carcinogenesis can be initiated by a rapid single event, best exemplified by the carcinogenic effect of a split-second exposure to ionizing radiations (e.g., from atomic detonation) (40, 351)~. More often, however, it appears to be characterized by a slow multi-stage process, preceded by non-specific: tissue changes, as exemplified by cancers arising in burns. Evidence is pre- sented in~ another section ofl this Report that cancer of the lung in cigarette smokers, as well' as experimental cancer induced by presumed carcinogens in smoke, is preceded by distinct histologic alterations whic6 can progress to the development of "cancer in situ." These need not proceed to the formation of invasive cancer, and may regress following, removal of the stimulus: The character of "precancerous" change varies in~ different organs; e.g., in the bladder it is manifested by the formation of "benign" papillomas; in the oral cavity, by theJbrmation of white patches of thickened squamous epithelium-leukoplakia-al non-neoplastic reversible change. The evolved cancer is also subject to further changes. Often, rapidly growing variants develop, a process termed progression (119). Almost every species that has been adequately tested has proved to be susceptible to the effect of! certain~ polycyclic aromatic hydrocarbons identi- fied in cigarette smoke and designated as carcinogenic on the basis of tests in rodents. Therefore, one can reasonably postulate that the same poly- cyclic hydrocarbons may also be carcinogenic in one or more tissues of man with which they come in contact. Experimental studies have d'emonstrated! the presence of substances in tobacco and smoke which themselves are not carcinogenic, but can promote 142 ~s..;,..
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carcinogenesis or lower the threshold to a known carcinogen. There is also some evidence for the presence of anticarcinogenic substances in~ tobacco and tobacco smoke (107). Threshold In any assessment of carcinogenicity, dosage requires special considera- tion. The smallest concentration of benzo (a) 'pyrene known to induce carci- noma when dissolved in acetone and applied to the skin of mice three times weekly is 0.001 percent (380). Subcutaneous cancer follows injection of only 0.00195 mg. of benzo(a)pyrene in 0.25 ml. tricaprylin. Whether there is a threshold for effective dosage of a carcinogenic agent is cont'ro• versial at the present time. The evidence.for the existence of a.threshold has been summarized by Brues (43):. When pulmonary tumors were in- duced in mice with dibenzanthraceneand'~urethan byH'eston et'1 al. (172, 232')1, a linear response was demonstrated at higher doses but a curvilinear re- sponse appeared at lower doses. At extremely low d'osage, the possible effect of the agent became obscured! by the incidence of spontaneous pulmonarytumors. In the case of induction of cancer by ionizing radiation, it has been claimed that there is no threshoU (210')1. It is conceivable that thersisno threshold for certain neoplasms, whereas there: may be one for others. Neither the available epidemiolbgic nor the experimental data are adequate to fix a safe dosage of chemical carcinogens belbw which there will be no response in man (43, 172, 210, 232). CARCINOGENICITY OF' TOBACCO AND TOBACCO SMOKE IN ANIMALS There is evidence from numerous~ laboratories (31, 42,92; 93, 1105, 1:32, 139, 263, 296. 297. 338, 3712, 373. 382, 383)~ that tobacco smoke cond'ensates and extracts of tobacco are carcinogenic for several animal species. Several laboratories obtained negative results (154, 262, 267, 268). The nature of the test system is critical in studies on carcinogenic activity ofl such complex mixtures. The relatively high suscept7bilityof mouse skin to carcinogenic hydrocarbons has made it a favorite test object (6, 278). A second test system also used is the induction of pulmonary adenomas in mice. This will be detailed in the section on Experimental Pultnonarv Car- cinogenesis. A third system which has been used less frequently is the induction of subcutaneous sarcomas in the rat whose connective tissues have been found to be susceptible to the carcinogenic action of many different chemicals as well as of complex materials. Another test, which has been used in some studies and can be read within five days after painting the skin of mice with a carcinogen, consists of determining t'he number of sebaceous glands and the thickness of the epidermis (342a). However, the reliability of this procedure as a bio-assay for. carcinogenesis is open to question. Skin. Many investigators have shown that the application of tobacco tar to the skin of mice and rabbits induces papillomas and'carcinomas (31, 42, 92, 93, 714-422 0-64-111 143
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105, 132, 139, 263, 296, 297, 338, 372, 373, 382, 383)1. Wynder et al. (382) applied a 50 percent solution of cigarette smoke condensate in acetone three times weekly to the shaved backs of mice so that each received about 10 gm. yearly. The animals were usually painted for 15 months: More than 5 gm: annually was required for the induction of epidermoid carcinoma and more than 3 gm. for the induction of papillomas (372, 373). Since the carcinogenic potency of! a smoke condensate can be altered by varying condi- tions of pyrolysis, the manner of preparation of the tar is of importance (392). This may be one reason for the negative reports (154, 262, 267, 268) encountered in the literature. Extracts of tobacco usually have weaker carcinogenic activity than do the condensates of cigarette smoke (93, 390). Gellhorn (126) and Roe et al. (290, 293) have reported'that condensates of cigarette smoke have cocarcinogenic or promoting properties. It was found that the application of a mixture of! benzo(a)pyrene plus condensate of' cigarette smoke to the skin~ of mice resulted in~ the production of many neoplasms, whereas the same concentration of benzo (a) pyrene alone failed to elicit tumors. Gellhorn (126) found that the tobacco smoke condensate ap- peared to accelerate the transformation of papillomas to carcinomas. Anti- carcinogens have also been reported in condensates of cigarette smoke (107). Nicotine is not' usuallyy considered' a carcinogen on the basis of animal experiments (346, 3911). Removal of nicotine or other alkaloids did not diminish the carcinogenicity of condensates of! smoke for the skin of mice. The induction of pulmonary adenomas in mice by urethan~ (120)~ and! of skin tumors in mice by ultraviolet radiation (121) are not altered by the administration of nicotine or some of its oxidation prodlicts. Subcutaneous T issue Druckrey (92) found! that cigarette smoke condensates or alcoholic ex- tracts of eigarette tobacco regularly induced sarcomas in rats at the site of subcutaneous injections. The material was injected once weekly for 58 weeks, the totall dose administered being 3,2 gm. The animals were followed, thereafter, until death. Approximately 20 percent of the animals in each experiment developed the neoplasms. Druckrey also carried out similar ex- periments with benzo (,a) pyrene and found that the amount of this polycyclic aromatic hydrocarbon in smoke eond'ensates or tobacco extracts cannot account for more than a few percent of the activity of the tobacco products. This same discrepancy between the quantity of benzo(a) pyrene in smoke con- densates and the carcinogenic potency of the condensates has been reported by several investigators using the mouse skin test (192, 93, 126, 372; 390). Mechanism o f the Carcinogenicity o f Tobacco Smoke Condensate Tobacco smoke contains many carcinogenic polycyclic aromatic hydro- carbons (Table 2, Chapter 6). Benzo ( a) pyrene is present in much larger concentrations than is any other carcinogenic polycyclic hydrocarbon. The inability to account for the carcinogenicity of the tobacco products, except to a very minor degree, by the amount of benzo(a):pyrene present was unanticipated. Both Druckrey (92) and Wynder (372) emphasized that 144. O W ~ Q: C!' ~ ~ N
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the benzo(a)pyrene concentration of various t'obacco and smoke prepara- tions is only sufficient to account for a very small part of the carcinogenicity of these: materials. One hypothesis suggests that promoting agents present in tobacco and tobacco smoke, such as various phenols, enhance the potency of the carcinogenic hydrocarbons so as to account for t'he biologieal activity of the tobacco products. Further, possible synergism between low levels of the severall known carcinogens in the tobaccol condensates and extracts may also enhance the carcinogenic potency. Other Materials of Possible Importancein, Carcinogenicity PESTICIDES Pesticides currently used in the husbandry of tobacco in the United States include DDT, TDE, aldrin, dieldriny endrin„chlordhne, heptachlor, malathioni and occasionally parathioni (see Chapter 6)1. The: first two are used more commonly than the others nearer the time for harvesting. TDE has been detected in tobacco and its smoke (242), an& endrin has been extracted from tobacco on the market (34, 35). Aldrin and dieldrin have been found to increase the incidence of hepatomas in mice: of the C3HeBiFe strain (68). Aldrin is metabolized to dieldrin, and the effect may be due only to the latter or some subsequent metabolite. DDT has been shown to induce hepatomas in trout (153) andl rats (253)~. The possible role of these compounds in contributing to the potential carcinogenicity of' tobacco smoke is not known (see also Chapter 6, section oniPesticid'es). LACTONES The lactones have been suggested as contributors to the carcinogenic effects of tobacco. Attention, was focused oni these compounds by the dis- covery (74, 74A, 291, 292, 362) thati,td-propiolactone, used as a sterilant and preservative, is carcinogenic,for mice. Coumarin„a 8-lactone, has been used as a common flavoring in t'obacco: Hydroxy- and methoxy-coumarins are constituents of the leaf itself and are carried over in the smoke. Also the y-laetone, ,(3.levantenolide, is present in both tobacco and smoke (354). The follbwing,lactones (not suggested to be present in tobacco) have been found to~ be carcinogenic for animals: y-lactones (patulin, penicillic acid, methyl protoanemonin)~ and S-lactones (parasorbic acid lactone and aflatoxins). RADIOACTIVE COMPONENTS Potassium 40, a/3-emitter; has been reported to be a source of radioactivity in cigarette smoke. The amounts of this activity taken into the lung, even by the heavy smoker, are minute when compared with the daily uptake of K 40 from the diet. Furthermore this material is highly, soluble and it is rapidly eliminated from the lung tissue thereby prevent'ing any local build~up (300a). The .-particle activity due to the radium~ and thorium content of tobaccoo smoke, even for the heavy smoker, is less than one:percent of the atmospheric radon an& thoron inhaled daily by any individual 047a) . A recent but still unpublfshed'report holds that Po 210 is the major source of radioactivityin~ cigarette smoke. The amounts calculsted! to be absorbed are higL enough to merit further study as a possible factor in carcinogenesis (282a)!.. No data 145
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appear to have been~ published on the uptake by the tobacco plant of radio- active constituents from fall-out (e.g., Strontium 90 and Cesium 137). over a long period of time is not understood. but the biological action of mixtures of the:known carcinogens and promoters genic activity. Promoting agents have also been found in tobacco smoke and by painting the bronchial epithelium of dogs. The amount of known carcinogens in cigarette smoke is too small to account for their carcino- tion to the skin of mice and of rabbits, by subcutaneous injection in rats, Condensates of tobacco smoke are carcinogenic when tested by applica- Summary CARCINOGENESIS IN MAN ii Despite the many uncertainties in the application to man of'~ research results in animals, the animal data: serve a purpose in indicating potential careinogenicitiy. The greatest consistency is observed in respect to those groups of chemical compounds which are carcinogenic in~ many species. Several, of the polycyclic aromatic hydrocarbons present in tobaeco smoke f'all int'o this category in that they are carcinogenic for most animal~ species tested. Since the response of most human tissues to exogenous factors iss similar qualitatively to that observed in experimental animals, it, is highly probable that the tissues of man are also susceptible to the carcinogenic action of some, of the same polycyclic aromatic hydrocarbons. The results of exposing humans to pure polycyclic aromatic hydrocarbons or to natural products containing such compounds have been reviewed by Falk et; al. (108). Polycycl'ic Aromatic Hydrocarbons Cancer induction in man by the application of "pure" polycyclic aro- matic hydrocarbons has not been reported. Klar (1188) reported an epi- theliall tumor on, his left forearm that appeared three months after termination of an exper,iment in which mice were painted with 0.25 percent benzo (a) pyrene in benzene. Cottini and R'Iazzone (63) applied 1.0' percent benzo(a)pyrene in benzene to the skin of 26 volunteers in daily doses and observed& the sequentiall development of erythema, pigmentation, desquama- tion, and verrucae. The changes were more pronounced in older than in younger volunteers. After 120 applications, the experiment was terminated and the lesions regressed within, three months. Rhoads et al. (286) de- scribedl similar changes in human skin painted with the same carcinogen. These reversible changes were similar to the initial changes in the skin of men, who ultimately developed invasive cancers following industrial ex- posure to carcinogens: Cancer of the skin of the fingers has not been re- ported' in cigarette smokers, despite the intense discoloration so often seen at this site (212). Howeverr, spont'aneous cancer of the skin of the fingers is very rare. 146 1
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SOOT Cancer of the scrotum in~ chimney sweeps subjected to prolonged massive exposure to soot was a common finding in the eighteenth century (279)~. As many as one in every ten men engaged' in this occupation developed can- cers (204). Sporadic cases of cancer of the skin~ at other sites, such as the face (60), the ear,, and the penis (264), were also: described. The neo- plasms usually oecurred~ in men between 18' and 47 years of age (213), possibly reflecting the early age at which boys entered this occupation. Whether there is an increase in cancer in persons now working in industries involving exposure to "carbon black" is being debated (108). The chemi- cal and physical properties of "carbon black" vary widely (109, 110). As early as 1922, Passey (266) found that cancer of the skin, could be produced experimentally by extracts of soots. More recently, Falk et a]. (111), showed that polycyclic hydrocarbons in the "carbon black" were present in processed rubber, and rubber extracts were found to be carcino- genic for the skin of mice. Also Falk and Steiner (I109, 110) found, furnace• type black rich in pyrene, fluoranthene, benzo(a)'pyrene, benzo(e)pyrene, anthanthrene,, benzo(g,, h, i)iperylene, and coronene in particles having an average diameter of 80 mµ or larger. These compounds were not present in channel blacks which have smaller particle size: The amount of benzo- (a) pyrene extracted from different soots varies from none to 2 mg. per gm. (307). COAL TAR AND PITCH Butlin ('50)in 1892 described cancer of the skin as an occupational hazard in the coal tar industry. The distillation of coal tar yields many different organic compounds wit6 a residue of pitch containing polycyclic aromatic hydrocarbons (300). Henry (166) reported that up to 1945; 2,229 of 3,753 cases of industrial skin, cancer-studied were attribute& to exposure to tar and pitch, the remainder to mineral oils. The latent period for in- duction of this type of cancer is estimated to be 15 to 25 years. Most reports about this type of cancer have come from England (166), but they have also appeared from other countries (44, 73, 231, 310)1. Bonnet (32) reporrted'an interesting case of pulmonary cancer in a workman exposed to hot tar containing three percent.benzo(a)pyrene. He estimated that 320 µg, of the carcinogenic hydrocarboni could have been inhaled' hourly. Car- cinogenicity of botih, creosote oil and anthracene oil for the skin of workmen has beenidocumented (18„39, 259). MINERAL OILS So-called paraffin cancer is not caused! by parafHn but by exposure to impurities in oils used in the process of purification (165; 203). Recent work (321) has confirmed the view that refined paraffin wax does not contain polycyclic aromatic hydrocarbons and that it is not, carcinogenic. The danger incidental to exposure to mineral oils has been decreased by extraction of carcinogenic hydrocarbons with sulfuric acid' (164). Bioassay of mineral oils indicates that their content of carcinogens varies with their 147
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geographic origin (348)~. Animal tests show that the carcinogenicity of mineral oil' increases as the temperature of distillation increases or when, cracking is instituted for the formation of new compounds. A variety of carcinogenic compounds has been isolated from~ different fractions. Some fractions presumably free from benzo(a)pyrene have nevertheless been .found to be carcinogenic. Coal tar contains 0.3 to 0.8 percent benzo(a)i- pyrene, soot 0.03 percent, an& American shale oil 0.003 to 0.004 percent (51). SUMMARY There is abundant evidence that cancer of the skin can be induced in man by industrial exposure to soots, coal tar and pitch, and mineral oils. All of these contain various polycyclic aromatic hydrocarbons proven to be carcinogenic in many species of animals. Some of these hydrocarbons are also present in~ tobacco smoke. It is reasonable to assume: that these can be carcinogenic,for man also. CANCER BY SITE The seveni prospective: studies described and summarized in Chapter 8' provide a natUral point of departure for considering the relative risks, for smokers and' non.smokers, of cancer at specific sites. The consolidated findings (Table 1) identify eight sites as displaying higher risks of cancer among cigarette smokers, who in recent decades have been the predominant consumers of tobacco. These sites are lung, larynx, oral cavity, esophagus, urinary bladder, kidney, stomach~ and prostate. The mortality ratios for cigarette smokers vis-a-vis non-smokers range in descending order from nearly 11 to 1 for cancer of the lung and bronchus to 1.3 to 1 for prostatic cancer. For five of these sites-lung, larynx, oral cavity, esophagus, and urinary bladder-cigarette smokers have a substantially higher cancer risk than non-smokers. The smaller excess risks among, cigarette smokers for cancer of the stomach, prostate, and kidney deserve comment. The prospective studies are. not in complete accord as to an association with smoking history, for cancer of! the prostate and kidney, and in some of the studies which were conducted with other objectives in mind, the relationships of prostatic and renal cancer with smoking history represent incidental findings. No other evidence can be adduced in evaluating and interpreting,the prostatic and renal' mortality ratios, since the effects were not large enough to draw the attention of investi- gators. For these reasons, cancer of the prostate and kidney will not be dis- cussed further at this time. This decision does not imply a conclusion that the findings must be artifacts, but rather that jiudgment on these sites should he suspended until more data become available. The case for considering cancer of the stomach in more detail is not much stronger than for prostate and kidney, but the consistency among the pros- pective studies is better. In addition,,the st'udies report a stronger association of~ smoking history with stomach ulcer. Clinical impressions of this relation- 148' -1.::....,. ..... ..'«~t..:,:...x„ ..".d:,...a. . .. , . -- .- ,.,~,......
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TAsLE 1. Ezpected and observed' deaths and mortality ratios of current smokers o f cigarettes only, f or selected cancer sites, all other sites, and all causes of death; each prospective study and all studies United Cali- Calii Cana= Site of cancer British Men in States ! fornia fornia dian Men in Total' doctors 9 States veterans occupa- Legion ~ vrtcans 25 I ti0nal I States I Ltmg and Observed 129 233, 51 19 138' 98 317 399 1,933 bronchus, Expected 6.4 23;4 43;3 8.7 19.9 27,1 41.5 170:3 162-3a Ratio 20.2 , 10.0 I 12:0 - 15.9 4.9 11.7 9.6 10.8 Larynx, 161 Observed 7 17 r ' 14 3. 6 5 23 75 Expected 0.0 1.3 2.4 0.0 4.0 0.0 6.3 14;0 Ratio --------- 13.1 5.8 --------- 1.5 --------- 3.7 5.4' Oral Cavity, Observed 6 22 54 7 10 20 33 152 140-8. Expected Ratio 0;0. --------- 7.8 2:8 8.1 6.6 7:2 1.0 5.2 1.9 5.1 3.9 3.6 9.2 37:0 4:1 ESophagus,150 Observed ' 7 18 33' 4 9 22 20 113' Expected 3:3 2,7 5.2 5:5 1.8 6.8 8.4 33:7 Ratim I 2: 1 1 6.6 6. 4' 0.7 5.11 3.3 2.4 3!4'. Bladder„181 Observed 12 41 55 13 7 38 50 216' Expected 13.9 ' 17.2 31.4' 2.2 1.8 22.3 22.8 111.6 Ratio 0.9 I 2:4: 1.8 6.0 4.0 L7 , 2.2 1.9 Kidney, 180 Observed 8' 21 34. 10 6 13 28 120'. Expected 0.0 14.0 23:1 0.0 8.3 9.:5 24.1 79:0. Ratio ________ 1.5 1.5 _________ 0.7, li4 1.2 1.5 Stomaclii.151 Observed 31 76. 9ii. 24' 25 76 91 413'. Expected . 28:3 33:7 61.5 31.4 20-5 41i2 68.6 285.:2 Ratio L 1.1 2.3 1.5 0.8 1.2 119 1.3 1.4' Prostate, 17Z Observed 15. 51 106 4' 19 48 75 318'. Expected 29.0 32:4'. 53:7 8.6 22,.1', 32:3 74.9 2531.0. Ratio 0.5 1.6 2.0 0.5 0.9 115 1.0 1.3' All Other Sites. Observed , 116' 290. 671 141 106. 237 571' 2; 13T Expected 112.0 228.3 505.7 109.4 120.6 192:.1 473.8 1,692:.0. Ratio 1.0 1.3 1.3 1.3 0.9 L 2 1.3 1.3 ' All Causes of~ Observed ~- 6l 72 3; 781 7, 236 1,456 1, 264: 4,001 6,813 26; 223 Death. Expected 1, 161.8 2,:227:7 4,043, 1 818. 5 799.4 2;420..1i 4, 183.3 15;65319' Ratio 1.44 1.70~ 1.79' 1.78 1.58' 1:65~ 1163: 1.68 I Includes all cigarette smokers (durrent' and ex-smokers). 2 International StatisticaliClassification number. ship undoubtedly stimulated some of the case-control studies of smoking and stomach cancer which have been reported. Stomach cancer incidence and mortality have been declining, rapidly in the United States im recent years, simultaneously with the rise inJung cancer. This and the presence of addi- tional evidence from retrospective studies justify reviewing stomach cancer in more d'etail in this chapter. Thus the six cancer sites to be reviewed here are lung, larynx, oral cavity, esophagus, urinary bladder, and stomach. LUNG CANCER Historical The earliest suspicions of an association between smoking and lung cancer were undoubtedly evoked by the provocative clinical observations that lung cancer patients were predominantly heavy smokers of tobacco. Early investi- gators, including Miiiler (250) in 1939 and Schairer and Schoeniger (309)' 149 ~. . .._1..~ ... ~. , ......~_. .a.r-.H..
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