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The-Health - Con.seq ; uences of SMOKING A PUBLIC HEALTH SERVICE REVIEW : 1967 TH. EpV\ , ~ Am I 0 U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE Public Health Service .,. .. _ ..r_ . ..... . .. .... .~:, © 92 .w._-r ~. ..... ~, .....z 9

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Foreword The Federal Cigarette Labeling and Advertising Act of 1965 (Pub- lic Law 89-92) requires that the Secretary of Health, Education, and Welfare submit regular reports to the Congress on the health conse- quences of smoking, together with any legislative recommendations he may wish to make. This 1967 Surgeon General's Report was prepared to provide the Secretary and the public with a review of the research findings which have taken place in smoking and health in the approximately 3% years which have elapsed since the Surgeon General's Advisory Committee issued its monumental 1964 report. Part I of this document was in- cluded as part of the Secretary's 1967 Report which he sent to Congress in July 1967. Part II, which provides detailed discussions of the re- lationship of smoking to specific diseases, is issued here for the first time. The 1967 report represents a review of more than 2,000 research studies published since the 1964 report. These additional studies con- firm and strengthen the conclusion of the Surgeon General's Advisory Committee that: "Cigarette smoking is a health hazard of sufficient importance in the United States to warrant appropriate remedial action." ' In a separate section of this report, acknowledgments have been made for the help of numerous scientists both within and outside the Public Health Service, who participated in the preparation of this report. These include the 10 distinguished scientists who made up the Surgeon General's 1964 Advisory Committee, all of whom were kind enough to review part I of the 1967 report before its publication. A special word of thanks is due Leonard M. Schuman, M.D., one of the 1964 committee members, who advised the staff in the final editing of the entire document. 4.Gl.fl~ebs.~/ /•'AWihl.J SURGEON GENERAL. yr , 0:. ;y:

Table of Contents Page Part I. Current Information on the Health Consequences of Smoking-----------------=--------------------- 1 Introduction--------------------------------- 3 Smoking and Overall Mortality---------------- 7 Some General Considerations-------------- 11 Smoking and Overall Morbidity---------------- 19 Smoking and Cardiovascular Diseases----------- 25 Smoking and Chronic Bronchopulmonary Dis- eases (Non-neoplastic)---------------------- 29 Smoking and Cancer-------------------------- 33 Other Conditions and Areas of Research-------- 39 Cited References----------------------------- 41 If. Technical Reports on the Relationship of Smoking to Specific Disease Categories---------------------- 43 Chapter 1. Smoking and Cardiovascular Diseases- 45 2. Smoking and Chronic Bronchopul- monary Diseases (Non-neoplastic)- 87 3. Smoking and Cancer--------------- 125 4. Other Conditions and Areas of Re- - search-------------------------- 179 ,: 0 r

PART 1 Current Information on the Health Consequences of Smoking x ZE

TABLE 2.-Changes in the lung cancer death rate in male British phy- sicians (age 36-84) compared roitkh cAanges in the rates for the male populatian of England and Wales for 3 time intervals between 1954 and 1964 (7) ta,g ~ aean..a. Pr I,ooo Tlma pslud pff~ Nenin B and W Btltllh PhyeldW 1954 to 1957----------------°--°___°________ 1.49 1.09 1958 to 1961________________________ 1.71 .83 1962 to 1964----------------------------------- 1.86 .76 Percentage change: 1st to 2nd period--------------------------- }15 -24 2nd to 3rd period--------------------------- +9 -8 lstto 3rd period---------------------------- t 25 -30

. . . . .. . , . .. , .~-~„ .. .:h•ai . ._.v. .. „ . .. .,...:. . ,.y,:.: . , ~:. . . . - . .... . . - -. .. - . ..r ,. . . : ., .. Acknowledgments l ,~ . .: Responsible for the preparation of this report was the National Clearinghouse for Smoking and Health, Daniel Horn, Ph. D., director. Staff director for this report was Albert C. Kolbye, Jr., M.D., M.P.H., LL.B. . . The professional staff has had the assistance and advice of a number of experts in the scientific and technical fields in and outside govern- ment. The staff gratefully acknowledges their contributions, often made at considerable sacrifice of time from their own professional duties. Although space does not permit a listing of all those who have participated in this project, the staff wishes to express appreciation for their cooperation and help. Special thanks are due the following: Aanrsarr, P~ms B., D.V.M., PH. D.-Ch1ef, Virology and Bickettatology Branch, Extramural Program, National Institute of Allergy and Infectioue Dtaasasm, National Institutes of Health, Bethesda, Md. . Auge, Bauce N., )1i.D.-Laboratory of Molecular Biology, National Institutes of Health. Bethesda, Md. . . . . . . . AasaD, WaarsM P., M.D.-Medical conaultant, Stroke Section, Heart Disease Control Progiam, National Center for Chronic Disease Control, U.S.P.H.S., Arlington, Va. Aorsasoa, Oacsa, M.D.-Senlor medical inrestigator, Veterans Administration Hospital, East Orange, N.J. , , . . A'•^=^^, Dsvm, M.D.-Medlcal consultant, Laboratory of Biology of Viruses, National Institutes of Health, Bethesda, Md. . A:ars, S~Haa M., M.D.-Director, Cardiopulmonary Laboratory, Saint V_in- cent'e Hospital and Medical Center of New York, New York, N.Y. .. . A~, Wa.r.rex B., M-D.-Medical officer, Heart Disease Control Program, :Qa- tional Center for Chronic Disease Control, U.S.P.H.S., Arlington, Va. Bstuttoca, Joax J., M.D.-Head, Department of Otolaryngology, Evanston Hos- pital, Evanston, ID. •. BLSSnore, Henaz, W., M.D.-Chief, National Inatitute of Neurological Diseases and Blindness, Perinatal Research Branch, National Institutes of Health, Bethesda, Md. B®u, Goaoos W.-$tatietician, Operational Studies Section, Cancer Control Pro- gram, National Center for Chronic Disease Control, U.S.P.H.B., Arlington, Va. Bast.rasa, Boacax, M.D.-Director, Office of Director of Research, National Heart Institute, National Institutea of Health, Bethesda, Md. . , Blao, BlcaeeD J., M.D.-Profeseo; and chairman, Department of Medicine, Wayne State University, Detroit, Micb. . . _.. Busa, Sruena• B., M.D.-Medlcal consultant, Heart Disease Control Program, National Center for Chronic Disease Control, U.S.P.H.S., Arlington, Va. . .. • ..;J.: -4 .... . . :....... -I: '~'.tL>fi . . Gy ®

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I s a E THE NATURE OF THIS REPORT . ... ......... .:...,'4St".-.-....,..,.- This report which provides a summary of current information on the health consequences of smoking, is based on the review of the research reports which have become available since the study of the Surgeon General's Advisory Committee was released. Public Health Service staff members consulted the literature and requested additional infor- mation or interpretations of the published data from the research scientists when needed. During this review a complete bibliography, containing some 5,700 citations, was compiled; it is now in manu- script form and will be published shortly (19). The advice and comments of experts within the Public Health Serv- ice, particularly the Bureau of Disease Prevention and Environmental Control and the National Institutes of Health, as well as of specialists outside the Public Health Service, were solicited especially on matters involving judgment and evaluation. , ... ,. . •., . . . The general criteria used by the Surgeon General's Committee have been followed. First, epidemiological data were evaluated to determine whether an association exists. In judging the significance of the as- sociation, its consistency, strength, specificity, temporll relationship, and coherence were utilized. The convergence of evidence from animal experiments, clinical and autopsy studies, and population studies re- mains the essential basis for evaluation of the significance of the associations identified. . . . . . This report presents, under the following headings, the major fmd- ings of research studies published in the past 3 to 4 years: 1. Smoking and Overall Mortality. 2. Smoking and Overall Morbidity. 3. Smoking and Cardiovascular Diseases. -. 4. Smoking and Chronic Bronchopulmonary Diseases (Non-neo- plastic). . 5. Smoking and Cancer. 6. Other Conditions and Research Areas. . Each of these sections is introduced by pertinent conclusions from the Surgeon General's 1964 Report, which are followed by discussion and conclusions of the preaent study. . . . ~..; sK , . . 4k » x

the time when there was also a substantial drop in cigarette smoking among physicians in general, and during the time that lung cancer There are no adequate data to evaluate the benefit of reductions in exposure that are more modest than those achieved by complete cessa- tion, although it seems reasonable to assume that a substantial reduc- tion in exposure is likely to be accompanied by some reduction in risk tion of risk compared to those who continue to smoke. tality for those who give up smoking as also reflecting a direct altera- case can now be made for interpreting reduced rates of overall mor- These findings are shown in Table 2, which has been derived from Doll's report (7). The lung cancer death rate among men in England and Wales increased from 1.49 per 1,000 in the period 1954-57 to 1.86 per 1,000 in the period 1962-64, a rise of 25 percent. At the same time, the lung cancer death rate for British physicians dropped from 1.09 per 1,000 in the first period to 0.76 per 1,000 in the second period, a reduction of 30 percent. This reduction in death rates from lung can- cer among all physicians is larger than would have been anticipated from examining only the experience of those physicians who had stopped smoking before the study began and indicates that the ex- perience of ex-smokers in prospective studies probably understates the benefits of giving up smoking. With these findings the case for cigarette smoking as the principal cause of lung cancer is overwhelming. The reduction of rates eaperi- enced in ea-smokers as compared with continuing smokers is clearly shown in the case of lung cancer to be a reflection of a significant change in risk. Since the concern that selective bias might have ac- counted for the earlier findings has been contraindicated, a stronger length of the cessation period increases. as the rate of smoking among British physicians decreases and the report by Doll (7) suggests that this trend is becoming more marked as against another population in which it is not common. A more recent the effect of giving up smoking is judged by the mortality results in an entire population in which the giving up of smoking is common rates were rising in the male population of Great Britain. This situa- tion is not unlike that of a controlled cessation experiment in which relative to those who do not reduce their exposure.

Ixe pl ts rs Smoking and OveraHl Mortality QviONCLIISIONSOFTHE SIIROl GENIIIhLiS. 1961 R$PORT CIGARETTE smoking is associated witk a 70-percent increase in the age-specific death rates of males, and to a lesser extent with in- creased death rates of females. The tot'al number of excess deaths causally related to cigarettee smoking in the U.S, population cannot be accurately estimated« In view of the continuing andmounting evi- dence from many sources, it is the judgment ofl the Committee that cigarette smoking contributes substantiallly to mortality from, certain speeifie diseases and to the overall death rate. In general, the greater the number of cigarettes smoked daily, the higher the dhath rate. For men. who smoke fewer than 10~cigarettes a day,. according to the seven prospective studies, the death rate from all causes is about 40 percent higher than for nonsmokers. For those who smoke from 10 to 19 cigarettes a day,, it is about 70 percenthigher than for nonsmokers; f'orr those whoo smoke 20 to39 a day, 90 percent higher; and for those who smoke 40.or more, it is 120 percent higher. Cigarette smokers who stopped smoking,before enrolling in the seven studies have adeath rate about 40 percent higher than non- smokers, as against 70 percent higher for current cigarette smokers. Men who began smoking before age 20 have a substantially higher death rate than those who began after age 25. Compared.with non- smokers, the mortality risk of cigarette smokers, after adjustments for differences in age, increases with duration of smoking (number of years), andl is higher in those who stopped after age 55 than for those who stopped at an earlier age.. In two studies which recorded the degree of inhalation, the mortality ratio for a.given amount of smoking was greater for inhalers than for noninhalers. . The ratio of death rates of smokers to that of nonsmokers is highest at the earlier ages. (40-50) represented in.these studies, and decPiness with increasingg age.. - Possible relationships of death rates to other forms. of tobacco: use were also investigated '•'. The death~ rates for men smoking less than 5 cigars a day are about the same as for nonsmokers. Fbr men smoking more than 5 cigars daily death rates are slightly higher. There is.some indication: that these kigher death rates. occur primarlly in menn who have been smoking more than 30 years and', who. inhalethe smoke to sorn e dhgnee. The death rates for pipe smokers are little. ifat all higher than for nonsmokers„even for men who smoke10 or more pipefuls a day and for men who have smoked pipes more than 30 years,, 271~394 0--67-2

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'es, of'; ?er er- ,nd he or .ion !ars ina, ble at it"' ish ent lie. ers had a comparatively lower rate,. which was still 36 percent above the rate for nonsmokers "' * Men smoking combinations of ciga- ret'tes plus cigars and/or pipe also had elevated death rates for overalll mortality,but these were not elevated to the same eatent as those of men smoking only cigarettes. "The death rates for overall mortality of pipe smokers and cigar smokers were not appreciably different from those of nonsmokers; "For cigarette: smokers as compared to nonsmokers, overall mor- tality ratios were elevated after 5 years of smoking at any t'ime in their life and remained elevated as.long as they continued to smoke cigarettes.. "Mal'e current cigarette smokers who imhalerl had a death rate for overall mortality 52 percent higher than that of those who did not inhale. "An urban/rural comparison was made between males of equivalent cigarette smoking habits and nonsmokers. It was found that the death rate for overall mortality of. urban. dwellers (persons with a history of 5 years or more.of city residence) was 12 percent higher than that for rural dwellers of comparable smoking habit$: "Respondents were classifiedl into occupational groups based on their history of occupation. No evidence was found in this study of clear-eut associations between cause of death and occupation. Further, occupation didl not appear to modify tlhe established asaociationn of cigarette smokers with death rates in excess of those of nonsmokers." SOME GENERAL CONSIDERATIONS Iky The problem of how best to measure the relationship between smok- ing and mortality has been discussed in the Surgeoni GeneraI's 1964 Report as well as iir some of the prospective stludy reports. As the amount of data. available. increases, the person-years of observations in the many population subgroups that are worthi examining increases so.that stable rates may be computed and compared. A brief discussion of three measures of comparison available and their utility seems desirable as confusion frequently arises over these measurea 1. Mortality Ratios: Obtained by dividing the death rate for a classification of smokers. by the death rate of a comparable group of nonsmokers. 2.. Differencesin. Mortality Rates.: Obtainerl by subtracting from the death rate for smokers, the death rate of' a eomparable group of nonsmokers. 3: Excess Deaths: Obtained by subtraeting, from the number of deaths occurring,in agroup of smokers„ the number of deaths 11

t6 3. Exceea Deatha aa a Percentage of Totad Deatha-As with mor- tality ratios, this statistic appears to be highest in the age group 45-54 where it reaches 43 percent in one group of men and 38 percent in the other. Hammond's data by 5-year age groups show the highest rate at ages 45-49, where it is 44 percent. Reviewing both study groups it appears that for men between the ages of 35 and 60 approximately one-third of all deaths that occur are excess deaths in the sense that they would not have occurred as early as they did if cigarette smokers had the same death rates as the nonsmoking group. For women, the percentage is much lower, reaching a peak of 9 percent of all deaths in age group 45-54. It should be noted that this measure not only de- pends on the differences in death rates between the smokers and the nonsmokers, but also on the proportion of smokers in the group. Thus, even with a large difference in rates between smokers and nonsmokers, a population with very few smokers would have very few excess deaths. This measure is therefore an indicator of the public health sigruficmrce of the differences found since it measures the number of people affected and therefore the magnitude of the problem for society as a whola Once the magnitude of the excess is identified the problem becomes one of determining (1) how much of the eacess would not have oc- curred if it had not been for cigarette smoking and (2) how much would have occurred anyhow. It should be noted that much of the ex- cess has already been identified as belonging in the first category. Of the remainder, little of the excess has been clearly identified as belong- ing in the second category-that is, not caused by smoking. With most of that remainder there is uncertainty as to the category in which it. belongs. MEasunes oF Earosoxs Studies involving smoking, whether epidemiological or behavioral, have been concerned with measures of exposure to tobacco smoke. For the most part, these studies have been restricted principally to the in- dex of number of cigarettes smoked over a specified period of time, usually an "average day." The heavy reliance on numbers of cigarettes alone as a measure has produced important findings but it has possi- bly obscured others. The new reports on the prospective studies have provided a substantial amount of data to support the concept that many elements should enter into an overall measure of exposure. Such factors as age at beginning smoking, duration of smoking, and inhala-. tion have all shown some independent contributions to the overall effect, along with numbers of cigarettes. A recent report (12) has at- tempted to develop a more adequate measure of exposure in which various individual components of dosage would be combined to form composite scores. .~, ._ 14 u.+-.Fr._:. u... . ... . . _ a a..n_.Gr..- ~ _-.L < I

CHAPTER 1 Smoking and Cardiovascular Diseases CONTENTS Page timoking and Coronary Heart Disease....................... 47 Coronary Heart Disease Mortalit'y .................... 47 Coronary Heart IDiseasel4forllidity ..................... 53 Manifestations of'Coronary Heart Disease .............. 58' Cardiovascular Response to Smoking and/or I+Iicotfiete.... 60 Coronary Blood Flow inrn Normal Subjects .......... 60 Coronary B1ood Flov in Subjects With Cbronary Heart. Disease ................................. ... ........... 6'.I. Carbon.-Monoxidie Effectl ......................... 62' Studies on In Vitro Thrombus Formation ..... ..... 64 Autopsy Studies ................................................ 6'.5~ Smoking andl Cerebrovascular Disease..................... . 66' Smoking andl Aortic Aneurysm ............................ 69' Cited References ........................................ 6'.9. Supplemental References................................. ............ 76'~ 45

T Smoking and Overall Morbidity r THE TrmE of the Surgeon General's 1964 Report there was no A information availiable on the overall' disability associated with smoking. To incestigate the. relationship between smoking and' mor- bidity, the National Center for Health Statistics of the Public Heal!Gh Service introduced questions about cigarette smoking into iits National HeaIth. Survey,., beginning in. July 1964. This. Surveyis a continuing study conducted'since195Z. Inn carrying on th is.Su.rvey,interviewers eaahh year vi'sit 42,006W fami- lies (selected as a, probability sample of the civilian, noninstitiutional population of the United Stat'es)) and'question them about illness, dis- ability, and days absent from work because of illness„as well as the nature of tfiee illness.. In the year ending in JYme.1965, they inquired (after all other questions about headtlh had been asked) about the smok- ing habits of'persons in the family who were 17 years of age or over. The National Health Survey is concerned with three overall meas- uresof the impact of illness. 1. Days Lost From Work.-These are days absent from job or busi'- neasbecause of illness or injiury. They apply onlly to those persons who are currently employed and are therefore heavily concentrated in agegroups I7-64.. 2. Bed Dnys.-These are days when the person is sufficiently ill or disabled so as t'o spend all or most of' the day in bed,, either at home or ini a hospital. All days spent as a hospital patient are included. 3.. Days of Restvicted Activzty.-These are days when.a person cuts down, his usual activities for most of a day because of an illness or an injury. Dayslost from work because of'illnessand bed days are, of eourse, counted as days of restricted activity. This represents the most general measure of di'sabillty available in the United States today:, Table 3 summarizes the findings in a form similar to that used for summarizing, the overall mortality utilizing t.hreemeasures of. mor- bidity effect: Morbidity ratios,,difPerences in rates,,and'eaeess days of d'isability. f

Os by 11 HIGiHLIGITTS OF CURR.ENT INFORMATION dfiffer- iJ3ficmlt tudies 3ition, ang is J Even §ymp- itug is hough ratory !h one e have alities dem• 'ieredk bron, dl air ang is' IflrIDs's lchiall dYuced iveo- ~rtant fmnary thiis rm or ;e evi- IItal) intant ~ put NPhy- 1. Nlew data.confirm and to some extent strengthen the conclu- sions of the Surgeon General's 1964 Report. 2. Cigarette smoking is the most important of'the causes of chronic' non-neoplastic bronchopulimonary diseases in the United States. It greatly increases the risk of dying not only from both chronic bron. clutisbut also firom pulmonary emphysema.. 3. Cessation of smoking is followed by a reduction in mortality from chronic bronchopulmonary disease relative to the mortality of those who continue to smoke. 4. Even relatively young cigarette smokers frequently have demon- strable respiratory sy~mptoms and reduction in~ ventilat;ory function.

4. Cessation or appreciable reduction of cigarette smoking could delay or avert a substantial portion of deaths which occur from lung cancer, a substantial portion of the earlier deaths and excess disability from chronic bronchopulmonary diseases, and a portion of the earlier deaths and excess disability of osrdiovas- + cularorigin. f: A51~'f.i:'Y't,}'-4 . NATURE OF RECENT RESEARCH FINDINGS ` ~ Since the Surgeon General's Report was published in January 1964, there has been a proliferation of additional studies and reports on smoking research. In the 12 years'preceding that report, some 3,000 articles were published reporting research; since 1964, there have been ry.t more than 2,000 additional studies. az These studies have helped to clarify the role that age plays in the rt; relationship of smoking to health; the similarities and differences in the ways in which men and women are affected by smoking; and the influences and effects of stopping smoking, particularly in the case of lung cancer where there is significant data to show that sharp reduc- tions in lung cancer deaths follow closely reductions in cigarette smoking. The studies also suggest the importance of a variety of measures of exposure; add substantial new information on the magni- tude of the morbidity problem associated with smoking; and provide more adequate data upon which to base estimates of the magnitude of the mortality problem. Historically, concern about the effects of smoking began with ob- servations of the extremely high frequency with which lung cancer patients were identified as cigarette smokeia Thesa observations took i on a fuller meaning with the first publication of the prospective studies "i' in 1954 when higher overall death rates among cigarette smokers were identified. The rates were found to exceed the difference that could be accounted for by lung cancer alone. Until that time, the possibility remained that although more cigarette smokers appeared to suffer from lung cancer, if there were no significant excess overall mortality, some other cause or causes of mortality would have had to be underrepresented among cigarette smokers. The Surgeon General's 1964 Report concluded that cigarette smokers do have higher death rates than their nonsmoking counterparts. This has changed the emphasis of the present problem away from the ques- tion tion "does cigarette smoking cause diseasel" to the more precise questionsof: . . .- ...< .. : •.:. . ~. _..:..: , ~: 1. How much mortality and excess disability are associated with smoking4 } e 0 _j ;4+,»'iA ~n!r:eel r'_@;',l96 a.

nd d- tb the risk associated with smoking:The Surgeon General's 1964! Report had considered the possibility that differences between respondents and nonrespondents to the questionnaire might have introduced a bias and had attempted to callculate a maximum estimate of that bias. .S'r[7DY OF MENI AND, . VSTOMEN IN' 25 STATE$ (Thisreport isbased on 3,764,571 person-years of:ezperienee and 4.3,221 deaths occurring among. 1,003,229 ®ubjects--140,56'8W men and M,871 women-between the ages of 355 and 84 from October 1, 1659; to Feb ruary15;..1980;. when they enrolled in a prospective stndyy and answered detailedd questionnaiirea inciuding.g questionson thePrsmoking•habP.ts.. Hammond. (11:)1.) .. . . . . . . "Death rates of both men and women were.higher among subjects with a history of cigarette. smoking, than among those who never smoked regularly. "Death rates of current cigarette smokers increased with number of cigarettes smoked per day and degree of inhalation. "Death rates were higher among current cigarette smokers starting the habit at a youngxge than among, those starting the habit later in life. Among both men andl women, the difference between the death rates of' cigarette smokers and nonsmokers increased with age.. "Among men,. the death rates for ex-cigarette smokers were lower than for men currently smoking cigarettes wlienn they enrolled in the study. Death rat'es:s of ea.cigarette smokers dacreasedl with the length of! time. since they last smoked cigarettes; "* ** Total death rates and death rates from most of the common diseases, occurring, in both sexes were higher in men than women, were higher in men. who never smoked regularly than in women who never smoked regularly, and were far higher in men with a histury of'cigarette smoking than in women with ahistory of regular cigarette smoking. "The difference between the dieath rates of subject's with a history of cigarette smoking and subjects who never smoked regularly was far greater among men than women. Female cigarette smokers (as a group) have been far less exposed to cigarette smoke than male cigarette smokers of the sanye ages, as judged by number of cigarettes smoked per day, degree of inhalation, and the number of' years they have smoked. Many female cigarette smokers smoke only a few cigarettes a. day; do. not inhale, and have been smoking for only afew years; theic death rates are about the same as the death~ rates of' women who. never smoked regularlp." ng Se 11e STUDYOF' BffiTisn pHyaIOIIAN® (The mortality off nearly 41~,O0& men and women inn the medical profes- sion in the United %inglom has.iheens followedlfor 12yeara. During,the.

Ssaea, MUaaerJ., Ph. D.-Speclal advisor, Office of ttie. Director; National CancerInstitute,. National'Institutes of Health, Bethesda~ Md. SmaL,. JAncrs S.,M:D:-Ctifef,.Field Staff, Coordination and Development Section, Heart Disease Control Program~ National Center for Chronic. Disease Control, U.S.P.H.SI, Arlington, Va. . .. . SratNSS, Wus:xnM, M.D:-Medcall officer, Heart.Disease Control Program, Na- tlonal Center.forOhroniceDisease Control, U.S.P-H.S:,,Arlingtun„Va: STamvo, Jdaa„ M.D.-Chairman of Department of Pathology, Louisiana. State. University, School of Medicine, New Orl'eans, La: THOes, TnoxeS J.-Statlstlcian,. Heart DilseaseConhrol'. Progrem, National Center for Chronic IDisease.Control„ U.S.p:H.SL, Arlington, Va:. `-- - UNOeawoon„ PevL„ M.D;-dssistant professor of. obstetrics and gynecology, University of South CarolinaMedicsl. School,. Department of Obstetrless and Gynecology, CharIeston,. S.C. . - --Wasxuse, Eownc6 M:r).-Chlef; Applied Physiology Laiboratory;. Heart Disease Controll Program; National~ Center for Chronic Disease Control, U.S.P:H.S.,.. Arlmngton;, Va.. - . IWain,, EuJAS L.-ACting Director, Division of Health InterniewStatisti<s, National Center for Health Siatistics, U.9.P:H.&, Washington, D.C. Wbocssr, Tntnaoae D. Deputydirector„ Office oftheCenterDlrector,. Nattonai. Center for. Health Statisties,U:S.P.H.S., Washington, DX. WYnnae, EanESx L.,.M.D. Assoolate memher, Sloan-H:ehtering,InstituteforTech. nology, New York;. N:Y:. . YAaecocrNSSY, Mrcawa, M.D'.-R.eseareh ehemist, La6oratory of. Molecular Biology, National. Institutes of Healtti„ Betheadg, Md. - 2o~r, WrccrAMJ., BtLD.-ASsoeiate Direetorfor Collaborative Studles,. National HeartInstitute, ,NationalInstitutes.ofHealth,.Bethesda,Md., .. The following professional staff'of the National Clearinghouse for Snuoking and Heallth contributed to the~preparation of this report: Robert F: Clarke, Ph. D:, Emill Corwiny Robert S. Hutahings, Selwyn. WaingFow, and! David Q"i.. Wenuber,, M,D. s, lf ,t< :f d

I more in the presence of other known "risk fa.ctors" for coronary heart disease. Eemale cigarette smokers also have higher coronary heart disease death rates.than do.nonsmokiing femaTes,,slthough not as high as that for males. In general, the death rates from this disease increase with amounts smokedt, Cessation of cigarette smoking is foll'owed'.by a, reduction in the. risk of dying from coronary heart disease when compared with the risk incurred by those who continue to smoke. ' 3, A greater frequency of advanced coronary arteriosclerosis is noted in male cigarette smokers„especially in those who smoke heavily. 4'. AdditionaI evidence strengthens the association between cigarette smokimg and cerebrovascular disease, and suggests that someof the pathogenetic considerations pertinent to coronary heart disease may also apply to cerebrovaascuIar disease.

(iONCLII6IONS OF THE .5't7ROEON', (I`ENERAL'81964 REPORT Gun.gCarcer 1.. Cigarette smoking is causally related to lung cancer in men; the magnitude ef'the.effech of cigarette smoking far outweighs all other factors. The data for women, though less eatensive; point in the same, direction. 2: The. risk of developing lung cancer increases with duration of' smoking andl the number of cigarettes smoked per day, and is dimin- ished by discontinunng smoking. 3. The risk of'developing cancer of the lung for tlhe combined groupp of pipe smok.ers,, cigar smokers„ and! pipe and cigar smokers is greater Ghan for nonsmokers,, but much less than for cigarette smokers. The data are insufficient to. warrant a conclusion for each gFoula individually. Oral Cancer 1. The causal relationship of the.smoking of pipes to the develop. inent of cancer of the Iip appears to be established. 2'.. Althouplr there are suggestions of relationships between cancer of other specific sites of the oral cavity and the several forms of tobacco use;.their causal impliications cannot at present be stated. Laryngeal Cancer Evaluation of the evidence leads to the judgment that cigarette smoking is a significant factor in the causation of laryngeal cancer in the male. Eeophageal Cancer The evidence on the tobacco-esophageal cancer reiationship support's the belief that an association exists. However, the data are not ade- quate to decide whether the,relationship is causal. Cancer of Urirurry Bladder Available datia~ suggest an association between cigarette smoking and urinary bladder cancer in the male butl are notsufficient to sup- port judgment on the causall significance of. this association. Stmnack Cancer IITb reTationship has been established between tobacco use and Stomach cancer..

he Ils high jcrease Iqed,hy I i when ioke: osis is leavily. garette ; of the , ;e may Smoking and Chronic Bronchopulmonary Diseases (Non-Pleoplastic) CiONCLII8ION8 OF THE .SIIROEON C'sEMERAr:'s 1964 . REPORT 1. Cigarette smoking is the~most important of the causes of chronic bronchitis m.the Unitedl States, and imcreases,the risk of dying, from chroniobronchitis. 2. A relationship eaists, between pulmonary emphysema and. cig- arette smoking but it has, not been established that.the relationship is causal. The smoking of cigarettes is associated with an increasedd risk of dying from pulmanary emphysema., 3.. For the bulk of' the population of the United States, the impor- tance of eigarette.smoking as a cause of chronic bronchopulmonary disease, is much greater thani that of atmospheric pollution or occupa- tional eaposures:. 4.. Cough;,sputham prodYnction, or the two combined are consistently more frequent among , cigarette smokers than among nonsmokers. 5.Cigarette smoking is associated with a reduction in ventilatory funetion- Among, males,cigarette smokers. have agreater prevalence of breathlessness than nonsmokers., 6.Cigarette smoking does not appear to cause asthma. 7. Although deatli, certification shows that cigarette smokers have a moderately increased risk of death fromm influenaa and pneumonia, an assoeiation.of cigarette smokingand infectious diseases is.notother- wise substantiated. CURRENT INFORMATIiON, 1967 Additional evidence from the four major prospective studies indi- cates that cigarette smokers liave a markedly increased risk of' dying from chronic bronchitis. and pulmonary emphysema. The range of risk varies for cigarette smokers between three and 20 timesthe mor- tality rates for nonsmokers, and depends in part on the total amount smoked and the age, group studied. Female cigarette smokers have similarly.increased mortality risks although. somewhat lower than those for males. Cassation of cigarette smoking is followed by a lower mortality risk relative to:o those:whocontinueto smoke. Generallyi,pipe 29 _(, C. af

which would have occurred ifthat group of'smokers had ex- perienced the same mortality rates as a comparable group of' nonsmokers. In the examplc which~ follows this has been reported as a percentage of'all deaths in the appropriate age group Table 1 presents, in summary form all', three measures for five age groups of. mem from both~ the U.S. veterans study and Hammond's study andi for the same age groups of' women from the latter study. The, statistics were derived from, the cited' publications to provide reasonable comparability and may vary slightly from the figures combined in ot'her ways; Also it should be noted that the age: groups are not definedlidentical9y and the experience reported covers some- what different time periods. The smoking group analyzed is "cur- rent cigarette smokers," i.e., those who, were smoking at the time of' enrollhnent into the:st.ud'y, and the comparison group. is "never smoked regalktxly,"' i.e., those who hadl never been regular smokers of any form of tobacco. The number of'deaths im each age-sex group is given to indicate the relative stability of the figures, in that column. Thedata in the veterans study are largely concentrated in age groups 55-64 and6Cr74. In Hammond's study, age group 35-44 is less stable than the succeeding groups both~ for men andl for womem , 1. DY'orGality ILatios:-For men, these are at their highest in age group 45-54,,d'iminishing in eaoh subsequent decade. In both studies mortality ratios appear to be somewhat lower in the preceding decade 3544. However, with the smaller numbers of cases available in that age group, it may be that selectiive factors contribute to, the finding. For women the mortality ratios are mueh smaller than for men, although the same pattern is suggested. In general, a mortality ratio has been considered tb refllectt the degree to which. a clkssifica- tion variable identifies or may account for variations in death rates.. As such, it is a measure of relative risk whicll, indicates the importance of that variable relative to uncontrolled variables-an indicator of potential tiiological'aiynifioau:ce. 2.. Differences in NorttrdityRates.-These increase consistently with increasing age in all three study groups, except for the oldest age group in women where there is paactically no d'ifference in the rates for smokers and nonsmokers. Differences between smokers' rat;es and nonsmokers' rates are much, smaller for women than for men, as are the d'eath rates themselves for men and women classified simi- larly with respect to smoking. This measure reflects the added proba- bility of d'eathh in a 1-year period for the smoker over that for the non- smoker. As su& it is a measure of persarucD heaL2h aiyni'rioaa ce, a means for the individual to estimate the addedd risk to which he is exposed. Deat ~ t Mort DiHe tol Exee tot Deat ~ Mor1 Dige 10' Esce to Dea~ I G7 12 ~II v ~

r a I n 100 'be in 'he "of lc- tte of 1i- .'rle 6e 2. How much of this early mortality and excess disability would not have occurred if people had not taken up cigarette smoking4 3. How much of this early mortality and excess disability could be averted by the cessation or reduction of cigarette smoking4 _ ::! . . . „ 4. What are the biomechanisms whereby these effects take place and what are the critical factors in these mechanisms4 To answer these questions one must not only study the details of the relationship of overall mortality with cigarette smoking, one must also turn to the specific causes of death and disability and to other kinds of evidence. ..,: : , The research carried on since 1964 is of three principal varieties: Epidemiological studies, especially those which involve surveys of large portions of the population; a health survey which has revealed new information about the relation between smoking and illness; and a vast amount of experimental, clinical, pathological, and behavioral research which adds to the understanding of the precise ways in which smoking affects the body, plus other closely related or peripheral information. In the area of morbidity or illness, the primary addition to our knowledge is from "Cigarette Smoking and Health Characteristics," a report (16) of the National Center for Health Statistics on the frequency of illness among smokers and nonsmokers in a large proba- bility sample of the U.S. population. Regarding epidemiological data, new reports from four of the major population studies have been published since 1964: 1. The Dorn study of smoking and mortality among U.S. vet- erans (13). 2. Hammond's study on smoking in relation to the death rates of 1 million men and women in 25 States (11). 3. The Doll and Hill study on the mortality of British physi- cians in relation to smoking (8, 9,10) . . 4. A Canadian Smoking and Health Study of Canadian pen- sioners, including veterans and dependents (1). The principal features of the additional data provided by these four studies are: (1) The extension of the time period of followup, (2) the additional data available for specific age groups among men, and (3) the inclusion of substantial data on women. In all, the pro- spective study reports now available are based on more than 108,000 deaths, an increase of about 43,000 deaths over the 65,023 summarized in the 1964 report. About 19,000 of these additional deaths were among women.

Introduction a.: In January 1964, an Advisory Committee appointed by the Surgeon General of the Public Health Service issued its report (15) on the relationship between smoking and health.* The conclusions of that Committee were summed up in the sentence: "Cigarette smoking is a health hazard of sufficient importance in the United States to warrant appropriate remedial actio¢" , In the 31h years since the publication of that report, an unprece- dented amount of pertinent research has been completed, continued, or initiated in this country and abroad under the sponsorship of governments, universities, industry groups, and other entities. This research has been reviewed and no evidence has been revealed which brings into question the conclusions of the 1964 report. On the con- trary, the research studies published since 1964 have strengthened those conclusions and have extended in some important respects our knowledge of the health consequences of smoking. _ The present state of knowledge of these health consequences can, in the judgment -of the Public Health Service, be summarized as follows: . . 1. Cigarette smokers have substantially higher rates of death a¢d disability than their nonsmoking counterpaats in the popu- lation. This means that cigarette smokers tend to die at earlier ages and experience more days of disability than comparable nonsmokers. ; 2. A substantial portion of earlier deaths and excess disability would not have occurred if those affected had never amoked. . 3. If it were not for cigarette smoking, practically none of the earlier deaths from lung cancer would have occurred; nor a sub- stantial portion of the earlier deaths from chronic bronchopul- monary diseases (commonly diagnosed as chronic bronchitis or pulmonary emphysema or both) ; nor a portion of the earlier deaths of cardiovascular origin. Excess disability from chronic pulmonary and cardiovascular diseases would also be less. *"Smoking and Health. Report of the Advisory Committee to the Surgeon General of the Public Health 9ervice." It te Creqnently referred to In this menu- ecriPt as "the Surgeon General's 1964 Report." . ® ® .4 0 n a ME

on one or another aspect of the problem of smoking and varied health consequences'have been undertaken. P$rrTc Un:cEx The relationship between cigarette smoking, and death. rates from peptic ulcer, especially gastric ulcer, is confiiTned. In addition, mor- bidity data suggest a similar relationship, exists with the prevalence of reported' disease from this cause., TOn.1CCG ADYRGYOFI.ti. Tobacco amblyopia is now believed to, be a manifestation of nutri- tional amblyopiay which is aggravated by the inhalation of tobacco smoke.Various vitamin B, factor deficiencies may be involved and there is evidence to suggestthat chronic Iow vitamin B,z levels may potentiate the toaic effects of cyanide in tobacco smoke. t~itRRffiOSIS OF THE. LIVER Ihlcreased mortality of smokers from cirrhosis of the liver is found in the, prospective studies.. This has generally been thought to be largely secondary to an association between smoking and heavy con- sumption of alcohol. Published data are inadequate to test this interpretation.. MATr.RNAL. .SbTOBINO AND INFANT BIRTH'. WEIGHT Further studies have confirmed the fact that . women who smoke during pregnancy tendto have babies of lower birth weight, but data.arelacking to determine either the mechanism or the significance of this' finding. P8YCIIOSOCIAE, ABPECTS'. Therehas been a sharp increase.in the attention devoted to be- havioral' research since the. Surgeon General"s. Report.. A number of new concepts ha've been develbped: andlmore sophisticated multivariate approaches are being used. However, because of the recency of these stu'dl'ies, very little inthe way of'find'ings has beempubli'shed onwhich firm conclusions may be based. r

4 0 ® Boaey, HoLtra M.D.-Cllnical investlgator, Veterans Administration Hoapttal, Denver, Colo. . CAaaor, Braasxtx E.-Biometric Branch, National Cancer Inatitute, National Instltutes of Health, Bethesida, Md. - i CHAnwres, DoaAin R., M.D.-JDlrector, National Center for Chronic Disease Control, U.S.P.H.S., Arlington, Va. ~ ~ De LA roamra, Josara L.--Chlet, statistical methods, Cancer Control Program, National Center for Chronic Disease Control, U.S.P.H.S., Arlington, Va. •. A DtTara, DAx¢y M.D.-Aesistant profeseor of medicine, Harvard Medical School, Bostton,Maee. -:u•. ARo ^:R[!:: ?-, r,b.:_aKK;.sr1; Doeas, Oaoaoy M.D.-Asaociate chief, Division of Scientt8c Opinioae, Trade Commtasion, Washing4on, D.C. .._y :..- . c.t. .. . _,~y, '. Y~ Dortr, Joe~a, M.D.-Director, Cardiovascular Health Center, Aibany Medlr al College, Union University, Albany, N.Y. EASTMAN, Nmouse J., M.D.-Professor emeritus of obsttetrics, Johne Hopkins ' Hospital,Woman'aClinic,Baltimore,Md. ! i-sF -~. ,. . . - .. - ~Eii Eeareu, Fnaarame H., M,D. Profeesor, University of Michigan School of Public Health, Department of Epidemiology, Ann Arbor, Mich. .. . .Ii Esttea, S. PAar, Jr., M.D-Deputy chief, Heart Dleease Control Program, Na- tional Center for Chronic Disease Control, U.S.P.H.S., Arlington, Va. "Evwxs, Roaisr, Ph. D.-Department of Sociology, University of Wiaconaln, Madtson,Wis. ,..: . . . , .. ;c!i1 FAis, HANS L., Ph. D.-Assaciate scientific director for carMnogenesis, National Cancer Institute, National Institutes of Health, Bethesida, Md. . .~~i Faaus, Bc.rrAa:x 0., Jr., M.D.-Professor, Department of Phystology, Hareard ~ School of Public Health, Harvard University, Boston, Mass. Hbz, Baanasn H., Ph. D.-Acting Chief, Experimental Reeeamh Braneb, IWary-Control Program, National Center for Urban and Industrial Health, U.$.P.H.S, Arlington, Va. . . . ... . - , " .,.. i :rI Foz, $AMaac M., III., MD.--Chief, Heart Disease Control Program, National Center for Chronic Disease Control, U.S.P.H.S,, Arlington, Va. Orrrr.raoan, Acux, Ph. D.-Profeesor, Johns Hopkins Sehool of Public Health and Hyglene, Johns Hopkins University, Baltimore, Md. Om.n, Ro.rAi.s J.-Statiatlcian, Operational Studies Section, Cancer Control Pro- gram, National Center for Chronic Disease Control, U.B.P.H.S., Arlington, Va. HAENezar, WntuY M.--Chlef, Biometry Branch, National Cancer ~nst[tute, NatlonalInstitntesofHealth,Betheada,Md. , I .~`~~HAi.rass, MAX, Ph. D.-ASalstant chief, Biometrics Research Branch, NsUonat Institutes of Health, Bethesda. Md. .. . . . .., . . ... _ ~".,.p HAMMOND, E. Cvri.ES, Sc. D.-Vice .^V . preaident, epldemlology and statistical re- ; search, American Cancer Society, New York, N.Y. HASa:ecc, Wu.rsAY L., Ph. D.-Physical activity consultant, Heart Disease Con- trol Program, National Center for Chronic Disease Contrul, U.S.P.H.S., Arlin6. ton, Va. . . . g HAYra, Rrcnsan, D.D.S.-Aaslstant to the chief, cancer detectlon,. Cancer Control~ Program, National Center for Chronic Disease Control, US.P.H.S., Arlin~: ton, Va. . ". . -. . HsixaecxwN, Faeu, Ph. D.-Research psychologist, Heart Dfeesse Control Pro- gram, National Center for Chronic Dtaease Control, U.S.P.H.Q., Arlington, Va., Haea, CArnearnE B., M.D.-Asslstant to the chief, Cancer Control Program, Na- tional Center for Chronic Disease Control, U.S.P,H.S., Arlington, Va. "`'`• Hrooins, I. I. T., M.D.-Professor, University of Michigan School of Public Health, Department of Epidemiology, Ann Arbor, Mich. ' Y J ® 4

HorrYAan, Dnnama, M.D.-Aeaoclate member, environmental carcinogeneda, Instltute of Neurological Diseases and Blindness, National Institutes of Health, Scawsan, J. Taeonose, M.D.-Section head, Epidemiology Branch, National sota, School of Public Health, Minneapolis, Minn. SCHUt[An, Laonsao M., M.D.-Profeeaor of epidemiology, University of Minne- Chronic Disease Control, U.S.P.H.S., Arlington, Va. Ross, Wn.t.feu L., M.D.-Chief, Cancer Control Program, National Center for Arlington, Va. Control Program, National Center for Chronic Disease Control, U.S.P.H.S., Rosrns, Mosrox-Chlef, program evaluation and project design, Heart Disease rado Medical Center, Denver, Colo. Parrr, T'aoYAe I.., M.D.-Assistant professor of medicine, University of Colo- Hospital Andrews, MSHCB, Andrews Air Force Base, Washington, D.C. Penrseos, Ww.reY F., M.D.--Chief, Obstetrics and Gynecology 9ervice, USAF Center, medicine and blostatistics, Denver, Colo. MURPHY, EDMOND A., M.D.-Aesociate professor, University of Colorado Medical Program, U.S.P.H.S., Arlington, Va. Morrnr, P4saa. W., M.D.-Deputy chlef, Chronic Respiratory Dlsease Control National Institutes of Health, Bethesda, Md. Mosaisoa, BAYwaD H., Ph. D.-0IDce of the Director, National Cancer Institate, versity, School of Medicine, Atlanta, Ga. . MoLesa, Roee, M.D.-Profeseor of medicine (pulmonary disease), Emory Unl- Urban and Industrial Health, U.S.P.H.S., Arlington, Va. MeacsnD, Rroaum E., Ph. D.-Injary Control Program, National Center for of 1FSas, Dallas, T'es. Lovnoa, R. G., M.D.-Professor, Department of Internal Medicine, University National Heart Institute, National Institutes of Health, Bethesda, Md. . Lonecl., Hasr.ar, M.D.-Office of associate director for collaborative studies„ Public Health, Baltimore, Md. Lv.mxrerD, AaasaAY, M.D.-Professor, Johns Hopkins School of Hygiene and Chancellor, University of Texas, Austin, Tex. Lsmersras, CHAaurs A., M.D,-Vice chancellor of health affairs, Office of the Food and Drug Administration, Washington, D.C. Laosros, Msav[x S., M.D.--Chief, Cell Biology Branch, Division of Nutrition, Center for Air Pollntion Control, Washington, D.C. LANDAU, EMANUrr, Pb. D.-$tatistical advisor, Office of the Director, National National Institutes of Health, Bethesda, Md. Hrvmse, DesN E.-Statietician, Biometrlcs Section, National Heart Institute, Research Triangle Park, N.C. - - Horia, Psln, M.D.-Director, National Environmental Health Sciences Center, %oraza, SUeurltAH M.-Scientist, Chevy Chase, Md. ~,_ . National Center for Chronic Disease Control, U.S.P.H.S., Arlington, Va. Rcaar; Heans, M.D: Mediml corisoltant, Heart Disease Control Program, Harvard Medical School, Boston, Mase. .. ~ ,,. . . . . . ~ KANNEL, WII.LLM B., M.D.-Aseociate medical direetor, National Heart Institute, Arlington, Va. . . .. .. . - . . . . , .. . . . , . Isassnr, Atsrar P.-Chief, Epidemiology and Surveillance Branch, Injury . Control Program, National Center for Urban and Industrial Health, U.S.P.H.B., National Center for Chronic Disease Control, U.S.P.H.B., Arlington, Va. IYaoDER, C. A., Jr., M.D,-Chief, Chronic Respiratory Disease Control Program, Sloan-Kettering Institute for Cancer Research, New York, N.Y. Bethesda, Md.

r- 5 t in Ilest ups. , ely hat ers (the hs de- the I~us, ~:ers,cess -[Ltk r of iety, mes oc- uch ex- of' ~'lg- ost it +Or n A dosage score was developed as a function of the average number of cigarettes smoked per day, the "5tar" (smoke solids minus moisture) rating of the brand of cigarette smokedy,and the portion of the ciga- rette actualdy smoked..In ad'dition, qµestions, on both depth and fre- quency of inhalation were developed. Nbrmative data have been ob- tained from a national survey sample of'smokeis: In general, althoughh the various measures refleeting, exposure are interrelated, there aremany individualswith high exposure on one measure but, low ex- posure on another. Furthermore~ there are systemati¢ dflfferences in some of these measures of dosage between men and women, between heavy and light smokers (by the usual criterion of numbers. of ciga- rettes), etc. The existence of a dose-response.relat'ionship hetween ex- posuree to cigarette smoke and the risks most clearly associated with cigarette smoking is now generally accepted. 1i~'ynder:and Idoffmann (20) have shown in.laboratoryexperiments with animals that the tum.origenicity of cigarette smokecan be reduced.by alteration in t'he cigaretts.whi!ch reduces the "tar" and nico- tine content. They use the term "indicator" for "tar" and nicotine con- tent (the two measures tend to be used jointly since when one is high the other tends to be high, unless the nicotine has been removed in processing)., or other measures which, reflect t,his 'typeof relationship, lacking the identification of specific agents which~ are responsible for the effect. Bock,. Moore, and. Clark (2) have independently shown, a similar variation in carcinogenic activity of tobacco "tar" obtained from different typess of cigarettes.. The preponderance of scientific evidence strongly suggests that the "tar" and nicotine content of cigarette smoke is a meaningful factor in the measurement. of. dosage. (r'ESeA1II0N OF, 5'MOHINU The cessation of smoking is, of course, an extreme examplo of the reduction of' dosaget. Data from the prospective studies show a reduc- tion ini bot1t overall mortality and! mortality from specific diseases among those who have stopped' smoking when compared with those persons wlio continue to, smoke. This finding has been somewhat ob- scuredi by the fact that, ill health is a fnequent cause of' giving up smoking, so that death rates and disability rates for ex-smokers as a group tend to be high for aminitial period of time following cessation. Ifm this connection, the Study of British Physicians shows that among the totaL grovp, of' physicians in the study (smokers, ex- smokers, and those who never smokedy, combined) there was a rEdtrc- tion in the standardized lung cancer death rate from; 0.69 per1,p00 in the first 5!years of'the stud'y (1951-56)~ to 0.64 per 1,000 in the sec- ond 5 years.of'tlhe stud'y (1956-&1). This reduction occurred during

pfically 2: Cessation of cigarette sm:oking.sharply reduces the risk of'dying, spo fromlungcancerrelativetotheriskofthosewha~continue. ~r than 3. Although additional experimental studies substantiate previous Paliti experimental' data, additional research is needed to:specify the tuxnor- ges o initiating and tumor-promoting agents in tbbacco smoke and to elu- s w` cidate the basic mechanisms of the pathogenesis of lung cancer. ILARYNGEAr1 CANCER . rtality Ll'-Hill ationi- r pro- 1 scale orm; ion of y this iokers judg- ~Okers ort hip I Tlieiconclusion of the Surgeon General's.1964 Report that cigarette smoking, is a significant factor in the causation of laryngeal. cancer in. tlie male is supported by additional epidemiological evidence. 'QTHER CANCERB. Additional evidence supports the conclusions of the Surgeon. Gen. crnl's 1964 Report and indicates a~ strong association between various forms ofl smoking and cancers of the buccal.cavity, pharynx,and esophagus. In the absence of further information concerning the in- terac.tibn of smoking with other factors known or suspectedl as causa- tiree agents, further conclusions cannot'.be made at this tiime, although acausative relat.ionship seems likely., :ldklfitionali epidemitalogicad, clinical, and . experimental data strengthen the association between cigarette smoking and cancer of the urinaary bladtler, but the presentlyy available data are insufficient to infer that the relationship iscausal. a 37'

0 0 0 0 Other Conditions and Areas of Research CONCLUSIONS OF'rHE SII60EOIG(~.TENt'.RAI.'s1964 REPORT Peptic FRcer. Epidemiological studies indicate an association between cigarette smokingand papticulcer which is greater for gastric than for duodenal ulher. Tobacco Amblyapia Tobacco ambIyopia [dimness of vision unexplained by an organic lesion] has been related to pipe and cigar smoking by clinical impres- $ions. The association has not been substantiated by epidemiological oresperimental studies. F'irrh,osi,s.s o f'the. EiverIncreased mortality of smokers from cirrhosis of the liver has. been shown in the prospective studies. The data aremot.sufficient'.to support a director casual association., 1laternalSmoki;ng and Infmzt Birth Weight Women who smoke cigarett'es during pregnancy tend to have babies of lower birth weight. Information is Iacking nn the mechanism by which this decrease in birth weight is producedi It is not known whether this, decrease in birth weight hasany influence on the bio- logical fitness of the newborm, Psychoaocial' Aapects The overwhehnimg evidence points tothe conclusion that smoking- its beginning; habituation, and occasional discontinuation-is to, a large extent psycholbgically and sociallp determined.. Thisdoes not rule out phy,siological factors, especially m respect to habituation; nor the existence of'predisposing constitutional or heredity faetors. CI7RRENT INFORMATION, 1967 By and' large the contributions to knowledge in thisarea of varied, considerations have been meager, although a number of investigations 271-394 O-47--4: 39'.

Reren (tan fi ~ er ee {tuber o ewh he Finth ned ~oking: IBn risk Ine dis- trnward group ) along iens,, is s.t with Indimgs 7owing :inuing e bene- 1 non he em- ~;,eneral Data ~ were ill in ~ were sthan j days oking: Smoicing and Cardiovasculiar, Diseases CONCLTTSIONs OF '1Bm ..~IIRUnoN GrxER.1L: s 1964 REBORT Male cigarette smokers have a higher death rate from coronary artery dfisease than nonsmoking males, but it is not clear that the association has causal significa.nce. CURRENT INFG}R14fATIION, 1967 Important additional epidemiological information frorm five pros- pective mortality studies confii'msAhat cigarette smokers havee sub- stantiully higher death rates from coronary heart disease than do nonsmokers. This is, true for both men and women although the relationships are less marked in women. Cigarette: smoking also, markedly increases an individual's susceptibilit'y to earlier death from. eoronary disease. In general, mortality rates inerease with increasing amounts smoked.. Cessation of cigarette smoking is followed by a reduction in the, risk of coronary heart disease mortality relative to those who con- tinued tm smoke. Epidemiological evidence indicates that there is little risk of'coronaryheart disease associated with cigar and/or pipee smoking. The Surgeon General's 1964 Report indicated a median mortality ratio. of 1.7 for current cigarette smokers, with a~ range from 1.5 to 2.0. Additional evidence from the, Hammond study (11) indica.t,es that young,smokers betweentheagesnf 45 and 54 havethe.highestmortality ratios.--three times; as great for men, and twice as great for women if they smoke 10' or more cigarettes perday,, as compared with non- smokers. In general, the mortality ratio shows the most marked in- creases with increasing amount smokedi for the ages under 65. Whil'e the cigaret'te, smokers older than 65 haue lower mortality ratios than those under 65y the public health significance of the relationship in the older population is substantial because of the: large numbers of people over 65' who die of' coronary heart disease.. Studies of U.S!, veterans (13)y,Canadian pensioners. (1), British physicians (8, 9,10)~, 25 0- 1

~uJ6TEttea F0.d fr0/ib I I GT and ove I 395 40.1 44.8 1'. 1 4',.7 2 146 15. 1 1512 1.0 0. 1 0 G®arette ~o neva n sreww viest r for ~n 11 gher for women who had smoked lV-20: cigarettes per day; 48 percent higher for men and 79 percent higher for.women who had smoked 21-40 cigarettes per do:y;',and 83 percent higher for men and 140 percent higher for women who had smoked more than 40. cigarettes per day. Tlierelationships expressed by all three measures are somewhat higher among, men aged 45-64 than among men aged, 17-44, but lower among women aged 45-64 than among women aged 17-44- Inn the survey year, there were an estimatedl399'million workd'ayslost in theUhited States because of illness. A total of'77 miill'non da}rs, or 19 percent, were excess csorkdays lost because of the higher rates which exist among persons who haue ever smoked cigarettes as'compared to t.hose who never smoked.. This exeess loss is highest in men 4564, where it represents 28 percent of all days lost. BEa, DArs For those withh a history of cigarette smoking, classified' by heaviest amount smoked;the average number of dayswas 10: percent higher for men and 4 percent lower for women who had smoked less than 11 cigarettes per d'ay;,22 percent higher for men and~17 percent'higher for women who had smoked! 11-20 cigarettes per day; 22 percent'high- er for men an& 57 percent higher for women who ha.d' smoked 21-40 cigarettes per day; and 53lpercent'higher for men and 192 percent higher for women who had' smoked more than 40! cigarettes per day. Rel'ationships with smoking are higher for men than for women for all three measures except for age 17-44 in whichthedifferences'.in mor- bidity rates' between smokers:and nonsmokers are ahout the same. For the entire population 17years of age and older there were an estimated 853 million bed-days in the survey year. A total of'88 million of these days, or 10 percent; were "excess" days lost'because of the higher rates which exist among persons who have ever smoked cigarettes as com- pared to those who never smoked. Excess days as a.percentage of total bed-days is.highest for men aged 45-fi4, where it is 28 pereent'.. DArss oF REszarcTro Acnvlrs For those with a history of cigarette smoking cllaseil5ed by heaviest amount t smokeds the average number of'days was 12' percent higher for men and 4 percent higher for womem who had smoked less than 11 cigarettes.per day; 32:percent higher formen andl22 percent for women whohad smoked 11-20 cigarettes.per day;: 39'percent'higher for men. andi 48 percent higher for women who had smoked 21-40 cigarettes per day;:and.81 percent higher for men and 146 percent higher for women who had smoked more than 40 cigarettes per day. Again rates are higher for men than for women in all three measures except for age group 17-44, in which differences in morbidity rates are higher for women. There were an estimated' 2,369 million such days 21

(14) LUwDxax;.T..Sbmkinginrelationtocoronarpheart.diseaseand.lungfunc- tlon In twins.. Acohvia control: studp. Acta bfediea Seandinavea (Stock- holm)d80 (supplemend455):: 1-75,1900. , (15) U.S- Puaczo Trae:-xa Skavrcn- Smokingg and health. Report of the Advisory Committee tao the Surgeon General of'thePublic Health~ Service. (Wash. iugton).. U.S. Departmentt of Health, Education„ and Welfare,. Public Health Service publication.No. L103,1964-387 pp.. (16)U.S.. Pvnrac Heesru Seav[ce: National.Center for Health~ Statistics. Cigar- ette smoking and bealth characteristics, United. States July 1964 to June 1965. Washington,, U.S: Departmentt of Health,. Education, and Welfare, Vital and Health. Statistics series, 10, No. 34, Publie Health Service publicationNo.1000,.May 1907. 61 pp:. (17) U.S. PUSL[o. Hesnrm Seaencz. National. Center for HealtbStatisti'es, litortality from diseases associated with smoking: Uhited.States, 19Ci0-G4- Washiagton„ U.SI Department ofHealth„ Education, and Welfare, Vital andi Health Statistics series 20;, No. 4, PublieHealth Service publication No.1dW',.October1966: 45 pp.. (18). U.S. Puaaw HnALTH Seavioe. National.Center for Healtb Statistics. Dtor- t911ity-trends.in the United. States: 1954-&i. Washingtonj U.S:.Department of'Health, Edueation,.and Welfare, Vitalland Health Statistics series 20, No. 2„ Public HealthService publication No. 1000, June1966,.57pp. (i19)U-5:. Posctc HEALTH Seavma. National Cleariugbouse for Smoking and Health.. Smoking.g andd health bibliography, cumulation.1967' [In: press). 523'pp. (IP0). Wxsneny E. L:, H6a€meNN, D. Experimental aspectsof tobacco carcino. genesis. D1.seasess of the Chest.. (Chicago)~ 44(4) :337-344. October 19&9. K -v"`lr: -

CURRENT INFORMATION, 1967 The primary addition to knowledge in the areas of smoking and. overalll mortality comes from the four major populatiom studies.. Ad- ditional periods of'followup have provided a.broader base from which. it becomes possible to estimate the excess deaths related to cigarette smoking iu the U.S. population, and from which firmer conclusions may be.drawn as to the role of various exposure factors in the assoeia-_ tionsfound- Thecontributions since 1964 of each of the four population studies to the relation of smoking and overall mortality, as summarized by the authorsi are set.forth below., .STr7DY~ OF U.S~.. VPaERA'-'P6 (An. 81AI yearfoIlbwup of293;&i8 persons holding. UiB: Gbrernmenti life insurancee policies; Commonlti, referredd to as the. Dorn 8tudyaftery the late Dr.. Harold F.IDora: The most.recent report is bFHahn (13).) "* * * the increased mortality risk associated with cigarette smok- ing was foundi to be higher in the more recent calendar time. period' than in the initial years of the study. "* ** mortality ratios of'current cigarette smokers compared with~ those who have never smoked are 1.7 for deaRh from all causes,,10.9' for lung cancer„ 12:2 for emphysema without bronchitis, and.1.6i for coronary heart disease. Paralysis agitans was the only cause of death associated with significantly lower mortality for smokers than for nonsmokers; "For all' categories of current smokers,, risk was related to amount smoked. The risk for cigarette smokers was much greater thanthatn for pipe or cigar smokers. Current smokers of cigarettes, cigars„ or pipes experienced a mortality risk significantly greater than that for non- smokers if they smoked more than four pipes or four cigarsd!aily or more than an occassional cigarette. "There was a positive relationship between d'uration of cigarette smoking and mortality risk from all causes of'death for at least some cls;ssifications of smokers. "* *' * probabilities of death for ex-smokers of cigarettes revealed a. d'ownward trend in risk asduratiom of''time discontinued: increased, when othervariables--agebegan smoking, amount smoked, and cur- rent age-were controlled *' *' *-The data can be regarded as evidence against the constitutional hypothesis." Calbulations are presented to note that observations made during the study suggest the possib'clity that data from respondents (those who answered.the smoking quest'ionnaire) may in fact underestimate

advisnrg (Wash- ~°y Putlltr .s.. Cigar- to June vRelfare, Service attsties. t9'u0-8h. e; riitat lication s. 141'Ub irtment nies 20, 9p ig and press]. PART II Technical Reports on the Relationship of' Smoking to Specific Disease Categories VJ

in the survey year;l 306' million, or 13 percent, were excess days lost because of'the higher rates which exist among persons who have ever smoked cigarettes as eompared' to those who never smoked. Excess days as a]percentage total restricted activity days'was highestin men. aged 4"0-64: To help evaluate these general indices of morbidity as measuredi by various kinds of disability days it is necessaryto turn to the conditions which are reported more frequently by cigarette smokers than by non- smokers: Since these are either self-reports or reports made by a re- sponsible member of the househoddlfor others in the household, the diagnostic accuracy of'the reports is obviously less than one could ob- tain from direct medical examination. ?I evertheless, the bulk of' the reports on chronic conditions reflect what a physician has previously told the patient or the family with regard to a diagnosis, of the condition. Chronic conditions (one or more) are reported by 11 percent more of the men and. 9 percent more.of the women who have ever smoked cigarettes than by those who have never smoked', cigarettes. This is especially high. in those who have reported their highest consumption rate to haFe been over two packs a day (32 percent higher for men and143 pereent higher for women). At the lower levels of consumption the rates reported are 21 percent and 25 percent higher for those smoking 21-40 cigarettes per day, bu6.only 6' percent higher for men and 7 percent higher for women for those smoking 11-20 cigarettes per day and onlly 1 percent higher for botL men andl women. who have never smoked more than 10 cigarettes per day.The differences are especially m arked among present smokers of more than two packs per day whose rate of' reporting three or more chronic conditions is 73 percent higher for men and 143 percent higher for women than for those who have never smoked cigarettes. Applying differences in prevalence rates to the entire U.S. popula- tion 17 years of age amdl over yields the estima6e that there are approxi- mately 11 million more cases of' ehronie illness annually than there would be if alli people had the same rate of. sickness as those who had never smoked cigaret'tes:.A large:portion of these are accountediforby conditions classified as "chronic bronchitis and emphysema,"' "heart eonditions,p1 "peptie ulcers,"' and /0sinusitisl° All but the last of these have previously shown substantially higher mortality rates among cigarette smokers. Sinusitis, being a nonfatal condition, has not. been identified iir the studies of mortalit.y previously reported.. The "heart condition" relationship is most markedi in the.category °artleriosclero- tic heart disease including coronary disease." The age-adjusted incidence rate of acute conditions for persons who hadl ever smoked. was 14 percent higher among men and 21 percent higher among women than the rates for "never smokers."' However, 1 I c E I

A regularly; but the effect of smoking as measured.either by differences in death rates or by mortality ratios is greater for men than for women. At least part of this can be accounted for by the lower ex- posure of~ female cigarette smokers whether measured by number of cigarettes, duration of'smoking, or degree ol.inhalation. 4. Previous findings on. the lower death rates among those who have discontinuued, cigarette smoking are confirmed and strengthened j by the additional data, reviewed. Kahn's analysisof es-smokers in the U:S. veterans study-controlling, for age.at whichthey beg^an smoking, amount smoked, and current age-reveals a downward trend in risk relative to those who continued'.to smoke asthe duration of time dis-' contimued increases:. ThnBritish physician study„in wh'ucha downward trend'is reported in lung cancer death rates for the entire group (smokers, ex-smokers, and those who never smoked, combined)~ along with a very sharp reduction in cigarette smoking by the physicians; is the best available example of a controlled cessation experiment with~ reduction of risks resulting, from reduction of smoking. The findings of this report support the view that epidemiological data showing, lower death rates among former smokers than~ among continuing, smokers:cannot be dismissed as due to~selective biasand that the bene- fits of.giving up smoking have.probablybeen understated. 5: Cigarette smokeis: have higher rates of disability than non- smokers, whether measured by days lost from work among the em- ployed population, by days spent ill in bedy or by the most general measure--da,ys of "restricted activity" dhe to illness or injury. Data from the National Health Survey provide abase for estimating that in. 1 year in the United States an additional 77 millioa man-days were lost from work, aw additional 88 millionn man-d'ays were spent ill in. bed, and an additional 306 million man-days of restricted activity were experienced'because cigamette smokeis.h avehiglier disabil ity rates than nonsmokers. For men age 45'5 to 64, 28 percent off thedisabil'uty days experienced representt the excess assoeiated with cigarette smoking.

) 4 first 10years.4,597 of the.men and 306of the women diled. Dhese deaths , were analyzed in relation to.smoking,habits reported.bydoctors in reply toa questibnnaire.sent to.themo in 1961-~both.sexes=andiagaia in 1957,, men, and 1960, womenL Doll and Hill (8; 9).), " * * ' An association with smoking is found, in differing degrees,, in men for seven causes of.death,[whieh aecounted'for 39 percent of the death rate]-namely, cancer of the lung, cancers of the upper respiratory and digestive tracts, chronic bronchitis, pulmonary tuber- cul'osis, coronary disease without hypertension, peptic ulcer„ and cirrhosis of the liver and alcoholism. No association is found svith~ the remaining 61 percent of the death rate, and this, includes such major causes as other forms.of cancer, cerebrovascular accidents, hypertem sion, myocardial degeneration,, suicide, and accidents.. "In women, the few deaths at present.available show an association only between smoking and, cancer of the lung. "' * * If the excess deaths in smokers under the age ofi 65 years from (a) cancer of the lung, (b) chronic bronchitis and emphysemay (c) coronary thrombosis, without hypertension be taken as attributablE to their cigarette smokii7g,, then the total' mortality from all causes at ages 45-64 years is increased thereby by approximately 50 percent " The report states: "One of the striking characteristics of'. British mortality in the last half-century has been the lack of improvement in, the death rate of:men~ in.mid'dle life. In cigarette smoking, may lie one: prominent cause." ST[IDYOF CANADIAN PENBIONIItB (The purpose of the studywastoinvestigate the relationahipe.betweenresidence, oceupation;, smoking habits, and mortality from: chronic diseases particulardy lung cancer. It.was.initiated by a questionnaire which was sent to Canadian veteran pension recipients during theperiad 9eptember. 1955M through. June. 1956. Beturass from: 78.000, men,, and 14,000 womeny mostly widows, were analyzed. The men were mainlyy World War I and World War IIi1 vet-_ erans, but some BoerWar and Sorean War veterans, ass well as somee non-veteran~ pension recipients were: Included.. The age of most of the men at'the beginnfingof the study ranged from.30 to.90.yearsand.the. distribution.wasctiaracterized by thee agess of inen.eligible for servicei n ~ th e two . Worl d W ara. . For eaeh~ respondent dyingbetween: July 1, 1956, and June 30, 1962; the: cause of death was related toinformation om his questionnaire about age, history of' smoking, habits,, residence: and occu7mtion.. Among.the respondentkduring the6years of followuID there were:9;491. deaths of' males; and 1,7044 deathsa of females~ which weree analyud. (1'k.) "Current cigarette smokers had a death rate for overall mortality 54 percent higher tlian that of nonsmokers •' "• Ex-cigarette smok- 10 y,

studies of smoking and mortality have been updated on the basis of longer periods of observation on each study subjeet. Current findings are therefore more definitive and, permit more detailed analysis of the interrelationship of cigarette smoking to other significant.variables such as age, sex, and the nature of the smoking habit in terms of amount and duration of smoking. Pertinent findings are presented below from the studies of veterans in the United States (b9) and Canada. (14) and the extensive data reported by Hammond (47); Doll and Hill (,16, $6, E'7)., and.Borhani (17). The relative eacess mortality associated with. cigarette smoking is generally expressed in terms of a mortality ratio:. This statistic is defined as the ratio of the number of observed deaths among smokers, to the expected deaths among, smokers,if the age-specific mortality rates observed among non-smokers had prevailed (6Q)~.. The process of computing the eapected number of deaths among smokers; takes i to t d fo diff ib d u t i th dis ti n accoun a r any an j s s enences n e age tr on u of the smokers and the nonsmokers under observation. Generally ^ smokers,are defined as persons currently smoking cigarettes;, and non- I smokers as those lvho never smoked or who never smoked. regularly. ) Table 2'shosvs the mortality ratios for coronary heart disease deaths t among current cigarette smokers according to the amount.smoked 1~ dhily in U:S. and'Chnadian male veterans. TABLE 2. C'oronaryhearCdisease. mortaLityy ratios, age-adjvated arnoag.~, curren.t cigarette smokers &y amount smoked daily Clgyrett® smoked dsily U.der 10-20 Y1-N . Nlme tAen YU U.$..male.vetC[aa9----------------_----- 1.3 1. 7 1.8 2,01 Canadian male veteraus.-__--.-____--__--- 1.6. 1.6 1. 8 creased lvithinereasing intensity of cigarette smoking. Sllghtly higher ratios are reportedin the U.S. veterans study for current smokers of cinarettesoniv: "f. 9ucn®: U.S. veteransatudy (61)' end, Cavadian pensioners etudy. (tO,. In both studies (17e, bl')' the mortality ratioswere similar and in, p`- current cigaret'tee smokers(taW1e 2A). From these dat'a, itt appears that cessation of cigarette smoking, is followed by a reduction in risk of coronary heart disease mortality as compared to those who continue specific coronary heart disease mortality rates for ex-smokers and The U.S. veterans study also permitted the. comparison of age tlo smake cigarettes.. 48

and cigar smokers are much less affected tham cigarette smokers by" General's 1964 Report that cigarette smoking is the most important of'f the causes of chronic.c bronchitis in the United States, and incroases Additional evidence strongly supports the conclhsion inthoSurgeon sema esist.does not detract from the validity of this inference. monary empl'iysema6 The fact that other causes of pulmonary emphy- strongly suggeststhat cigarette smoking may well play an important pathogenic role in many, allthough not necessarily all„ cases of puP- d'ence (epidemiological, clinical, pathological, and experimental) deny the presence of the effect. However, the presently available eviL suspected: toxioeffect, but additional research is neededl to confirm or in the pathogenesi's of many though not all cases of human pulmonary emphysema. Additional indirect evidence eaistss to substantiate this lar tissue of human lungs, in which case this effect might be important It is suspected that srnoking has a direct toaie:effect upon the alveo- itu esperimental animals eaposed'to cigarette smokee. mucosaa of tlherespirat'ory tract. Bronchial changes have beenprod'ucedl the fact that constituents in tobacco smoke are harmfmll tu, the bronchiall ' Additional clinicall and experimental laboratory evidence confirms of much greater importance., pollution may also cause respiratory disease, but cigarette smoking is chopulmonary disease.. Si:milarly, oecupational exposures and air itary and constitutional factors in the pathogenesis of chronic bron- onstrates that cigarette smoking is of greater importance than hered- of ventilatory function, than do their nonsmoking. twins This dem- twin is a~ smoker and the other is not-show that those who smoke have a much greater frequency of respiratory symptoms and.abnormal!ities disease, studies of twin,paiTs in Siweden (4, 5, 6, y 14)-in which one usually followed by improvement of these cbaracteristics. Although some individuals may have an increased susceptibility to respiratory tbms and decreased ventilatory function. f'.essation of smoking is' relatively young cigarette smokers show increased respiratory symp- associated with~ symptoms of chronic bronchopulmonary disease. Eveti' support the relationship between smoking and mortality. In addition; recent information from morbidity studies indicates that smoking is, entiation of chronic bronchitis from pulmonary emphysema di®ical~6 when considering the epidemiolbgc data. Nevertheless autopsy studies Problems of nomenclature and diagnosis make satisfactory dfffer-' these diseases.. the risk of dying from chronic bronchitis. 3o

he basis: o i¢t findi malysis~ 0 t variable Y terms o Ipnesente (52) anl (47), Do mokiing itatisticc ii , smoker mortality te process :ers takes stribntion ienerallly and non~ •egularlyu se deaths ; smoked and in- ~ higher Pkers of af age- irs and ippears in risk pntinue I TASnE' 2?:. Annuad death rate per 1Q0,0CI0 from sorone.rg he¢rt disease' by age, ciryarette-smoking st¢taa and number of' eigarettea smoked' per day, U:S: veterans sEvdy ~s .u ss- ss ee~- i4 simltnr smoked per dsy 1' i ' Current ri®ereae~. Ex- emokers,~ Cmnent'~. dgorette . Es: amokers,'~ ' Cuereot rigarette Er amokersr~ smnkers mrnka~'~ I ®okers Ilto 9~--------------- 195~ 125~ 594 432~. 1~.374~. 1'r.105 ~ t0~.to211'------------- 298 133 ~ 830: 567~ 1;577~ ' 1„260 _T.to39------------- 390 57~ ' 912' 743' 1,701 1,366 40~.----------------- 502~. ________ I 11,.101. 646~ 1,955 1,482 '• This isahe eur.rent rate af smoking for eorrent cigarette ®okere'.and themuimumrste ettsfmd for ex- c~OYPI,! 4nokels'. ,'lix-snmkers:who s[appedd for reams other theudo¢tur's erders. ?arxrx: U.s:.veterans study (6L); The Hammond study findings summarized in table 3 are based on coronatv heart disease deaths reported over a 4-year period among, npproXimately S.mi'llion persons (4411,p00 men.and 563',UC10'women.). ['...tn1.E 3,-Coronary )ieart•t disease mortality raSios' among, . currentcigarette smokers only„ by amount smoked daily' Age and sex \len: 45 to 54____._____________._ 55 to 64__________________ 6:ito 74'______.____________ 75~to 84__________________ Women: 45 to 54_ 55 to 64'____-_ _._______ ___ 65 to 74L_________________ 75 to 84L_________________ Non- smokerx l.o li. 0 L. & 1.0 1. 0 D. O1.01 I IInda 10 Ciqsr¢ttev mroked dsaY 10-19 al 1.9 1.6 1.4 a1 2.0 L6 1. 1 2.7 2.' 0 L9 a+ I 'Expected de2tks were icxstnsn.lll.. Sasxae; m=mond, E.. C. (47). Tables 3 and 4 show that both men and wonlen1who smoke cigaret't,es' have relatively higher death rates from coronary heart disease than nonsmokers, although men have higher rates than women. For each sesand for each age group,, themortalitty ratios'forcoronary heartt disease'generally increase with inereasedinten.sity of cigarettesmtok-ing' (table 3). Ti he highest mortality ratios for both men and women arte observed in the 45-54 yearage-groop; the coronary heart.disease'.

' hea]th rs from iny mor- 3 lralenca "nutri- -obacco ad and Is may found to be y con- tt this 6oke k, but {cance O be- er of triate these chich Cited References (1) . Baar, E. W'.. R: A Canadian study of smoking and health. Ottawa, De-partment of National Health and Welfare, 1968, 137pp. (2) Bocx, F. G:, 3Sooae, G. E;,,CLAns, P: C. Carcinogenic activity of'cigarettef smokecondensate.. III. BiologicaTl activity of refined tarr from several types of cigarettes:,Journal of the NationapCaneer In.stftute (Wastiing- ton) ~ 34 (4) : 4811193, April 1965, . (.7). Boaaexr, N.O., HEOarne;,H: H., BaEecow,.R..Reportof a 10-year.followupr study of the San Francisco longshoremeu: Mortality from eoronary heart disease and.from alli causes. Journa4 of Chronic Diseases (StL Louis), 16:. 1251-1266;.1963i. (;.). Canear.oF, R. Drbann factorr and prevalence of respiratory symptoms and "anglua pectorie." A study of 9,168 twin pairs with the aid of mailedl questionnaires.. Archi.vesof Envi'ronmental Health (Chicago) 13(6') :. 7 43--748, December 1966. f3.). Conem.os, R,,, Fam=o;. L.,. JoRSsorr E., &wxr, L. Morbidity among.g monzy- gotic twins, Archivesof Environmental Healtlh. (Cllicago) 10(2) :346-3u'0,. February1965:, rr,). Cs:neacoe, R.,, F4meao,. L.,, Joas®ox;. E., %wra, L. Respiratory symptomss and "angina pectoris" inn twins with reference to smoking habits. An. epidemiological study with mailed questionnaire-. Arehives of. Environ- mental. Health (iCHicago) 13(i6) : 726-767, December 1060. r7)Docr., R: Cancerr broncbique et, thbac, Bronches (Paris)16(6):.313'-324, September-October 1966. (8); Dnnu, R., Hru., A,. BL Mortality in relaHon toemoking: 10 years'observa- tions' of Britistih doctors. (Part 1,) Bribish. Medical Journal (London) 1(5395 ) :'1f399-T410; May 30,1964. i? 1DOLL, R, Hmq A. BL Jfortalityy in relation to emoking:.10 years'observa- tions.of British..doetors., (Concluded.) BvitishMedicall Journal (London) 1(5396) : ,1460-1467;,June 6,1964. (10) SDOiL, R'.., Hua, A.,B:MortaRtpy'of British doctorsin retatioato smoking: observations onn coronary thromboais.. Tn:Haenazel;. W:,, editor. Epi- demiological Approaches to the Study of Cancer and Other Chronic Diseases.Bethesda; U.SS. Public Health~ Service,, Nattonal. Cancer Insti- tute monographNo:.19', January1966: pp. 20',r268- (11) Heusosn, E. C; Smokingin relation.to the death rates.of li.million men and women. fn: Haenszel, W:,, editor. Epidemiologlcal Approaches too the Studpof Cancer and'.Otber Diseases. Bethesda„U.S: Public Health Service, National CancerInstitute.monograph No~ 19, January 1966, Pp:.124-204. (12)HanN,. D., laean; F., WAixoaow,. S. Dosage patterns, of cigarette smoking in American adults. American~ Journal of . Public Health andd the . Nation's Health: [Il'upress]. (13.). RAHN,.H:A.The.DornstudpofsmokimgandmortalityamongU:S.veterans: report.on.8~Fi years ofotiservation..in: HaenzeL W., editor..Epidemiotogi- ca1 Approaches to the Study of Cancerand Other Diseases. Bethesda, U:S. Publ'.r.Heaith Service,. National Cancer Institute monographNo. 19, January 1966. IPp..1-125. -

SMOKING AND CORONARY I3EAtRT DISEASE Coaoxnar ElEanr DssEASE MonmAl.lTr' The relative importance of the association between cigarette'smoking, and coronary heart disease (4.~`IIID)) as compared to the' association of smoking witlh other diseases was previously described in the introdue- tion to chapter 1I1 of.the Surgeon. General's 1964 Report_ In~ the tinitied States more persons die from coronary heart disease' than from any other single cause;,andithis most common form of fatal cardiovascular dliseaseaceounts for a greater percentage of escess's lraths among cigarette smokers than do deaths from lung cancer. In 1964, there were' 1,798,000 deaths from all causes, of which almost:7:}.ita0C) or 30,3 percent, were dlue' to atherosclerotic heart disease,, iilclndingeoronarg heart disease. Tabl'e1 guves the 1964 death: rates forcnrnaa-ry, hearG' dzsease per 100;000,pelsons by age and sex : T, nr,a 1.-1964 deatTt rates for eoronary heart datisease per 100,000 persons by'age and sex ..' All.ages. 2SJ4 1iH 6S.u 65-6f' &5} 9oth.Sexe__~~. 285.11 6.9 53.2 205:.&. .576~3 1,.384..9 7 r 8,882:.9 Yfalcs'~_____' 354.2 111.0 90.9' 341..3 889:8 1,942':.4 0 t.409'.4 Nemnles____I 218.5. 3.0 17.4~~. 761,8 286:4 926.5 2 0. 6;.559'..0 ?arxea~ Sxtionai Cenffir 1br HealthStatiaGn (aI): These data illustrate the d'ramatic increases in the risk of death from coronary heart disease: as age advanees.. For malps therates among persons over the age of 45 appear to double~ from one decade to the next; among females the increased risk of death with advancing age is more dEamatic-a threefold increase every 10 years, Of perhaps' greater importance are the relatively low death rates among females, particularly lhelow the age of 65, , compared to males of comparable. age. Themortalitye differential between the sexes becomes less as age advances; , under 45 years; of age the coronary death rat8; among men.n is fivetimes as high as among. women and in the 75-84 year age group it is only about 1.5 times ashigh. ThH Surgeon General's 1964 Report determined a median mortality ratio~(99), (pp. 109-110).for coronary heart dfiseaseofe male.currente cigarette smokers; of 1.7. Since this report, five liarge prospective ' AIC death ratess tHroughoutt ttiischapters arem per 100,000population„ unlessotherwise.indicated. 411 lam a

eLABLe 3.-Co7nparison of 3 measures of relattianship between otigarette smoking and 3 types of daeability days by age and sex as: deri,ved frmn: the Nattional' Health 5?mrvey' (16) a Maie. Femele - lfii 1&81: a5 and 17-41'~. 1&6! 6@ and'~ ~ ~I OPe[' oVtT~ I F7ons-Loss DAYS Estimated'~..total!deys'~.(millions)~----- 112 127 21 80~. 55 4! R'ate::1~ . Never~smokedcigarettes------- 3~.4 5.6: 9'.8 4.5' 5A 5.0~~ Historyofcigarettesmoking____ 4.4 8.5, 9'.8 6.5~ 0.9 (r) IMorbidityratio"----------------- 1..3 1.5~ 1.0 1.4 1.3 (t) Difference in.morbidity rates 1'~ 1.0 2.9 0 2.0: 1.6 (1) Excess.day,s~~as percentage of tot'al'~_ I 20 28~ 0 18~. 11 0) RESxmcrsn: AcT[v7xr DnYS - Estimatedtotaldays~.(millions)----- ~ 305 386: 271 ~ 543. 469 395'. Rate: 1 ~ Never smoked cigarettes_______ 7:~.5 15.0. I, 32,9 9 13.3 , 221.6 40.1 . History of cigarette smoking~_ __ 10.6 22.9 ~ 37.9'~. 17.8 25:3~ I 44.8~ MorbidityratflotL._.,._____________._ 1..4! 1.5:. 1.,2'~ 1.3 :. 1.11 1.1 Difference iu~morbidityrates 1 3.1 !. 7.9' 5..0 4.5: 2.7 4.7 ~ EROeas.days as percenfiage~of total'''_ 23! 28~ 8 14 5' 2~ Beu DAYS Estimatedtntial~~days'~.(millions)~_____ 1~11. 1181 100~' 210 ~. 168. 146~ Rate: t Never~~smoked'.cigarettes------- _ 2'.7~ 4.6'. 13!.4! 5.4! 8.0, . 15.1 . History~of cigarette smoking___ 319~~ 6~.9~. 1310. 6.7~ 9.2' 15.2' - hlorbidityratlo~i'----------------- _._ 1L4~ 1 .5' .97~ 1.2~. 1. 1 1.0:. Difference ia~morbidity rates' e'- 1.21 2'.3: -0.4. 1.3 '': 1.2~. 0.1 . Excess days as percentiage~ of total 23' 28: -1. 10~. 6I 01 I Rateis:deaued av:"days.pea person per'yeer." r Besed on too few smukersfor stable rates. r Iaorbidity Ratloa-Mnrhikily raNfbr ey®ettc amukerrdivided by.morAidieY rate/or these mMe'.+veaer mubd dqarc[tea. e D1Herence in.ffiorbidity Aates-Mortidity rate for ciparefle.amoRere minua morbldlfyratefor thu.cwRorv neeer emoled GymeHa'. e Ezcesa deatksamung cigarette smokera (i.e., additional days of 3ieabiaty that oe<ur among p7garette'. emokers per yem aboae those wb10ti would LaPe oecurred if smokers had the eame,rates as thoee who never smoked cigarettes). Thi4Is expreasmi as a percestege o1'aa dlsabiaty Gays oecurring In.that ege.sexgroup.. DAYB~~ LOST FAOM~. WORH ~S6 For those with a hist'ory of cigarette smoking, classified' by' heaviest amount smoked, the average numberof days was 7 percent higher for men and 15 percent higher for women who had smoked.less than 11 cigarettes per day; 33'percent higher for men and 60 percent higher 20,

~ lost ever tscess ~ men ~d by jtions ~ non- a re- dy the Gd ob- if the yously4 the more aoked 'his is iption. r men. ption those r men es per 6 have s are s per s 73 n for ypulh- ?rosi. ~here ~b had orby eart ~Ithese tnong been "heart ~ulero= who rcent ever, u particulhr cautiom must be taken in interpreting the results relating specific acute conditions to cigarette smoking because of the relatively large sampling error connected with the estimates for the several types of acute condiGions: Since the National Health Shrvey is not a prospective study, itdoes not. identiiFy the rate at which various types of' morbidity develop in comparablee groups of'smokers and, nonsmokers, but reports the recent existence of such. disability. Therefore, the findings are much more, significant whemt'hey support relationships previously identified than when new relationships are identiRed.. It should; not be surprising that causes of mortality which are associated with cigarette smoking have, a, counterpart in disease or disability associated with smoking. e+.sthe primary source of data in the United States on disability„ the Survey report, being based on a national probability sample, provides a solid base for estimating the excess overall disability asso, ciated with cigarette smoking.. HIGHLIGHTS OF'CIIIi!RENT INFORMATION ON OVERALL MORTALITY AND. MORBIDITY 1. The previous conclusions with respect to the association bel smoking and mortality are both confirmed and strengthened by the recent reports. The added period of followup and analysis of deaths of nonrespondents as well as of respondents in. the Dorn Study sug- gests that the earlier reports may have understated the relationship.. 2. More information is now available for specific age groups than previously. A comparison of t;hree ways of measuring the relationship indicates that cigarette smoking is most important among, men. aged 45 to 54 both in terms of'mort'ality ratios and escess deathseapressed as apercentage of total deaths. Nevertheless,, although both of these measures decline with advancing age, the increment added to the d'eath rate, which reflects one's personal chances of being, affected, continues to increase with age, For men between the ages of 35 and 59, t.he.eacess dea.ths.among current cigarette smokers account for one out of every three deaths at these ages. For women, with their lower overall eaposure to cigarettesi the comparable figure is about one death out of every 14 at ages 35 to 59. 3. Women whol smoke cigarettes show significantly elevat'ed death rates over those who have never.smoked regularly. The m agnitude of the relationship varies with several measures of dosage. By and llarge, the same overall rel'ationships between smoking and mortality are observed for women ashad previously been reportedi for men, but at a lower lbvel.. Nbtonly are.the death rates for men who have never smoked regularly higher than those forwomenwho have never smoked z_ : ~

determined qualities (28), irt physique (77, 93), in personality (37, 47;1e8) 65„ 68, 69)„ and' in social, cultural, religiousy and economic characteristics ( ¢6,19;,68; 81). Age _ ....- ,~.:~'' ,` . The effect ofage: on the incidence of coronary heart disease with regard' to cigarette smoking is shown~ in table 7 based on recent d'ata from the Framingham Study as yet unpubli'shed. TAal.e 7.-lvtoid'erace rates and mortiidity ra.2ios for coronary heart disease by age' and smokii(g status of men 12-year ezperience;. Fr¢- mingliam., Mass. Age 35 to 44-_ 1: 4 4:.1 2: 7 1L 0 45 to.54--"------------------ 4.6 11.1 6:,5' 1L 0 55 to64---------------------- 16.2 25'.4 9.2 1L 0 Sooace: U:9. Public Health Servfce, Fremingtism Study (90. (Updsted'aDBI): When the incidence.rate of coronary heart disease.among, male non- smokersbetween 35-44.years ofiege is compared with.that among,older nonsmokers, the rat® is.seen to triple every 10 years. This marked increase in incid'ence among' nonsmokers reflects the effect of other important risk factors and perhaps accounts for the decrease im mor- bidity ratio as age advances. The independent effect of smoking on the incidence of' coronary heart disease is believed to he more appro- priately represented by the excess morbidity rates, which increase from 2.7 per 1,000 smokers in the age group 35-44 to 9.2 per1,000 smokers 55-644 years; of age. Fdxgh. Blood ATeBsure Although the inhalation of cigarette smoke is fiequently accom- panied by acute transient elevations in blood pressure, habitual smok- ers tend to have lower blood pressures than do nonsmokers (48). But, given the presence of 'high blood pressure in an individual'„smoking acts as an additionall risk:factor for the development of coronaryy heart disease (17, 28, 29, .9IOy 53; 55, 95,96). Both the independent and the combined effect of cigarette smoking is clearly shown in table 8 de- rived fiau the experience of the Framingham and Albany studies (30)., 54 T: T Il 0

I ex- of tedi age d°s dy: ide res mps me- ur- e of iked any ~ate the and ~ the im ~th ~g able the 5 TAE1,E 1L-E!ontparison o f 3 measuresi o f'redationsRip between cigaret te. smaking and overall death rates by age and sex aa derived from $ rrQl . or prospective studies (,11,13)' ese , ffi-4d 'LL64 NFBY.. !5-'!f. 7&84 l.r.Si VETEEANa:'.141EN Total deaths---------------- I 383 366' 13l 84& 17; 550! 1,932 Death rates.per'100,000: Never smoldedlregularly-_______ I 127 264' 1~ 056 2, 41'1 6t,214 Currentcigarette.smokers.----- ', 232 728 1~819' 4;082 8;.471 Mortality ratior------------------- - . 1..83: 2.76 I L 72: 1.67 1. 36 Difference in death rates per 100,000°----------------------- 105 464' 763'. 1,6211 2',257 Excess deaths aspercentageof's totali--------------------------- 33 43I 21. 17 8 HAMEfQND, IVIEN Totaldeattis---------------- _ 631 5,297 8,427 8,125 3,968 Dcath.rates'per 100,000: Never smokedlregularly-------- . 210 4'06 1,202 . 3't 168 7t 863 Currentcigarettesmokers------ 397 925 2,202' 4,788 9,674 \lortality ratio °------------------- . 1..89 2. 28 1.83 I 1. 51 1.23 Difference in.death rates per 100,000° --________. 187 519 1,000, 1',620' 1,811 Ez cess. deaths ass percentage of totali-------------------------- 33 38 25. 13 4 HAMMOND WOMEN Total.deaths---------------- . 727 2,826 3,915 5,115 4, 188 Death.rates per 100,000: Never smoked regularll}t-------- . 165 304 698 1,913 . 5,914 Current.cigarettesmokers------ _ 186 384 838 2,229 5;,846 itortalitly ratio °'_.................. . 1.13 1.26 1.20 1.17 .99 Difference im death rates per. 100;0003: ----------------------.-. 21 80 140 316. 68 Excesss deaths as's percentageof total'-_----------------------- -. 5 9 4 2 --_--_ "TheseEgures are deri6ed Irom the reftsences.5 yeersqe Qoupewme combinedNireetlr fromitde reported etativtlm wtthout adlustmentt te enFstandard ipapulatlUn. 3 Mortality rattav-Demp rotl/onewrent-.elyaretle amaken diMded by deWY ro(cJor (Aaue nAO xexr amoRel'. rera(oriql r'D I@erence tnn death retes-DeatN ratte jor emrentelyarette .nm kera mthm deat/ rafr for Nwe mbo* neoer araoRed '. rrputer(M:. t'E%aesa deathx smong cmrenC<Igarett9emokers (Le., addttlondAeWla that occurred amonCemreotg tigeretteemokxs per. year above these which would have oeemred ifamokera had the aeme. death rates m. thaae who.never atueked regulsrly). This le'm,areaedbo.a pereentage ofa6~deaWe ooaarln` In that'aQeeex . unto. 13 r

Autopsy studies of' smokers compared with nonsmokers specifically observing pathological changes in esophageal tissue have been reponted'd fTom.both smokers and nonsmokers who died from causes other,than esophageall cancer. The findings were simiTar to the abnormalities generally accepted as representing premalfgnant tissue changes of the epitli:el'iumm of the respiratory tract; that is,. epithelial cells with~ atypical nuclhii were found far more frequently in cigarette smokers than in nonsmokers. Tiissue sections with basaf celT.hyperplasia werem also found morefirquently in cigarette smokers and, as with the atypical nuclei, these findrings increased with amount of cigarette smoking. Additional data to: evaluate the relative importance of smok- ing and alcohol, independently and jointly, would help clarifyv' the significance of'these findings. UURINABY~ BLADDER CA',NCER The.Darn (13) and the Hammond (11) studies both show mortality ratios over 2.0. for smokers of over 20 cigarettes a day, but the Do1t-ItIi111 study (8, 9),.based on only 38 deaths, 5hows no apparent relation- ship:. Two retrospective studies have shown significantly higher pro- portions; of smokers among patients than among controls. Small scale metabolic studies suggest that cigarette smokiingmay block the normal metabolism of'tryptophan, which wouldd lead to the accumulation of carcinogenic metabolites in~ the. urine. Further studies to verify this finding and studies analyzing changes in the bladder tissue of smokers as compared with nonsmokers would be helpful in arriving at a judg- ment of the significance of the.elevated' death rates.found in smokers inthe largest of the prospective studies. STOSrACn'. e4Nn'PAYCaEaxxc: C9HaE6.. Epidemiological evidence does not show a significant relationship between smoking andl stomach cancer. An association between ciga- rette smoking andl pancreaticc eancer is implied, butl the significance of this association is not clear att.he present time.. HIG'HLIGHTS OF CURRENT INFORMATION LrrNG CANCER : 1. Additional epidemiolbgical, pathological, and experimental dat'a. ', not onSy conficm the conclusions of'the Surgeon General's.1964 Report: regarding lung cancer in men butt strengthen the causal relationship of smoking to lung cancer in women. 36 .,, 'r,

death rates among heavy smokers in this age group are three timesthe death rates' for nonsmokers for both sexes. The mortality ratios for both men and women decrease with advancing agre in each intensity category.. This trend may reflect.the effects of selective survival of smokers who have survived the elevated risks at younger ages of cor- onary heart d'isease and other diseases associated with cigarette smoking. Another eaplanation of the decrease in mortality ratios with agutg is that the effect. of smoking, while substantial in in.creasing death rates, cannot be expeeted'to be pnoport onate to all other causes of coronary heart disease as age adva¢tces: Considering the.adm-anced de- gree.of atherosclerosis generallly found among'nonsmokers over age 65,~ the deleterious effect of smoking is more appropriately represented by the ~ excess iutin death rates among' smokers. Tati1e 4 below shows j the observedi death rates from coronary heart disease among persons studied by Hammond and classifled by age, sex, and smoking status. Although the mortality ratios decreased with age, differences in death rates„which reflect tlhe numbers of persons who die in each age gpoup, increase. This could be interpreted to mean that, although relative to I other factors, the role of cigarette smoking tends to diminish with ad- j vaneing age,,the number of excess deaths per 100,000 smokers'continues ~ to rise with adsancingage., A TABLE 4.: A'ge-speciftc death rates fromm coronary heart disease per 100,000 persoms by age, sex, and smoking status Age end ses . smokem or. ciga<ettes oNy Kunsmokas ELCf9S tat6 9moke.(nUY. smoken ~ Moxtality retin Males: 45to.54 -_ __. __ 422 150 272 2. 8 55to64 . - 996 542 454 1.8 __. __._ 65~to:74 __ . ___ __ 2,025 1, 400 625 ll 5' 75to84___ __ __ 3{ 871 3, 132 739 1l2 Females: 45.ta.54!__________________ 66 33 33 2:,U~ 55to.64__________________ 275 163 1112 1.7 65.to, 74____.______________ 941 653 288 1.4 75- --------------------- 2;, 849 1,973 376 1.2 ~carCuistetl nom tt5e data. 9ouca: Asmmond', E..C. ((yl) l P.145+1 . The relative decrease in death rates from coronary heart dfisease associated with the eessation of cigarette smoking is illustrated by' table; 4A. , 50'.

ratio, is 2A. However, as shown in table 5y,the mortality differential~ between smokers and nonsmokers,are much larger at'the younger a ea~1g TABLE 5.-11~ortodity'ratias f'or different types of coronary heart diaerza by amokireg habits Age group 35'.to.44-----___---_- 45~.to~.54__--------.--- 55 W64-.--_----_--- 65Ito 74'------------- Mto 84 85 ~ plus -------------- Age adjusted-All ages_ ret't'e smoking. Men 45-64 years of agewho were lieavysmokers~ experienced.higher death rates from coronary heart disease than did nonsmokers independ- ent of'whether Uhey' were hypertensive or'nonhypertensive: insights on: both the indiependent and the interaction effects of ciga- deaths from coronary heart disease' among persons free of other serious diseasestates. In a prospective study of California longshoremen, I3brhani (17): reported on the mortality eaperience of more than 3,700 men obser =ed for'10 years. Table 6, derived from his data,.provides some additional. Non- ®oYem 1.0 11.0 1..0 1.0 ' 1,0: 1L 0 1.0~ Croup2t~CHD, All amounts ContlnWng d®arettee emakers 4.7 3.8 1.4 1.,4 1. 1 1.0 25 oI more per day. 9.7 3.5 1.6 1.S 2.0 (A) 1.61 2.0 Non- smokera 1.0 Oroup 3 CHD I ConabulYg elgsrettb ematecs All amount9 25 or mon per day ''8ce tent fordefinltlons. 'Nat®lculable; no rate fornonsmokers;bemuse ofsofewdfaths. 3 Very.few men in th19 category. 9tlUsea: Datain above table bsaed onn values hom.5tudy'of'Britlsh Physicians. Table 3(Yn. The mortality ratios shown for Group 3 deaths,, iLe.,CHD deaths~ accompanied. by some other complicating disease, suggest that;, for all age groups combined, smokers do mot have any special. risk to: this type of coronary death. However,,smokersbelosc the age of'65 appear to be at.a somewhat greater risL;,while no consistent differen- ~ tials are observed among persons in the older age.groups. In summary, the, study substantiates other mortality studies' RBdL ± ings that CHI7 mortality ratios (current cigarette smokers vs. non- ; smokers) increase with the number of cigarettes smoked daily, that the ratios are highest in the age group 4b-59, and that they dt?crease' : as age advances. Moreover, smoking apparently is associated with '

d;demi eflin 111G22 tie d ne da r 1982. tllisto- moaC heart c 1963. ~neet t'udies S[iclli r196a;

e a and Californi'a, longshoremen (3) also provide extensive adtlitional information about coronary heart disease in male cigarette smokers as compared to nonsmokers, supporting the above statements as they pertain to men. The study of British physicians (8, 9;, 10) suggests that male cigarette smokers have the largest increase in risk for., death certi- fied to coronary thmom'twsis-a subcategory of coronary heart disease describing acute coronary events, frequently occlusive, causing myo- cardiall infarction. For that subcategory, the mortality ratio is. also largestfortheyoungeragegaoups35-54: Prospective morbidity studies confirm the relationships between cigarette smoking and coronary heart disease. These studies also provide.the opportunity to. evaluate the effect of smoking independ- ently and in combination with other known "risk fractors,"'such as high blbod pressure and high serum cholesterol that are also impor- tant in the pathogenesis of coronary heart disease..It has been demon- strated that cigarette smoking not only operates as an independent "risk factor" but that it may com'bine with other "risk factors" to pro- duce even greater effects on cardiovascular health. Other types of evidence have~also been presented'to confirm the epidemiologic evidence. Autopsy studies.show that cigarette.smokers have a much greater frequency of advanced coronary arteriosclerosis than do nonsmokers. Clinical and experimental studies demonstrate that smoking produces abnormalities of' cardiovascular physiology that may help to explain the mechanisms of homy smoking may pro- duce earlier death from coronary heart disease.. Humam and experimental studies indicate that the nicotine ab- sorbed from smoking may cause an increase in the myocardial tissue demandd for oxygen yet at the same time the carbon monoxide absorbed from smoking nkty eause a decrease in the supply of available oxygen from the blood'.' necessary to meet the increased' myocardial tissue demand. Studies indicate that some persons who already have pre- existing coronary heart d'¢sease, not necessarily clinically obvious, may' be especially susceptible to, the adverse physiolbgical effects of smoking. Evidence also indicates that important differences may exist between normal individuals and those with. coronary heart dlis- ease in their ability to increase coronary blood flow to compensate for increased myocardial tissue oxygen demand. Smoking apparently can accelerate thrombus formation of human blood; suggesting another possible mechanism whereby smoking might increase the mortality from coronary heart disease, especially those acute coronary events cert'ified as "coronary thrombosis:" TThe convergence,of many types of evidence--opid'emiological, ex- perimental',pathologicaly and clinical-strongly suggests that ciga- rette smoking can cause death from coronary heart disease. These 26 i. 4 ® q,. fJ1

CURRENT INFORMATION, 1967 cancer that were shown to be associatedi with or caused by smoking.i icali evidence has been reported that substantiates; the conclusions of the. Surgeon General7s 1964 Report concerning the various sitea of Additional chemical, esperimental;pathol'ogical, and epidemiolog' 17eaths from lung cancer in the United States are continuing,to rise rapidly. Epidemiologicali evidence concerning cigarette smoking and lung cancer has confirmed positive relationships with increasingnum- bers of'cigarettes smaked„with increasingduration,,and':with decreas- ing age of initiation of the habit. Diale cigarette smokers of less than one pack a day have mortalitj< ratios as high as 10 and smokers of more than one pack a day have mortality ratios as high as 30. There is: a muclu smaller increase of the lung cancer death rates associated with pipe, and/or cigar, smoking than with cigarette . smoking. Additionall evidence provides specific information on the inereased mortality ratios of female cigarette smokers. These have significantly elewated mortality ratios ranging as high as 5 for the groups with greatost esposure: Lung cancer rates appear to t'ie somewhat, lower ~ for women who havenever smokedl regularly than formen who have ~ never smoked regularly.. The mortality rates for women who smoke, ~ although. significantly higher than for nonsmokers, are lower than ~ for men who smoke.. How much of this is due.to lower exposure to , cigarettes and how much to other factors cannot be determined from the data available. Ex-cigarette smokers are shown to have significantly lower death ~ rates compared with4hose who continue to smoke. As discussed under the general topic of cessation earlier iit thiss reportl,, the Snding.of re-, dktced lung cancer rates in the population of British physicians: (8, 9, 1 70) over a period of time in which the proportion of'cigarette smakers ~ was dropping significantly can Ihe interpreted as: similar to a: con- ; tsolied cessation experiment and provides critical confirmation of the judgment that cigarette smoking is the major cause of lung cancer and.that sharp reductions can.occur in the risk from lung cancer with. the cessationof smoking. Additional iinformation is available coneerning thepresenee of' knownn or suspected carcinogens:in tobaccosmoke-It'hasbeen reported that the °itar" andnicotinecont;ent.of cigarette smoke* tendsto reflect the tumorigenicity of. this smoke, and that a reduction of the "t'ar"' andi • The phrase."`tar'and. nicrotine" is ased here as a general Indicator oftotaif particuIate.matter In cigarette smoke.

tionaL IInstitutes of Heallth based on the 12-year eaperience in Framing ham (36).. Morbidit,y ratios derived from this publication are shown 'n tabie 10. ^-;: TABLE 10_ A'ge-adjusted morbedaty ratios for coronary lieart dzaeaa among smokers and nonsmokers according to level of vital capacity Vltalcepacity: Under.3liters____________.______________________ 3litets.or more_______-___.______________________ Ko.oken ol' eigsrettes 1.0 1.7 Cigarette mokel5 9avncnnxhePrmmngHemBesrtsthdF. (96). ,i H'ere again„ the independent and combined effects off cigarette smok I- ing are observed. j Ph ysical Inacti::vity' AA physically inactive or sedentary individnal seems to run a.higher risk of developing coronary heart. disease. (39, l(1; ¢1, 76). Spain (88) reported that, in liis prospective study of 3,000 men'tt* * * the re1'a- tiouship o'occupationall pbysical actibitry to smoking hab'rts reveaTed that one~of six sedl'ntaryr workers were heavy smokers and one of.S've strenuous workers were heavy smokers." Weinbll<tt, in reporGing' the experience of the Health Insurance Plan of Greater New York (100) alsoo found.thatd a]liglier proportion. (41.9h versus36.0'pereent) of cig- arette smokers wereclassified in the."mosst active" physical activity category. The independent and the combined effects between cigarette~ smok- ing and physical activity are shown in table' 11. The morbidity ratios for myocardialinfarctions are d2rived from published data. TABLE lll.-Age-adjusted morbidity ratios for myocardial infaretions among. smokers and' nogtsmokers according to physical activetyy level Phy-0cal sctivltr.' I Nonsnokem of Ngarettes' `lost.actlSfC________._________________.___________ 16east activc__________.____________.__.____.______ Cisarettn smoters 2.6 3:.4 5ocnce: Weinbl4tt, E. (lM). , 'Soc20e764JEPon:Hdental Stress Since.1i958y,researcli on socioenvironmental.stressin relation to eor- onary heart disease has increased greatly (83,9Q)~.. Among the factors studied that indicate a strong association with coronary heart disease incidence' and prevalence is socioculturaP mo'bility, that is, moving from one social setting tb' another. The interaction of this factor and 56 m i+ UT k 1 4 L91 43:

a high w] (88)', che rela reveal eoffiv ;ing t-he K (10©) of cig' tetivit cignrette smoking has been reported by Syme (90, 91) in both an ur- ban and rural sett:ing. Apparently in both areas cigarette smokers were more eulturally mobile than nonsmokers: The independent effect of' cigarette. smoking on the incidence of coronary heart disease is shosvlr in the morbidity ratios in table 12 derived from the North Dakota.studly (91). T.zBne 12.-Age-adjusted morbidity ratios for coronary, heart' disease among smokers am:d nonsmokers according to soeiocultural mobility .cttLttts' Sociooaltumi status ~I::blc__-------------------------------------- lilatdg mobile__________________________________ Never. smoked I current andl cigarettes fdrmer'cigarette li smuliers~ 1. 0 2.3 5~'.'au:: ]corth'Dakotastudy. (81)'. G', ,•..an.,fdityT'yPe Various investigators have lonbg suspected a possible pathogenetic roleof the central nervous system. in coronary heart disease (35). In t<erirsof reports, Rosenman (81,82) and Jenki'¢ts (51) have desc-ribed n perstma.lit3.~ pattern or overt emotional com,ples which, while assa ciated trith other known risk factors, appears to predict coronary heart di-ease more effectively than db'other risk factors. This emotional com - l;tiex. "n-huchthey have termed Behavior Pattern Type A, is composed of un enhanced competitiveness, drive, aggressiveness and hostility, aaid an escessive seuse of time urgency." Recent unpublished data based upou prospect.ive'observation of more than 3,000 mlenn for a. 4r/y-year period (,51) disclosesthatsmlokershave.ahighe]°percentage. (54.versu~s 17 t)encent) of type A persons among them..bloreover, the incidence of coronaryy heart disease is shown t'o be related independently to, both ;tnoking status and personality type. Morbidity ratiosi, derived from rhe' i'ncidenceda.ta, are~shown in table 13 which clearlyrdemonstratestheJiidepcndent effects of cigarette smoking and its interaction wi'th~ lrersonnlitv ch:aracteristics: T+BLE 13'.-D4orliiility ratios o,f cigarette smokers as compared to non- smokers' by, person:alityy type. Personnlitytype NonsmoHersof algsrettes Qllgareae emokers Behavior type IlL-------------------------------I 1.0 . I 2..0. OPhardortypc A________________________________I 2.5~I 4.4 eoeterC pnpublished dam from W estem ColleboraLlve Group Study., Ben EYSneLeco;,Callf. (Et). 67

li ~niolog- iions of .iites of ,joking. I to rise ng and 3,num- ccreas- ss than -fimore nicotine content is accompanied by a.reduction in the tumorigenicity: Htesearch is needed to identify and separate the tumor-initiating and tumor-promoting agents in tobacco smoke and, to elucidate their inter- act.ions in the pathogenesis of cancer.. Similarly,, while addit,ional data are aNailable concerning experimental' careinogenesis;, it is not yet certain that the typical eharacteristics: of'human squamous-cell lung cancer, with invasion and metastasis„ have been experimentally pro- duced by tobacco smoke in animals. It shouldl be noted that this may never be achieved not only because it may not be possible to duplicate man's smoking action for anatomic and physiologic reasons but. also because of species'' differences in cellular response. There is evidence that certain other exposures, for example, occupa- tional exposures to asbestos and uranium. ore may interact.with the cigarette effect to produce an enhancement of the tumor-producing effeet.. There is aiso information to indicate that the occurrence of second primary lung cancers in smokers may be more frequentt than preiouslyy indicated. ORAL. CANCER~. ;rnased .cantly s: with lower r.have nuoke, than re to 11from ideat.h under of re- (8,,9; ~okers con- bf the ancer F with F Substantial mortality ratiosare found for cancers of the buccal cavity and pliarynx: Mortality ratios for cancer of the pharynx are especiallly high. There is some evidence im7plaeatiing a1'cohol and/or dietary dbficiencies in some of these sites.. With the exception of the pipe-lip cancer relations: there are too few cases related to the indi- cidbal parts of the liuceal cavity to evaluate each independently, and; data acv inad'equate on the interaction of smoking with other factors. Although alll forms of smoking have high mortality ratios with these sites,..mort'alit'y ratios for those smoking cigarettesappear to.be some- what higher than for those smoking pipes and cigars, especially in the casenf cancer of the pharynx. LARYNGEAL CANCER Continued evidence from the prospective studies supports the exist- ence of a, high lartyngeall cancer mortality ratio for pipe and eigar ° smokeis as well as for cigarette smokers. I?ata,on the smoking habitss of patients treated for buceal cancer subsequent to thei'r therapy sug- gests t.hatcontinuing to smoke after therapy may increase the Iikeli~ hood of an independent l'aryngeall cancer. The epidemiological euiL d'ence supports the previousconclusion that cigarette smoking is a significant factor in the causation of cancer of the larynx. ~i' sOPH_1GF'1~~.L C.tNC6R Ad'ditlional datae from the prospective studies confirm the high mortality ratio previously found for smokers of all forms of tobacco. 351

smokers (7; 89)., particulhrlyheavy smokers, and nonsmokers in regard to greater. obesity, higher dietary fat intake,,and higher serum choles- terol leeels. Further analyses of'autopsy series are needed to determine the independent edects of cigarette smokiiig on atherogenesis. SMOKING AND CEREBRQVASQ>IILAR DISEASE An increasing amount of evidence has accumulated in the past few years relating the decelopment.of clinical cerebrovascular disease to cigarette smoking. Most of this!information has.come from the pros- pective mortality studies: Hammond has reported the following data from his'large prospec- tive study (47)ynot'edintable15'. TABLE 15,-Cerebral'axiscul¢r lesinns,. Age-standardized death rates, by. typeof smoking (lifetime history) and age at start.ofstud'y' Age ME N Never smoked regularl,y-_ _ _ _ _ _ _ _ __ _,_ _ _ _ _ Pipe,.cigar____________________________ Cigarette.and.othcr____________________ Cigarette.onl'y_________________.________ Total--------------------------- WOMEN Never smokedd regularly,_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Cigarette____________._______ Total--------------------------- ssEN Never smoked regularly _ _ _ _ - _ _ __ _ _ _ _ _ _ _ Pipe,.cigar____________________________. Cigarette and other____________________ Cigarette only.____._____________________ WOMT.N Never smoked regulnrly ________________ Cigarette_____.________.________________ 6eucr_.EI C..Henvnand (47). 66' 0-5,1 ~,1 &~741 CVLdeath.rates per 100,000'person-years. 28 25 28 42 35 18 38 25 11 00 .89 1. 00 1.50 1.00 2:11 92 349 100 369 129 361 130 477 116 391 57 228 88 315 64 238 1,358 '. 1,371 990'. 1, 168 1, 272: CVL mortality ratios 1.00 L. 09 1!. 40 1.41 I 1. 00 1. OB 11. 03 11. 37 1.00 1.54 11 00 11 38

tional , aers aj ; they male certi, myot alsd ;ych as qapor- ns rosis rate, biogy I'--- ab bed gen sue' re- us~ of r hiomechanisnn may help to explain why cigarette smokers have such an increased risk of developing coronary heart disease and of dying from it. An increasing amount of evidence has been accumulated in the past few years relating,the development of clinical cerebrovascular disease to cigarette smoking. Most of this information has come from mor- tality studies (17; 18), both retrospeetice and prospective, which show that both male and female smokers of cigarettes under the age of 75, as compared'to nonsmokers,,have higher death rates from cere- brorasouaar disease designated as the underlying cause of death on. their death certificates. This may be especially true for younger ciga- tette.stnokers age 45-54 where males had dieath rates about 50 percent higher than nonsmoking males; andi females had.death rates about 100: percent higher than nonsmoking females! Under age 75, mortalityy ratios for stroke increase as the number. of cigarettes smoked.increases. No association has been shown for. those aged 75 and over. The, new epidemiological evidmnce,, then,, indicates that cigarette smoking may be more closely associated with cerebrovascular disease thany previously indicated in the population between the ages of 45 and! 74 years.. Iif cerebrovascular'thrombosis (thrombotic brain infarction) accounts for'this association, it is possible that some,of the considera- tions of how cigarette smokingmay produce coronary thrombosis also apply to the pathogenesis of cerebrovascular disease'.. Further research is essential to understand the.reiat'ionships which exist between~ ciga- rette smoking und cerebrowascular disease. Additional epidemiollogical evidence from prospective mortality studies provides confirmation that cigarette smoking,is associated with inereased death rates from aortic aneurysm. (nonsyphilitic),, for both. menn and women. In one study of male smokers an increase in d'eatli, rates was noted with increases' in amount smoked. fIIGHP.IGH7PS' OF CURRENT INFORMATION 9is- 1. Additional evidence not onlyy confirms the fact that cigarette for smokers have increased death ratesfrom coronary heart diseaseifiut an 9190 suggests how these deat'hs may be caused by cigarette smoking. lier. : There is an increasing convergence of many types of evidence eoncern- ity ing cigarette smoking and coronary heart disease which strongly sug- ~prts gests that cigarette smoking can cause death from coronary heart ~ disease: ea- i 2. Cigarette smoking males have a higher coronary heart disease ~ death ratethan nonsmo&ing,males. This death rate may,.on the aver- ~~~t age, be' 70 percent great'er,, andy in some„ even 200' percent greater. or ¢7 : V~;.;-d<`,AV : ~

V F r nitrous oxide (18, 44) and the R,ubidium 84 (15) methods toa measur coronary bliood flow. In response to, nitroglyceru e the normal indi ~ vidiuals generally increased their coronary, blood flow significantly, but the coronary patients generally didl not. Aanmal studies. have also demonstrated the decreased ability of', atherosclerotic coronary arteries to increase coronary blood!.flow, as,i, compared to the coronary arteries in normall animals (94). Dogs withp experimentally produced coronary artery insufficiency allso show this decreased ability (12). Similar differences between animals with nor-I ma1 coronary arteries as compared to atherosclerotic coronary arteries, have been demonstrated'in response to ergonovine (80).. ~ The above studies indicate that the effect of nicotine upon the.car- diovasculhr system, mediated in part by the action of released cateehol, ~ amines, is generally to increase heart rate and cardiac output, and tl raise systemic arterial pressure.temporarily.,Findings concerning they effect of nicotine on coronary blood flow are presently thought to be- largely due to the indirect effects of nicotine upon the cardiovascular system. Other animal studies indicate that there maybe a direct action' of nicotine on the coronary vasculature to increase coronary vasculaa; resistance; thus tending to, reduce coronary blood flow. Thero are noi Imman studies on the direct action of nicotine by itself'an the coronarg ' vasculature; such studies, involving the direct injection of nicotine into diseased human coronary arteries, might be dangerous: 16Tormal: individuals apparentlyy can increase their coromary blood flows to eom-j pensate for the increased myocardial tissue oxygen demand,,but ap ` parently some pati'ents with coronary heart disease cannot, as shown by their response to smoking: ; Thus some patientswith coronary heart disease may be at a par-, ticular disadvantage when smoking, and under other stresses since, their coronary arteries apparently cannot dilate to supply blood flow adequate to meet the inereasedl oxygen demand associated with nico- tine-induced catecbolamine release. The interaction of the above ef- fectt with recent findings concerningcarbon monoxide, describedlin the next section, may be especially important in those individuals with, coronary heart disease. The present studies indicate that the effect of cigarette smoking on coronary blood flow,, in the presence of pre-' existing coronary heart disease, may, in part, contribute to the in-' creased incidence of acute myocardial infarctions that have keenI observed to be associatedi with cigarette smoking. No relationship be- tween tween the smoking effect on. coronary blood flow and'the pathogenesis of coronary atherosclerosis per se is presentl'y suggested. Additional research is needed. { C, ¢rb on D1'onaaide Effect The gaseous phase of cigarette smoke contains about 4' percent car- bon monoxide: This: quantiitry can inerease the levels of carboayhemo-

,~'~'IRP am

Bhtween the ages of 45 and 74 the death.rates from stroke for male smokers were 37 to 50 percent higher than those for mald' nonsmokers of comparable age. In female smokers the death rates from stroke were 38 to I11. percent.greaterthan those for nonsmokers. Above : the . age of 74 the difl'erences between the two groups were much less.. The data in Table 116 concerning'smoking and death rates from stroke are derived from the U.S. veterans study (52). TAncE 16y tYtortaltity ratios and death rates for stroke as underlying cause alruong, current smokers of cigarettes only Quantitry of eigsrettes smoked pec day. 0 I 14 1 10L20 1 ~ 21-39 . I 40+ >Cnrtalitr~ ratio~. (all agee)__ ___-_ 1.00 1.51 1: 42 1-.70 I'.. 59 ])~T1111 rates: accaato~64___ _ _ 59 92 112 125 130 ,1cn 65 to~74.__---__---_-- 280 ~ 323 312 382 502 -aU 9. ec[ervns study. (52). TS~"hen stroke was certified as the principal cause of death, the death rsres for smokers were higher than f'orr nonsmokers; however, no pro- nonncedd increase .vas noted in the mortality ratios as the degree of =mu;king increased. The death rates from stroke for all ages; was 59 prrcenC' higher in heavy smokers (40 or more cigarettes) than in uonsmokers. TABLE 17.-Mortnlity ratios and death rates for stroke as the un.derlyzng orcontri&utorydiagnosis am.ongg curren8smokersof cigarettesonl'y )f ortal ity ratio. (alll agcs) L ------ Death rates: Age 55 tb~64______________ -----tu ~ 74--- - ----- -- - - - 1.00 101 424 Quontity o[dgsrettes smoked per.day. 1-9 1..45 152 514 1.45 174 520 21-39 1.75 1.95 616 2 6 724 1.£3 9dc®ce: U:9. uetersvsstudy(BS). Stroke, listed as either the underIying or contributory cause of death on: the deathcertificate, was also associiutedd withprogressively increas- ingmortality ratios and deathratesastheh extent of smoking in- creased. bl'eavy smokers here had an 83 percent greater mortality from stroke than nonsmokers... Mortality data by underlying cause of death may often be mislead- ing; parti!cularly when stroke is eoncernedL, Many stroke patients have 67 d

MuZfipdedr'iak E¢ctora The method of anal'ysi's.trad'itionally employed'by epidemiologists, that of the comparison of rates for multiple cross-classifications lof tllle data, generally reqpires a l'arge.study population at relatively high incidence of signi&cant ev.ents.. Since coronary heart' disease incidence rates are lo c and study populations are necessarily small because of practical' and' practicabie limitations, defiinitive analysis of the inde- aald data. from the~ f+TIP study. include the observed associations of,, operates; Ti he pooled data fcom~ the AIbany and Framingham sttrdies underlyingpathophysiologicalmechanismst.lirough vhichariskfactot PP iildings from these analyses might provide some insights into the of each risk factor on.each of the subcategories of coronary disease of'a more complete analysis of the independent and'synergistic effects~ ing of'data from some:of the larger prospective.studies holds promise, definit.ireconclusions on any differences observed. IYowevery the pool,' mnriSy because the paucity ofl events in each category did not permit; the observed' coronary events into the three majpr subcategories pri- factors to the ineidenceofe coronary heart disease have not subdividedi Generally, investigators iiI their analysis of the relationship ofrisk uted!to coronary heart disease; 2. Nonfatal myocardial infarction; and 3. Angima.pectoris: 1.. Fatal myocardial infarctions, inchuding sud'dendeaths attrib festations or subcategories: Coronary heart disease is essentiallycomprised of'three major mani- m alit~,q, and blood pressure"' (95). MAIYIFES7PATION oF(,onoNARY HEART DISEASE aside from age itself,,are cholesterol, cigarette smoking,E.CC"r abnor- tations permit the conclusiom that "the most important risk factors, Consequently, Ti ruett and Cornfneldi believe that the present compu- tion given by the fmnct.ionn to observed rates is very good. risk function are not fullyy sati'sfiedby'the actual data, the approxima- heart disease. jVhale theoretical considerations underlying the logistic t'ar with respeet_t'o the other six factors in the development of coronary factor. These coefficients represent the relative importance of'each fac- stricted to two~ factors.at a time. Truett (95) applied a multiple lbgistin functiona proposed by Cornfield to investigate the independent effect on the incidence of coronary heart disease of seven risk.factorseAge, serum cholesterol, systolic blood pressure, relative weight, hemoglobin, cigarettes per day,, and ECG abnormalities. TLhe method was used in the analysis of data compiledi in the Fiamingham study during a 12-year period. A discriminant function coefHcientwas computad for each risk pendence andl interaction between risk fact'ors have generallly been re-. 58.

patients with coronary heart disease, evidently more severe, could n increase their coronary blood flow rate enough to compensate for decreased oxygen carried by the blood. Thislatter group of patien even though they had i!ncreased cardiac output, had less significam increases of coronary blood flow than those noted in the first grou of patients.. The coronary arterial-venous oxygem, differences and th myocardial tissue oxygen uptakes both decreased, indicating that th myocardial tissue oxygen demand was not being met entirely:. The reduction in the amount of oxygen. available too the myocar tissue caused by the absorption of carbon monoxide from toba smoke may be especially critical in persons with pre-existing corona heart disease; especially when they cannot significantly increase coror nary blood fl'ow to compensate for increased myocardial tissue oxyg demand The carbon monoxide effect may, in part,, eontribute to th increased incidence of myocardial infarctions that occur in cigaret smokers. Additional research is needed. Studies on In Vitro Tkrornbus Formation Recent studies have indicated't that cigarette smoking mayaecelerate thrombus formation of human bloodl in.vitro_ Platelet adhesive as measured byin vitro tests,,also appears to be increased.by cigare smoking (1, 43, 71„87). Other studies; comparing smokers with no smokers„ indicate that the platelet survical time of the smokers shortened (73) and the platelet turnover rate is increased (7Q).. Studies of'animals shotv there is also. an increased tendency for the platelets to adhere to the vascular endot.helium. Platelet adhesiveness.is reported to be increased in i-n vitro studies using the Chandler rotating Ibop (3£, 33; 3¢) ; these studies generally' show a consistent acceleration of the rate of thrombus formation: Other in vitro tests show changes in thrombus formation and some parameters~.of coagulation as; a result~oflsmoking~ (56; 66,.87):. How" ever, problems in experimentall design and the multiplicity of tes used; measuring either the same or overlapping portions of the com- : plicaterl coagulation process with varying results, cause difli'culty in evaluatingthese results (71). The mechanism of changes in characteristics of the platelets smokers isbeing, inn estig,ated, but there are indications that the release of catecholamines„ especially epinephrine, caused by the absorptio of nicotine during smolting may be intimatelyy invollved (71, 7$). in small doses, epinephrine has been shown to promote thrombus forma- tion and eoagulktiony but in large doses it inhibits these proceases Changes in. t'heelectlrical charge of t4le platelet membrane have aIso been implicated in increasing platelet,ad'hesiveness (101)',increasing adherence to the vascular endothellum, andd aceoleratingg thrombus formation as measured by the Chandler loop method. Some of the~ alderationsin thrombus formation may be mediated by aminteraction"~ 64 i

ity (37; honomi se with' mt data l heart ei Fra ratio mok 2..9 2.4 1.6 non- ylder rked' her mor- t,'on 0ro- ysse 000 Im- pk- nt, Ing W he le- ~~es TentE B.-Alge-ezdjusted m.orbtidity ratios for coronary heart disease among smokers and nonsmokers, according, to level' of systolic lilood IlressMre. Swto4c blood pressme: Ciidcr130 mm~..BIg~._-.-_____---_-.-.--------------- 1130 mm.t£g,and over_-.------------------------ Nbnsmokers of clgevettes 1..0 1.8 6lgerette amoke s 2.1 318 ~orn<x: 10.year Famingham and e.yeer Albany experlence (D0). High Serumz Cholesterol It is noti now conclusively known. if cigarette smoking, by itself can cause increases im serum cholesterol. Dietary influences as well as en- dog_ enous production and elimination of'cholesterol must be evaluated in cmcate'r detail' with simultaneous analysis of the roles of other risk factors, including smoking.. One study of a small population of' cwinsin Sweden, as reported by Lundman (67), suggests that smoking monozygotic twins tend to have lower cholesterol level6 than their. nonsmoking control'twins,,although thedifferences are not statistically si;_nificant. Other studies suggest that smokers generally have higher scrum cholesterol than nonsmokers (13,67, 88). However, given the presonce of high serurn cholesterol, smoking iilcreases the risk of cor- onarg heart disease (',95;,96)- The independentl any synergistic.effeetl of cigarette smoking is dem- onstrated by the data in table 9 d'erived from.the comliined eaperience of the Framingham and Albany studies (30).. T.~ar,a 9. -9ge-adjusted. rrtorbidityratiosfor coronary heart diseasearnoag smokerss ay( d. nonsmokers accord'ungg too level'l of serum cholesterol 3crum cholewerol]evel Low ~ . . . . . . _- . . --_ HighI .. -- .. .--- Nonsmokera or I eigaretle clgorettes emokere ll.0~ 2: 0 1.8 ' 4.5 : U,," isbclowmedisn. "high"ls aboxe medlau value of'.remm chloesterol. PorBCeI ]U-year Framingham and &year AlbsnNexpetlenoe (SO). PicTmzanary Fumcti;on; The acute effects of cigarette smoking upon pullmonary function are expressed mainly through increase in airway resistance- The dif- ferences.in pulmonary f'unct'ionbetweem smokers andl nonsmokers ap- pear to be greater than can be aceounted for by acute effects from a recentlyy smoked cigarette(50r91).. The relationship of coronary heart disease.to lowered pulmonary function as reflected by low vital capacity and. cigarette smoking is observed in the data published by the Na- 2RS-3940~-37- 3 Le._ _ S 55 }f. `t

concomitant coronary heart disease, or may develop pneumonia and other complications that may hasten death. The death certificate may carry stroke as the underlying cause or as the contributory cause of death, depending upon the,interpretatfion of the physician at the time: The important addition of these data is that smoking is associated with.a higher mortality from stroke, whether the stmoke is recorded as either the underlying cause or as the contributory cause of' dt:ath: Ti hese two studies indicate that smoking may be associated with a higher mortality from stroke in the relatively younger age groups (under age 74). More than one-half the strokes that occur each year are in the, group above age 75 and in, this group there is no evidence relat.ing. smoking to cerebrovascular disease:. Another large study has been conducted analyzing the mortality of 50.000 former students who entered Harvard University or the Univer- sity of Pennsylvaniaduring the years 1916'S0 (74„76, 76). From this population 171 deaths from cerebrovascular accidbntshave been identi- fied: A review of'the medical records from their eol'lege years has been carried out, and selected factors were correlated with the later occur- rence of stroke. Seven precursive "risk factors" present at the time of coldege attendance have been defined:. Cigarette smoking, liigh blood pressure,escess body weight, short stature, a.history of early parental death, a history of nonparticipation in college.sports, and a history of "lieart consciousness" (also shown to: be correlated with coronaryy heart disease).. Cigarette smoking and a1istory of earl'y parental d'eat'h were more st'rongly correlatedi with thromboticst'roke than with hem- orrhagic stroke. Students who smoked' more than 10 cigarettes daily were at twice the risk of having a fatal stiroke than were those who smoked less or not at all. In.1965'the FrarningT am, study (54)' reported that while an escess'' development of thrombotic brain infarction appeared ta.be associated with: cigarettesmoking, statisticall~yy significantt differences couldd notbedemonst'rated with the small numberof cases available at that time.. hfbre recent data fcom Framingham indicates that cigarette smoking inereases.the risk of stroke in males. The relatively small number of women smokers had too few strokes.for adequate analysis. The new epidemiological evidence, then,, indicates that cigarette smoking may be more closely associated with cerebrovascular disease in the population between the ages of 45 and'74 years than was previ- ously indicated. If cerebrovascular thrombosis (thrombotic brain in- farction) accounts for this, association, it is possible t'hat some of the considerations of how cigarette smoking may produee.eoronary thr.om- bosis a19o apply to.the pathogenesis of cerebrovascular disease: Further research i's',essential taund'erstand the relationships that exist between cigarette smoking andd cerebrovascular disease. 68 ea- ~

the prevalence of'these conditions,, as Lundman concluded; "was too low to permit of definitive conclusions."' Blood from the smoke-exposed lhng tissue of'dogs, directlyy perfus4 of cateclmlamines brmyocardial chromaffin tissue (641).. resultedl from sympathetionervous system.activity or f'rom the re1'ease similarly reduced. It was concluded that these responses to nieotine crease in.cardiac contractile force was also observed that could ba; cular resistance (38, 64.). This response could be reduced by vagal nerve stimulation or prior adminstration of acetyllcholine •,, an immediate in-" der conditions of constant flow rate resulted in increased coronary vas- D"areet injection of nicotine iiitathe left coronaryartery of dogs un~ significant. observed in t:he particular normal persons studied, it was. not though a trend towards a slight increase in, coronary blood flow was not reproduced in a more recent study (IB).. IIm this latter study, a1= blood flow in normal men;, in response to cigarette smoking (11), were caused by cigarette smoking:. Earl'ierfindings.of increased.coronary dfium despite the increased nzyocardial tissue demand for oxygen sufficiently to maintain a. compensatory blood supply to. the myocar- apparently normal subjects can increase their coronary blood flows The action of'smoking and/or nicotine on the coronary blood flocc of normallhumann subjects has not yet been definitively established, but cardiovascular system (16;.63, 85). Coronary Bdood Flom in Nbrnaad S'iubjends postuln,ted mechanisms of action involved in nicotine''s effect on the Iation of sympathetia gangliay release of norepinephrine from locali stores, and release of antidiuretic hormone are included among other vascular system is more compllexhhan the release of catecholamines from the ad!renall medulla. Direct and indirect (via the carotid body andlotherclicmoreceptors) stimulhtion~ofthevasomotorcenter,stimu- effects can be blocked by the injection of tetraethylammonium chloride andi markedly reduced by adrenalectomy (Q$).. Nicotine has been re- peatedly shown to release endogenous catecholamines (57, 58, 59, 60, l0?). However, the mechanism by which nicotine ~ affects the cardio- served with.catecholamiires (epinephrine and norepinephrine):. Tlie; section under a separate subheading. These effects parallel those ob-' , contraction,, alll resulting in an increased myocardial tissue oxygen demand (16). Coronary blood flow studies.will be reported in the next physiologic effects on the cardiovascular system of experimental ani: mals and of man.These include increases ire heart rate, systemic arte- rial pressure, eardiacnutput, stroke volume, and velocitynf myocardial CanmovAscLZ..aa RESPONSE To Sbrosxwa Axn/on NrcorrNn 2Gsnoted in the Surgeon General's 1964 Report, nicotine has definite 60

P measu Inal indT enificantly, 1 ibility ©, 3flow, )ogs wi Shocv thi icith no Y arteri x the car catkehol it, and t rning t ght to be, )vaseula .ct action vascula'n re are no coronarg; nicotine Normal: s tocom „but ap, show s G a par 'es since bodl flow 7th nico e bove.ef- ribed' in ~als~.witk Kect of !'of' prer thein- ;re been Rhip be- pgenesis ditional globin saturation of cigarette smokers from 2 percent to 10percent (91). The average nonsmoker, depending on environmental esposure;, nsuallk has less than 2 percent earbosyl'temoglhfbin saturation (10). Since smokers of one pack or more a day may have chronically elevated carbosyhemoglobin levels of'more than 4 percent (9), there may be appreciable differences in the carboxyhemoglobin levels between some. heavyy cigarette smokers and. nonsmokers: In addition to displacingpayhemoglohin, carbon monoxide effects a, shift in the osygen-hemoglobin dissociation, curve (2, 3, 4 5„6). This'i may result in a decreased release of'oxygen at the tissue llavel. A series nf'studies (61, 6°3) has been performed on young adults to.analyze the effect of cigarette smoking on carboxyhemoglobim levels, and the conserluent effect on some parameters of cardiopulmonary function. .\rt increased post exercise oxygen debt was observed after cigarettee amoking as compared to controls. This, in part, may reflect not onlyy vetuilatorv disturbances but also a decreased supply of oxygen in tllr blood due to the carbon monoxide effect, resu'lting in less aNailablee osvsen to meet the. increasedi tissue demand. Similar post-esercise ocv,en debts have been noted after inhalation of enough carbon monoxide to produce comparable blood levels of carliosyhemogl'obin (21), 'The consequence of the smoking/carbon monoxide effect appears to 8e esperially important in. the myocardium where relat'ivelk more nxcgen is normallly extracted fromtheaoronarycirculation as com- paredo t'o other organ systems.. (Coronary venous blood usually lv2s an oxygen saturation of less than 25 percent,wliereas blood leaving some other organs is about. 75 percent saturated witli.oaygen (I'5).)~ Dogs were exposed to carbon monoxide to elevate their carboxy- hemoglobin saturatlion levels (9)_ In response to inhalation of' carbon. tnonoside there was an inc.rease in coronary blood flo}v'but a decrease coronaryarterial-venous oxygen differences; Patients with crnronary heert disease were also studied following inhalation of enough carbon monoside to elevate their carbosyhemoglobin saturation levells to the rmage of 5 to 12lpercentl(9),. In response to carbon monoxide there.was >,renerally an increase in the cardiac output andi the coronary blbod flow in most of the.patient& While the systemic artlerial-venousoaygens differences varied, either increasing, or decreasing, the coronary ar- terial-venous oxygen differences decreased, indicating a decreased osygen extraction by t'hee myocardiall tissue despite the myoca¢dium's incre2secl demand for oxygen. These, decreases in myocardial oxygen extraction are related to increases in the carboxyhemoglbbin satura- timu levels. IIt was observed that some patients evidently could eom-pensate by increasing their coronary blood flows adeg,nately to supply the myocardiall t issue wit'hh suffieientt oxygen„ as indicatledd by aa risein. "nyocardial oxygen uptake in these individuals. However, the other 63 ~~

itimes the a'atios' fo intensity rvival of N of cor 'cigarett'e 11 qh aging ig dcat 'auses of need de- rver age resented w shows persons status. in death ~ group atl-e'to 9ith ad- ntinues 2.8 8 1.8 1.5 1.2 Isease I bd by T.4sf.E 4A.-Coronary heart disease (men). Age-standardized death rates for ex-ezgaretfe smokers with history of eigarette srnokting on1y, by former number of cigarettes smoked per day and years since last cigarette slnok'ing. Deatti,'rates far current cigarette smokers wiUi history of cigarette smoking only and men who never smoked regularly are shown for concpariaon. Men aged'. 80-63 9moked.1-19 cigmettes e day Smoked 20} cigarettesia day, F.ceiRarette smakers rince.lh'~tmigsrettesr Number Number Dmth Number Number Death, of inen ofdeeths rate of inen ofdeatbs rate I"nder 1.year_________ I to~.4 years__._._______ 5 roI vears-____-__ 10= vcars___'_______- 1'btal cx- smokers_ _ _ _ _ Curnent cigareGte smokcts___________ \cl~er smoked regu- I.'vIG'_____._____.____ 746 1,844 1,770 4,209 8,569 22,808 55„728 27 51 48 84 210 781 1,114 11,005 718 725 498 635 947 502 2,244 5,435 5,803 8,142 21,624 56,886 55,728 77 1195 152 206 630 1,895 1,114 f 1,070 1,003 732 679 813 1,029 502 'rnur or mcre, but less4hau79 desths cipentedtasome of the nompunent byeer'age gmupe. +orxcs:nnmmond„E. C. ((3'r). P. n81. nar7.vfud.Fliu Ta a prospective study by, Doll andi Hill (27) of morta'l'ity among ISrit ish physicians whose smoking haliits bad been previousLy recorded, there were 1,369' deaths irtthe course of 10'yeals in which the underly- i u;:'c:luse was coronary heart disease (2'Y, table 1). The physician popu- lat.ion utidcr' observation totaled 320,185'5 person years. The C1TD d,aths were classified into three major subcategories: Group 1,com- pnising 35 C13D dca.ths in which an associated condition reladed to ,m ck ing; e.g:, lung cancer, was recorded on the death certificate; Group -', cmnprising 721 CTT'D, deaths in which no other significant contrtihu- tory canse of'deatl] was recorded on the death certificate; and Group 3, rmu.prising, 613 CHD deaths which were' associated with some other rontribu'tory cause, including conditions known to predispose to coro- uary heart.disease, e.g., hypert'ensioni,diahetes, and obesity. The'CHD death rates for smokers and nonsmokers based only on Group 11 deaths, while suUjectto large vari¢tiony shosvt'he largest differentials (data not >fmwn), Among smokers of 25 or more cigarettes daily, the age-ad- justed CHDdeath rate was nearly eight times that in nonsmokers. P3asadl oniGroup 2¢oronary heart disease deaths~~ presumably uncom- I1lScatad by any other significant disease, the mortality ratio of age- ndjltstedd death rates among continuing cigarette smokers to, non- smokers is found to be 1.6, and for heavy smokers to nonsmokers the 61 M'

CHAPTER 2 Smoking and Chronic Bronichopulmonary Diseases (Nbn-neoplastic) CONTENTS PaQe Litroduction-------------------------------------------- 89 ' ('lircenic Bronchopulmonary Disease blortaIitS _ _ _ _ _ _ _ _ _ _ _ _ _ _ 9D~ ('ltconie Bronchopulmonary Disease Morbidity_ _ _ _ _ _ _ _ _ _ __ _ 96 tiaudies Relating Smoking t'o Respi~ratory Symptoms-___- 96. `'rt'.udics Relating Smoking~ to: Phlmonary.Functio¢r_-_ _ _ _ __ 99: Relation of Smoking t'o Heredit}.: or to Constitutional FacLors__ 101 P!ttlmlogy Stttdies-------------------------------------- T04 .9aiim.ul EsPeriments____ _._ ____ ____-________ _-___-______-_ 106 Piliatusic Effects'of Cigarette :Smoke __------- -------- ____ _ 107 (Yther Factors Associated with~ Cllronic, Bronchitis or Em, phcsem¢ or Both -------------------------------------- 108 Additionall Consid'erart,i©ns Regarding Smoking and Erm. phvaetna, ----------------------- - ------------- 110, ('".ted References--------------------- ------------------ 111 ti.9rplLmental. Referenaes------------ ___ _______ 117 E'!]r394 0-64 4 S7

I I i$'eren 1 TABt.e 6.-lltortali#y' ratio froms coronary heart disease among male Inger a, hypertensives and'nonhypertensinea by amoltin.g history and age Blood e 8e A m t - Nb ou t ge gr p art dtisems wr s a ua Pr n- mmokere r' evy ®nkere? HD clgerette ers P6 or more Per day .9 deaths at, ftr nsk to ' V I f 65 ren- I find non- that :rease witli other (117)I '' rved'd onaI 'iga- Oter ~nd- 45 to 54______---_.-__ NonH,yp eite ns ive---------- `--- 1.0 Z 2 Hypertensive`---------------- 2.5 9', 8 55 to~64------------- Nonhypertens.ive-------------- 1.0 58 Hypertens[ve----------------- 5. 9'. 9:4 , nypertensivet are d2fined as thare having syetolie tibod prmmre ef' 1BO.mm. Hg. or over or dfastbae hlondlPressureof95mm-Hg.araver:Nonhyperteosiaeshaveaysto11eb1uodprexmrel~thenlfiWmmi ng rx tl:aiohc hlood pcecntrellsvthan 95 mm. Frga t Nonsmokers in this Pertlcularr stiWdY ere de9ned.aattlnae nat mtukfog any cigarettesor IPSw thsirs.3U r:garettes per day. Bmokers eie those who smoke BUUr moreperday- 3orecc: Bothant, N. e:,.et al. p11: .\n analysis was made by Schor (8G) of 181 adult males who died f rom coronary heartt disease generally Iesss than 2 years after receiving a periodic health examination. The results of this study and those of Dol f and. Hi11' suggest that sudden death from previously undetected coronary heart disease frequently occurs among cigarette smokers. If this is true„it may, iiu part, account for the small differentials'in the iprecalence of coronary heartl disease between smokers and nonsmokers observed in sotne morbidity prevalence surveys. As will be described in the following sectiott„ longi'tudflnal, prospective morbidity studies dso show that smokers are more likelq to die fronm sudden attacks of f-oronary heart disease. Cosomnur HEntrr IDrsFass Monnml lln chapter 11 of the 1984 Surgeon General's Report, severallprospec- ricestudies.on t!]ieincidence of'coronary heart disease (Z'4,.~''1, 78, 88), established that smokers tvere subject to higher rates than nonsmokers. The relationship was reported to6e mmoremarkedl und'er 50 years of age than among older persons and appeared to be associated with myocard'ia1 infarction but not with angina pectoris. Since the: 1984'4 report, recent findings fcom Iarge-scalle; on-going prospective studies have been reported, providing additional insight on the interaction bet lceen smoking and other important' coronary heart disease risk fac- tors. Current findings are summariaed.in the following pages includ- ing tablhs 7 to 13. Whenever possible;data are shown separately for findings related to angina pect'oris and those pertaining.to myocardial. infxrction, including sudden death attributedltlo coronary heart dis ease. Higgins (50) has'drancn attention tot,he fact that`rntany factors; fuaw influence or be affected by smoking habits, and' obscure those differences between smokers and nonsmokers whichl are directly re. Inted to the use of toUacca" In her review of the li'taerature;, Higgins id'ent'ified differences luet ueen smokers and nonsmokers in ggnetically Also may includ0mortaSitydata: in thfia pregentation.. 68

«w , pTINE tas defini nental anl temie arte nyocardia ire oxygp in the n 1.those ob, rine). Th m c}dbrid is been re 58, 59, 60 !he cardib :hoIamines rotid bod ~ter,,stimu from loe nong othe ect on th blood flb tshed, 41u ~ood flowi r myoca r oxygt 1' corona (11)„wer study, al I,flow w was r dogs un anary va igalnerv tediate i ~ could o~.nicotin `he rele ~perfiu I 61 O. W ~'. D0 . ra , t into the coronary artery, failed to increase c,oron¢r}r resistance (38).Thaseffect was thoughttot be seeondaryto that of h'ustaminet lmown to act as a coronary vasodilator; which apparentlyis neleased from the lung tissue of dbgs dUring their exposure to smoke (8). . When blood from the smoke-exposed lung was perfused through the systemic circulation of' dogs while the coronaries were being perfused with non-smoke-exposed blood, the typical release of cate- cholamines, occurred with many of the usual effects on cardiovascular parameters exeept that the.coronary vascular. resistance increased under tihese experimental conditions, apparently due tlo the i'ncreased'. '. actirityof the sympathetic nervous syst'em (38). jince itis well known that exposing dogs to cigarette smoke without. isolating and separately perfusing the coronary circulation normally reeults in an increase ofl tlhe coronary, blood flow (38), the manipul_ationn of exI erimentall conditions as described suggests that there is a. niaskin,g effect by the catecholamines on. nicotine's direct action on olie coronary circulation. (38~)., 7liwse;tudies may relate;byanalogy,.to humans and indicate that smolcinw, in~ "normal" individuals, may produce at least two actions that can atTiect.coronary blood flow: (1) a decrease in coronary blbod. Iloxc b, v a possible direct action of'nicotine on the coronary circulation (demonstrated in dbgs), and (2) an increase in coronary blood flow as, rhe usual resultant of varying responsesto the intermediating I action of eatlecliolaminesandiotherphysiologicprocesses (demonstratedl in botiu animals and humans). O„wl?ary Blood Floca in Su5 jeeta v.+ith G'branarr,l fle4rt Disease The effeat of cigarettle.smoking on coronary blood flow was studied in p:Itients with coronary lieart disease (:79).. As was seem in normal hlarts, sigmificant increases i'nl heartratey arterial' pressure, and triltac output were noted... In cont'rastlto the nortmal individuals =tuilied, patients with coronary heart disease distinctly showed a mm•h less significant compensatory increase in their coronary blood Flores. These results were confirmed by a, later study (16)y using, the Rnhidium 81 metlhod to estimate coronary blood flbw. 1Phisstudy also *howed tjtatl in tlle coronary patients studfiedy there was no adequate i Compensatory increase in coronary blood flow to meet the increased mpocardial tissue demand for oxygen. Coronary blood flbw appar- ently decreased as a. resultof cigarette smoking;, in this particular tndy -nonpp of coronary patients_ Although the decreases noted were m t tuarked, tlieyy werestatist.ically signifi'cant, and i~ndicated that a difTerence existedbet seen these coronary patiettts as compared to the nnrmal subjects studied. A differenee in the coronnry hlbod flow response t'o nitrog)'ycerine hass also been demonstrated in n~ormaL subjects compared. to subjects tcitdk coronary heart disease. This was shown in studies using the yri "alA~ 1 na~

1IIlcould ite for # pati 3lgnifi iist gr t and that ely. igoca a toba 'corona 3ase co te ogy, tte to cigare cceler siven ciga rith no tokers . St'udi platele studi I nerall mation dsom . HDw of tes he com ulty slets i reL orptzo _ forma pcesses ke also ~easimg bmbus of the ~itction with serum-free fatty acids andl eholesterol (70) but current evidence eeSgeststhah inhalation of cigarette smoke acts primarily through other independent factors (101).. Thus,eigarette smoking may cause .n.accelerationn of the in a;itro thrombus formation.of human blaood.It is reasonable to~ suspect that cigarette smoking, in part by affecting the thrombus-forming process in human blood, may account for some of the.escess coronary heart disease deaths that occur in cigarette smokers; espeeially some of the deaths certified as "acute coronary thrombosis:" Further research is necessary before any definite con- cluFioncanbe made:, AIITOrs4 STQnn?s Thc t,'woanost sigpificant pathological studies of'the relat'ionship of emokind history to atherosclerotlic changes in human coronary arteries have 6een reported by Auerbach and Strong. Auerbach (7) studied 1,372 males for whom a.smoking history was available and who had died' of' causes other than coronary heart disease. He found that the lK1rFrntage of men with an advanced degree of coronary atherosclerosis wasl igher.2mongcigarettesmokersthanamongnonsmokers, and that the percentage increased' with amount of cigarettesmoking, Both amr,nr smokers and. nonsmokers the percentage of men witlbadvaneed curonarc atherosclerosis: al?;o increased with age~ This relationship held up even when the following were eseluded: men with a history of diabetes; men who; had died of any type of'heart disease; and men whoseheart'~sweighed 400 gm. or more. A matched set analysis was alsocarried out ('reiucludfing,some diabebics and heart disease deaths) m,~l again tlhepercentage of' men with advanced' coronary athero- ~clorosis was less among nonsmokers than among mem who had been current cigarette stmokers, and this peraentage increased. with the an ountsmoked. wtrong (89) in a study oflcoronary arteries from.645. auEopsied males, 20 to 64 years of age, eaclhded patients with diseases he thought to be associated with smoking (emphysema, lung cancer, etc.), or with coronary heart disease (myocardiallinfarction, hyper- tension, diabetes, stroke; et'e:)'. He found that the mean percent of coronaryy intimal surface occupied by raised atherosclerotic lesions Was approximately twics as great in lteavy smokers (25+ eigarettes/ day)',, and aboutone-thirdlgreater in light smokers (less than 25%day), than in nonsmokers. Galoi:fied lesions and mean coronary walll thick-ness measured radiographically were on the average highest in heaky smokers andl lowest in nonsmokers. Differences among these smoking categories weree generally greatest at' younger ages. These autopsy studies suggest that smoking,, in addition to the acute immediate effect associetedl with the act of smoking;, has a chronic effect leading,ta advanced degrees of atherogenesis. However, these findings may, in. party reflect the differencesnot;ed between 65

niologis eeations o ively big „inciden iecause the ind y been de loglst lent eff tors:, Age moglob lsed in a 12:yea: `each ri "each,fa x'coron ze logis ]proxims at com k facto ',G abno I . aorma i !hs attri ip of Ibdiixid ibries p qt pe t.he poo s prom tic effec ~disea E'into th ilsk facto m studi tions o' cigarette'smoking with each of the tlireemajor manifestations. Ititir- biditv ratios have been derived from these studies and are presented in table14. T.{enE 14. Age-adwsted morbidity rati;os for subcategories of coronary keart di:sease among smokers and nonstnokers Diseasecstegory Fatal myoeardialiufarction_-_______ Yon-fatali mvocardtal infaretion_.-_ _ _ ,{nqina penkoris~____________._.___-___ Framingham.Albsny Non. emokers of' elgarettes I, Clge!'etle ~okers. 1. 0 1.0 1.0 2.41 2.3 ' 1, 1 Health Insurance plan Non- smokersnfClgarettes Cigarette mmokers' 1..0 1. 0 1.0 2:,1 1.8 1.7 Socxce: Second Reporf of the.Lombined Esperience Jrom Altiauyand PrgmingLam Studies (f0). IIn. ;mtfl~hed nat.h from Heatth InsuraGCe Flsastudy{1t0). "Bhe association of cigarette smoking to angina pector s is not a~ con- =istant one. A clear-cut association was.found in the Health Insurance Plan Study (ratio of 1.7) ; a similar association is also found in un- t,nblished data from Fiamingham considered separately. Hbwever, no association between cigarettn+smoking and the incidence of angina pe,toriswas found in the Albany esperience., Cederlof (19), in his ;nalysis of prevalence data on angina pectoris obtainedl by question- naire. found no statistically significant difference in prevalence'rates hehccen 453 monozygotiotwin.paiis with dissimilar smoking habit's: In a larger study of about9,000 persons from the twin register where genetic factors were uncontroldedy Cederlof (19, .°ZO) did find' a sig- nitlcantly- hig)ter prevalence of angina pectoris among, smokers than nonsmokers;,partieulanlyinmen (ratioof 1.6) (G7).. 6'riedman (4z?) antb Epstein (:Y6)) have clearly described the in- inerent biases in prevalence'stu'dies which may lead to findings of risk graliielrt.s that arc different from those obtained in prospective inci- dence studies; One of these limitations is that fatall cases are under- represented in a prevalence survey. Thus, since it appears thatcigart ettesmoking is morecloselj* related to the incidence of'fatal myocar- dial infaratim s than to other forms of coronary heart disease, it is ea- hectetl that morbidity ratios derived from prevalence surveys would be lolcerthan those'eomputed from incidence data. `Vit1L these restrictions m mind, Russek (83) in aza survey of. 12,000 men in 14 oceup'ationall groups foundd that t he morbidity rati o of coronary heart disease preva, ]oncennaongcigarette'srnokerswasashigh as 1.8. In contrast, im a study ' nf 77 identical and 89 fraternal t}vi'nsin Sweden, compnring smokers rvitlih their respective nonsmoking t'wins, Lundnian (67): reported no'o eXcess prec¢dence of overt or silent coronary heart disease. However, 69, m r+ . an .*

tiphysi problems of definition and one of the difficulties of direct comparison ~atios between studies, especially when different countries are involved. irctortalii e numb TABV>; 3. Age-adjusted'' mortality, rratios for smokers of cigaret'tis only ~ dise" bynumber of cigarettes smoked' daily 6 stud I Clgaffettea'.smoked per day at'.entranea to study Cause of death ~cgar Non- smokers jes' tl] I 7 k in the Ilin the D those Bronchitis or emphysema or both_ _ _ _ _ _ _ _ _ _ _ _ _. _ Bronchitis with or without emphysema(500-502)_ Emphysema (527.1) ~____.____________._._________ 1.0 ' 1.0. 1.0 1i 6.11 7..0 4.8 10-20 tU:O1 13.7 6.1 21:+ 10,41 14.6 6.9 I Calculated from (1L).. Sounre: Canadian Penaioners study(/E): A study among British physicians;, the first of the large prospective stndies, was startedl in 1951 with the sending of a. short questionnaiire to the 59;600, registered physicians then resident in the United King- dom. Usablb replies were received from 34,455 men and 6,192 women. Ten years of observ.ation of mortality in relation to smoking was recently reported for this'popnlation.by Dall and Hill (29; 30).. Their findings on mortality from chronic bronchitis as related to smoking inoluded emphysema and are given in table 4'. Only the standardized death rates were presented in the report but the mortality ratios have been cal'culated from them~ to offer an easier comparison with the other two studies. Againy it is clear that mortality from. these combined diseases (no attempt wasmade tb, differentiat'e, . them inthe~ published report) is strongly and directly' related to the amount of cigarette sntoking. TABLE 4. St¢nd¢rdized death rates,, per 100,000 population, for broncAitis andd emphysemaa form.ader smokers of etigarettes on,ly,, by number of cigarett,cs smoked' daily Cigarettes smoked per dayy at entranee.to study Csusc of desth Never smoked 1-14 1524 25} Bronchitis; (fncluding cmphylsema-502, )27.1)__________.____________________ 5 34~ 64 106 M ortaitv~ ratios ----------------------- 1, 0 I 6.8 12.8 21.2 SOURCE: SuGarc: gtudyatBritish Physicians{t9.,.3E1). 93

his associates (IQ). Deaths from chronic bronchitis and emphysem'a combined are similar to those reported for the U.S. Veterans study, of cigarettes smoked. The mOrtalityy ratios reported for both. d'iseases is much.lLigher among smokers and is,directly related'o to the number the number of' cigarettes smoked each dhy. Here, again, the mortaliby have been summarized in table 3 which gives mortality ratios by' Tasa:E 2. Age-ad'justed mortality rattios for current srt-iokers of cigare only, 8y number of cigarettes smoked daily Ceuse of death Bronchitiss or emphysema or both (500-502, 5271)__._________._________.____________ Bionchitis with~h or~ without emphysema (500-502)~.____________________________ Emphysema(527~.1)_____________________ Saoacgt U:B. Veterans study(p). person-years, for eurrenG'.smokers of czgareftes only TABCn 2h. Age-speciftc ann7ral probabilities of death,h per 100,000 t. Cigsretteasmoked per day etentranee to study. OrBslonal or never. smoked Chronic: bronchitis andlor emphy sema: Age 55~ to 64._____________ Aga65 to 74_______._._____ Chronio.bronchitis: Age55.to 64_______.______ Age65'.to Y4__ ___________ Emphysema~without broncbitis;~. Age 55~to 64_____________ Age 65~to 74________._____ VVhen the two-diseases are separated,.the ratios for emphysema in the Canadian study are simil9r to those for chronic bronchitis.in the U.S. study, the ratios for chronic bronchitis are similar to those attributedd to emphysema inthe United. States:This illustrates the person-years of observation at aoy single year orage In the 11LLyear.lhterval. Sooacz: U.S. Veterans study (4i).. welghtsproportional to thedistributlonoOtHe U.S.male populatlon In 19fi0. Not shown It]ese than SU. 2 12 2 30 10 66 00 1I4'1 I 5 5 51 15 22 30 7 27 26 52 78 Ill 39 322 5 46' 34 276 I Annual probabilitles'of death eteadr.a0ogle yearof ege wereeombined Yuto 14yeae ege graups by using 92

INTRODUCTION F uxro sE oF,Tf3I s~. RF.ISoRT This reportl reviews additional pertihent data relative to smo'king, uwdl chronic bronchopulmonary diseases-specifically chronic bron. rhit i4a nd pulmonary emphysema.. Tltc ruader is referred to the Surgeon General's 1964' Report (68) rnd nvcnt textbooks for background information on the chemistry of to1iiven smoke, the metabolism and toxicity of specific components of tobacco smoke,, the physics of its retention in the air passages andl the htu:es„and!the mechanicsof pultnonary function. DEFINITION6 'I iL'.-e.opeof this chapter will be limited.to emphysema and chronie: bmncs itis and it may be.useful to present definitions of both terms. There iiace been many definitions of chronic bronchitis and emphy- a•wa.. 1'hose.usede in the Surgeon Geeneral's.1964'. Report had been pro- pnsecl by the American Thoracic Soci'ety in 1962 (37). With the in- cmasiut_ publfic health interest in, chronic bronchopulmonary disease, nttempts havebeem made to develop precise definitions to ca.tegprize the=e diseases and to dsolate them satisfactorily from other pulmonary conditions. A task force sponsored by the. Chronio Respiratory Dis- oa~a Control Program of'the Public H'ealth Service and the National 'Pulnrcnlosis tssoeiatilon deliberated this together with related prob- 1'ems for ai week in O'etober 1966, They adopted the following d'cfiintions (7Y) : ~%an c&ronchitis is a clinical disorderrchanacterized by excessive mucous secretion in the bronchial tree. It isma,nifested by chronic or recurrent productive cough. The diagnosis of chronic bronchitis can Ne made onlyifotherbronchopulmonary or cardiac disorders are ex- chtded as the cause for these symptoms. The predominant pathologic rhanc+c is hypertrophy andhyperpiasia of the mucous secreting glands in thetraehea and bronchi.. PuZnwmamj empkyaema is an anatomic al't'eration of' the lung charxcterized by destruction of albeolns walls accompanied by abnor- mal enlargement of the air spaces distal to the terminal, nonrespira- torybronehiode:'These definitions willl be used to describe chronic broneMitis and empbysema~ as understood im the present report'. They are being used 89

Iar 93(49:: :I eiga- lies of stitute (E7)RINzLER, S. R':, TRavELL, 71, KARP, D:. Detection of coronary. atheroscl2- rosis in theliviag anlmall Sy the ergonovine abress test Science (Wash, ingtoa): 121'r 900, 1956. 181) . RosL:+nrAN, R,. H., FRtfipaeexs M.,. JsmExas, II.,, &rsxUa,. R., WvRac, ML, %osrrcHrg;, R. The predictionn of immunity to,coronaryheart disease. Journaliofthe American Medical Association. (Chimgo) 198.(11).:.1159:- 1162, DCC.12,1966. (F2): ROBEsnsAN, R..H'.,,Fag:DmAN;.M.,.SvaeIIa,.R., WusaL,MI, gosTICaE%, R''., HAHN,. W:,. WasTaaessN, N. T. A predictive study of coronary heart disease:.JournaP.of the.American:Medical.Association (Chicago) 189(1).: 15--22;,Julg 6, 1964. [Data iD Table13, this chapter, Unpubl7shedl) i o-I l RessEa„ H. I., Stress, tobacco, and coronary disease in >IortLAmerioan professlonalgroups.. Survey of. 12,000 men in. 11 occupational groupsj Journal of the.Ameriean. Medical Association~ (Chicago) 19`1(3).r.189- 194, April10;.1965. 6Aisse,. E. J.,. MACMAauN,. RI Cigarette smoking among.g high school stu- dents related to social classand parental smoking habits:. American Journal of Pnblie Hea1tL.andthe Nation's Il'ealth. (New York) 51(12').: 1750-17S9;.December 1961. S+yANEx, M., AvraDO, D. M. Cardiopulmonary effects of tobacco and re, latedi substances:..III. Pulmonary vascularr effects of cigarette smoke and nicotine. Archives of Environmental Health (Chicago)I 12(6).: Z17-724', June1966: ~'tiJ~ SCHQR,. S. S., ELSOM, $L. A:.,, EL9oM, K. 0:,. DIINx, .1., P. An evaluation of the periodic healthh esamination: A studyof factorss discriminating BetYCeen survival andl death fromm coronary heartt disease. Annals of Intemal Stedicihe (Philadelphia) 61(6): 1006-1074, December 1964'. ~: 71 Soowafy R. K., JasH¢,. K. C: EfYect of cigarette and biri smoking and tobaccoo chewing on blood coagulation and flbrinolyticactivity. Indian Heart Journal (Calhutta:). 17c 238-212„ July1965:, (Y3): 8rgrv, D. Ml, NATHAir;, D. T.. Smoking. habits and coronary atherosclerotic heart.disease. Journal ofltheAmerican Medical Association (Chicago) 177 (10) : 6LL4-688; September 1961. (•G9.) . STRONG. J. P.,.MOGN.L,.H. C., Jn, RICHAEDe,.,M. L., EOOEN,.D. A. Relatlon~ ship between cigarette smoking habits and coronary atherosclerosis in autopsied. males. Circulation;, Journal of the: American Heart Associ- ation (New York) 33-434 (Suppiement 3)< 311„Oatober. 196d (9p). SFSiE, S!. L., HORHANI;, N.. 0., RUEcIIrt.Er, R. W. Cultural mobility and coronary heart disease in ann urban area. American Journal of Epi~ demiblogy (Baldmore) 83(3):: 334-946',. November 19661 ( 91)SrscE, S. L.,„ HrarwN,. M. ML, E.YxeaLlaE, P. E. Somee social and cultural factors associated wtth thee occurrence of coronary heart disease: Jour nal of. Chronic Diseasea ( 8t.. Louis)17:: 277-289;.1964:. (52)SxME, S. L., REEDm, L. G., editors. Social stress and cacdiovascular dis- ease. Proceedings of the National Workshop C'onference.on Socio2nviron- mental Stress and Cardiovascular Disease, Phoenfa„ Ariz., Feb. 14'4 to 16, 19G6. The: Milbank Memorsal. Fund QuarterIy(New York). 45 (No.. 2, pt..2) -:1-192; April 1967. (93) THOMAS,.C. B.,Charaeteris[ics of smokers compared withmonsmokers In a population of healthy yonngadultc;.g Including observationss on family bistory,plood pressure, heart rate,.bodyweight, cholesterol, and certain psyehologicc traits. Annallt of Internal Medflcine(Philadelphia) 53: 697-718, October1960: 75

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(94) Taevsa.r, J., Rxazun& S' H., KAar,.D. Cardiac effects: of.nicotine in the for.EffiperimentallBiology and Medicine (New York) 123: 1R4-179, 1966+ (d00) WELNeLArr, E. Personal communication. Health Insurance Plan of'Greater '; New York, Apr..17,;1967. ~. (101) 1'FFRLS, El,. ScnnsvELREna,. H. Activity of nicntineande inactivity of kalin likreln and kallidin in aggregation of blood platelets. Nature(Londbn) ' 207: 871-872, Aug: 21, 1005. +~] (102) IS'EsTrAra,. T. C1„ CrroLLoxa, P: B., Enur~ooivwz, A. C1. Influence. of'f pro- + pranololi on homodynamic changes and plasma catectiolamine lecelss follbwingg cigarettee smoking and nicatine: Proceedings of the Society 3S7pp. ington.7, U.S,. Department of Health, Education, and Welfare, 1964. Committee tothe Surgeon Genera[.of the Public Health Service. [Wash- (99) U.S. PUSLxcHeALTa. SenvrcE: Smoking and Health. Report of'the Advisory 57i pp. Series 201. No. 2, Public Health Service. Publication No. 1000, June 1966 mentt of! Health, Education,, andWelfare;, Vitall and Health Statistics (98) U.S. Pvnnxc HsAr.xa'. SERVICE. National Center for Health Statistuce:.bfor tality trendss in the. United'States : 1954-63'. Washington, U.S,. Depart tion No:1000; October 1966.45 ~pp, Washington, U.S. Department of Health, Educationi and Welfare, Vital and. Heal.th Statistics Series' 20',. No. 4, Public Health Service Publica- tality from diseases associated with smoki'ng: United States, 1950-frt. (97)L'.S;PURLIC HEALrHSeevacE, National.Center for Health Statisties.. ]slor-' cation,.and Welfare, Publiu.Healtb Service;.PublicationNo. 1515, 1966'. (96). U.S. PusLxc HEAxau SERxzcE; The Framingliam Heart. Study. Habits and Coronary' Heart Disease. VEashington„U.S. Department of Health;. Edu- of' coronary heartt disease in. Framingbam.. [Unpublished. ] 266 pp. (95). TRUETT, Js„Coa:rrm,p, J:,. KAalvnr;, W. A multivariatee analysis of the risk. York Academy of~ Sciences. 90: 290.301, Sept. 27, 1960. rabbit with experimental coronary atherosclerosis. Annals of theNew' SUPPLEMENTAL REFERENCES 81. AaxxTAnE, et K.. Effects of. nicetine' andl tobacco smoke on blood pressure'1',' and release of'f catechol amineas from the adrenall glands. BkitishJournal { of Pharmacolbgy and Chemotherapy(London), 2:i1:, 515-52C.',. Uctober' 1965. 82. BALOxv, J. An2ERi. ~I., Rnscn, J... A. Cerebrall thromboembolism. AA dinicall appraisal',of 100 cases. Neurology(5tinneapolis).16: 559-564, June 1964. S34 BeLLET,.. S,. Atrial fibrillation intlie elderly patient. Geriatrics (Tfinne-~ apolis) 2T~(11).:'. 234-245',-N'ovember1906;. 84. BRBT, E. W'. R.,,WALKER, C;..BI,;BAIiER, P.,M. DELAQpts, F..U., SLCGREeeB,.~ J. T:,.:ifcKi:NzxE, A.. C. Summary of a Canadian study off smoking'and health. Presented at the Annual aCeetingg of'the Canadian. Public Health~ {i Association, @uebec; June 1, 1966. 7 pp. S5: BESTEaunN; E., MYAT;..G., TRavwm, V. Diurnal variations of platelet sticki-q nesscompared wittih effects's producedl by adrenaline:. Britfisk)fedical.Journal (London) 1: 597-4'i00;,SIar. 11„1967. ~ 86: Buao,.B. J. The effect.of nicotine and vasopressin on capillary capacity.'andy capillary blood', flow:, [Unpublished. ],7 pp:. ~ 76

I pia and te may ause of le time: ociated rded as tb. with. a groups h year 'idence lity of niver- m this denti- s been. sccur. time blood rental :story mary 3eath hem- 0aily who fceSs ated. not ime. SMOKING AND A;OE2.TPC' ANEUR1PSbi Idditional information on mortality d'ata conczrning, aortic aneu- ry:sm has been provided by the U.S. veterans study (52) and the Hram- mond. (47) studies, as noted in tables 18 and 19, respectively. T:asxE: 18.-Mortali6y ratios and age-standardtiieddeatfb rates for aortic aneury,sm in U.S. uetera.ns,.eurrent smokers of cigaretles only )t~rtg]itC ratio.---_---------- _ DEATH RATES Age: :ib to84----------------- fi5to 74~.-------_---. .,racs C.S.veteraos. tudy(9L). 1' lanE 19.-3lortality ratl.os and age-standardized death rates for aorttc aneurysrrt. 1(ortality ratio'.------'------------- Ik:atFirates---_--_ E Siimterv in parentheses indicnte death vat® of thnse who never srnoked regolarly., ~ornce: liammand, E. C. (yZ). It is apparent that there is. a close association between cigarette sinoking and death caused by aortic aneurysms; Thus, the additional.et+idence. conflrnus the previouslyobserved'nsso- 6ation between cigarette smoking and death due to nonsyphilitic aortlic aneurysm. CI1?ED REFERENCES ( l) Asnaz, P., DwyEr, A. W:,MtrJ:ns„J. H. D. Smoking and platelet stickiness. aancet. (London)2:.158-159, Smis24, 186i. !?a \sTncP, Pl An abnormalityintheosygendissoeiationcurveoftiloodlfrom patientsmith Duerger's disease and, Patientswitti nonspeciHC mfocar- ditis, Lancet (Lnndon) 2:1552-1754rNov: 28,.1964.. (-7) Asxati'r, P. Den•.kliaiskebetY.duing,af forskydninger iioksihaemoglotlEnets'dissociations-kurve. Nordisk Medicih (Staakholm) 76:I63.-I041. 1986. -•,/t: !.

S7, B[seAEOr;. A. M., WASesaMANN,. G. F. Releasee of cateeholaminess from~ adrenalinogenic and noradrenalinogenic tissue by the aetion of nicotine. "in; vitro." Archives Internationales dePharmacodynamieet de Therapie(G'and) 159'(2) :: 424-433, 1966. 58. ByAexnunN, H:, PAarax, H: W:,. %Ers, A. The.inter-relationsof el.'ectrocardi- ographic Hndingss and pliysical etiaracteristics' of middle-aged men., Acta .lledica Scandlnavica. Supplementum(Stockholm). 460: 318-341,. 1067.. 89. BLacaaunN, H:,. Taxtoa, H:. L., PAanrrr, 11 W., Hxnr.arsai J., Ezxs, A. Physical activity of occupation~ and cigarette smoking.. Relationship to.o ventilatory function and respisatory symptoms. Archives of Environ•mental Health ( Chicago ) 10(2 ):: 312-322;. February 1965: ~10: Boaxesr; N. 0L, HECHTES, H,. H. A longitudinal', study of blood pressure.. Angiology (\ ewYork).15 (12) :: 545-555, Decemtier 1964. Ell. BEARVAY, P.,. ALBBECHTBEN, G: El, ASTaqPy, T. Blood coagulation, fibrinol- ysis, and contraceptive hormones.. Journal of the American Medical Association. ( Chlcago) .199.(2 ) :: 69-74; Jan. 9,1967. s1_:. Baesnow, L.,.Bteu, P: EfortalitSfrom coronary heart disease and pbys- ical activity of work In California. Journal of ChroniCDiseases (St. Louis) 11(4).:4211144', April1960. ,,1S!.. BaowN, RI C.,,RrrzacexN, L.. Some factors associatedd with absenceof' cor- ouary heart disease in persons aged.65or. older. Journal of theAmerican Geriatrics Soeiety .(Baltimore) 15(3~).::23'9-250,1967. S'l il Bcacu, P~.. R,. J., R'owEnc, N. R: Smoking. nndi atherosclerosis' (letter). Biitish. Medical Journal (Londoa) 1:1050:-1051, Apr..23;,1966; S1', Bons, J.. H., Gmeoxs, W. R. The release of noradrenailue from aympathetic'c fibres in: relatiom to ealcium, concentration. Journal of Physiology (Lon- don) 181: 214-223~ .November1965. ~10. Brrxcs, A., PAas,. I: Ht Smoking.g and postabsorptive sernm lipidl levels. Journal of the American Medical Association (Chicago) 192(1) :: 52-a8„ Apn 5;.19651.. .<1I. Cancarbon monoxide raise.blood cholesteroS.levels?Ihledical World Sews'. (Sow Y.ork.) 8(1) : 26-27,.Jan. 6;1967:. s1'. RenEamr, B.. Urban factor and prevalence of respitatory symptoms and. "angina.tinectoris.P A sthdyof 9,168 twin pairs with the aidd of mailed ques-tionnaizes. Archives of Environmental Health'(Chicago) 13('A)~: 743- 748, December 1966. ~19~ CenFncuP, R.,JoxssoN, E., Lu.NnuwN, T. Om theval-udity of mailed ques- tionnaires in diagnosing "angina pectoris" and "tironchitis."Archivesof Enwironmental. Health (Chicago): 13(6) : 738-742, December 1966. s20: Cigarette: smoking andi heart disease. British Medical Jowrnal. (London.).. 2': 1404-1405, Dec:10,1966. S^_ll CaHaN, A„ Luns,. F.., ZACESxr, E. J.,. BING,. R.. JL A. newdiagnostictestw for coronary artery disease.using a eoincidence:counting,system. Minne- sota Medicine ( St:. Paul ) 49: :: 17-21, January 1966. `='. ConES, A.,.ZALESxI„E. J., LuEas;,E., R7Na„ R J. The use off positron emit- ter inn the determihation of' coronary blood: flow' in man. Journall of tiu- clear :1ledicine ( Chicago ) 6'::: Ci514W,1965. `2ti. ConaN, B: H, TaovAa,.C- B'. Comparison of smokei+sand.nonsmokers. II. The distribution of ABO and Rh (D)) blood.graups:.Bulletin of the Johns HopkinsHbspital. ( Baltimore ) 110 (1) : 1-7, January1962: "4. Craeuan;. K., PAULIN,. S., Weano, L. Coronary anguographia flndtngs in car- relation witbage;, body weight'y bloodd pressure, serum 16pids,, andd smok- ingLabits. Circulation; Journaliof th¢American.HeartA'ssociationi (New Y o rk ): 33'.: 88.R-901Y, June 1966.

i A., MoKE<Aiv, H.,. PAas,. II: A lbngithldinal study of coronary heart disease. Circulation; Journal of tlte American Heart Association (New. York). 28:,20-31,.July 196ff, (79) RnuArv, T. JL, FaANr;, if. J., MoGINa`r,. J. F., Zonr„ E.,, Hara.ears, H. K., 6rsa, R, I. 1129ocardial response tocigarette:smoking,ia normal. subjects and patients withcoronarg disease. Cilrculation;, Journai.of the Amer- ican. Heart Association (New York)23(3~).: 3C.5.3S9; March 1961. York.) 33-34! (Supplement 3) :]i83-181', October 1968: (7.i) PArrewseaoe.a,. R. S:,. Ja., Wzxo, A. L. Characteristiesin youth predispos- ing to fatal stroke in later years, Lancet (London). 1: 783'.-754',. Apr. 8, 1967. (76) ParPessneeEe, R. S., Ju:,. Woar,.l':A., Norxaer, J., Tnoane,.M. C. Chronic disease indormer.college students. 1. Early preculsors.ofs fataLcoronary heartt disease.. America¢Journal of Epidemiology (B'altimore) 83(2) : 314,828, 1966:. (77) P'ARNaan, I2'. W. Smoking.and.cancer. Lancet:(London) I:963, 1961. (78) PAUL, 0., LrrPns, 31..H.,,PHErAN, W. H.,.DuPEelTrvs, G:. W.,MaCMlrzex, (63); D.AnSaN,. R,. K.,. FvxonA,. P.,. Mvaner, Ji. F. Systemic and pulmonary vas- cular effects of nicotibeda anestheti'zed dogs. American Review ofRes+ piratory Diseases (Baltimore) 91(4):: 5"o6-.i64, April 19&5. (64)LEAneas, F. E:,. Losc, J,. P. Actiom of nicotine on coronary vascular re-sistance in dogs..American~ Jounral of Physi:ology( Washington ). 203 (4) : 621-625iOctober1962(65) LrxnsNPrr.n; A. M.. Emotional and other selected. characteristics of clga-e rette smokorts and nonsmokers ass related: to epidemiological studies off lung',cancer.and other diseases. Journal of the National CancerInstitute. (Washington) 22(2) : 259-232„ 1959, (66) Lrslxwmz,. J. B'adania, IDoswiadczalne. Wplyaru. PaIenia Popierosowna CeasKrzepniecia Krwii i Osoeza. Utvapnionego Oraz Czas Protrombinowy i 7rrombirowy Osoczau Ludzi. Polski Tygodnik Lekarski. (Warszawa). 18 : 1471r1473~ . 19C3. (67)Lc.wmAm;, T. Smoking in relation tocoronalT heart' disease and lung function in twina. A co-twiu controll studF Acta Medica. Scandinavica (Stockholm) 180(iSupplement 455).:1-73,. 1966. (68). MdAaTnra„ Cl,. WAr.onora,. E., EloarssoN, J. The psychology ofl smoking. Journal' of Abnormal Psychology (Washiugton). 56::.267-275; 1958I (69)MAreaazzo,. J:, D.,, SASVaw, OL. Psyohologicab andd relatedd characteristicsofs smokers~ and nonsmokers. Psychological Bulletin (Washington) 67 ( G):493-613, \ oremher 1960. (70) 1lintcarsocv, L..E., FYPe,.T. Effectaof'cigarette smoking on serum-lipids, 'blood-glucose, and platelet,adhesireness. Lancet.(London) 2: 182-1&t',. July 1966: (71) 3lbarnz, E. A'.,. Personal communication. University of Colorado, Febru- aryr 1967. .. (472) Muarnr„E1.A., MUSxasoL J. F., Tobaecoand thrombosis. American Journal of. Public Hpalth and the N'ation's. Health. (New York) 68(7) : 1061-ip73; July 1966.. (73) blrsrannj J. F., MvaPnr„ E.. A. Etfect of smoking on: blood coagulation andi platelett surriraIl in man.. British Medical Journal (London) . 1( &?.31) . :846-849, M a r. 30; 1963. (74) PAerrNnA,noe& R. S., Ja., Wn.LrAies, J. L. Youthful.precursorsof fatal strokc. Circulation::.. Journall of the American Reart. Association (iNew. 74 f ,.

w GEN] Padyn As tobac by to; Trh menl rene pher (3',4 Cc ben¢ pyr( (K,h Ien: (16. I late thou or i (5i (:a~ flu ar: cir . N c r v

;skrift erende qi-706i. :: The' llbbihm ilisub-' gation of to- tliala- t : dog 2'(6)" (79) CEUeawa;.. R.:,, Fa>Beao;. L., Jonssoir, E, „ %tira, L.. Morbidity amongmonoa zygotic twins. Archives of Environmental ffiealth (Chicago) 10(2).:. 346-350; February 1965. (20) CEDnawa;. It: FamEe.o;, L., Joxsso:r, E., Ee1a, L. Respiratory,symptomsy and. "anginaa pectoris"' in twins withh reference too smokingg liabits. Ar- ehivesof Ehvironmental Health(Chieago) 13:(6)': 726-737,. Decemher. 1966. (,t) CHECeEn:a, R•. B.,,B:avasHOtz, R: A.,. Ross,. J. C. Reaction of nonsmokers to'.carbon monoxide inhalatflon. Cardiopulmonaryresponses'.at rest and'd during exercise- Journal of the'Ameri:can. Medical Association ( Chioago ) ~ 19S(10) : 1061-1064,. Dec. 6j .1968: j22)Cxrsna;.T• S.,. LEAnEas~, F. E. Curdiostimulhtory responses to vagall stimu- Iationj . nicotine;, andd tyramine.. American.Journal of. Physiology (Wasb- ington): 211(6) : 1443-1446, Deeember.1966. 12.3) COHEN, B. H:,,THOUes,. C. B: Comparison.of smokersands nonsmokers. H. The distributionn of ABOO andi RH(D)blood groups. Bulletinn of the Johns. HopkinsHospttsl (Baltlmore).110: 1-7y January 1962. ,..,y) DA}rnea,. T. IL, KAivsEr., R':, B'„ Reuoassg, N„ STOKES, J., KAaAN, A:• Gonoosy, T.' Somefactorsassocikted.wit]a the development of coronary heart disease. Sixyears' follosvup eaperienceiin the.Framing5am.study. American Journal of Phblie Hea16hand ttie: Nation's Health (New. Y'ark). 49(10) : 1349:-1396iOct'ober 10UJ:. ~ 2J.v. DozL, R:,.Idru., A, B. liiortal[tyin relation to smoking: 10 years' observa- tions of British doct'ors. (pt. 1). British Medical. Journal (Londom)~ 1(a393): 1"399-1)110,May.30y 1961. ~,,1. Dos.n, R:,. Hn.x, A•.B. 6lortklltytn relation.to smoking: 10 years' observa- tions of British..doctors (Concluded'.). British~Mediral Journal (London). 1(5396)': 1460-1467,..June.O, 1964. i d~0Docn, R., Hixx, A..B. ffiorthliltyofBritish doctors in: relation.to smoking: Observations on coronary thrombosis. Im: Haenszel, W., E1litor„ Epi- (Rmiological.Approaches 1o, the Study ofCancer and Other Chronic Dis- eases. Bethesda, U.SI Public Healffi. Service, National Cancer Institute alonographSo:. 19, January 1966. Pp. 205-268. ~29): Durr-s, JL. T: Etiology of coronary disease:', Risk factors.ilnfluencing cor- ouarydiscase. Modern ConceptsofCardiovascularDisease (Baltimore). 35: S1i-86,, April. 1966i. Q81. DoYr:E,.JL. T., DAnFHEa;.T. R'y. KANxSS:, 1V. B., Hesms, A,. S., ]ICeHrrF H..A Cigarette smoking and.mronary heart dflsease. Combined experience of the. Albany andi Framingliam studies. New' England.Journal of Medicine (Boston) 266(16) : 796-9fi1, Apr. 19, 1962, . 1.30'1 DOYLE,. J', T, DAwaEa;.T. Rlr KAnNEL, \V. B., ExRCH, S.. H., KAHN, H..A. The relationship of cigarette smoking to'o eoronary heert disease. The second report of the combined esperience of the Albany. N.Y:, and Framingham, rilass.,, studies. Journal.of.the American. Medical Associa- tibn (Chicago). 190(10) : SBCi-P90, Dec. 7;.1964: 1,31) Dozr.E,. J.. T„ HesLlcv, A.. S.,, Hna.Eeos,. H. E., Foauer.,. P. F. Earlly diagnosis of iscliemlo heart disease. The. New England Journal of Medicine (Bes% t'un ) 261(22) : 1096-11'01,. November 1959. (32) ENar.i.mm~, H. Cigarettesmoklhg,and the'.iie vitro thrombosis.of human bloodl Journal of the.American hfedital Association (Chicago) 193(12).: 1033-1035, Sept .20, 1965. , (33) ENnEC.BESO, H., FvrreaaceH, bf: Smoking and acceleration of.the throm- botic coagulatiom off blood (:Abstract), Circulation; Journal of the 271-394 0-67-0'. 71 E 0 ~ ~ W: -M,41

iitions for lung. Ref- here near-' nphysema" Gtion. The d to have' ry emphy-; tulmonary it's:san es encoun- hy the re-; -ved in th 7e it iss dif&-~ hich seeks ic respira-~ eport: Re-, ely m thls' b udies, and t to pull; rontinued' Ion of thel ~ths iin the{ Ihoth have~ 0'in 196471; The increase and' aging of the population during the same period does not account for this rise, Age-adjusted mortality rateslor emphy- soma without mention of chronic bronchitis increased about ten times for. men, from 1.3 per 100,000 in 1950: to 12.6' in li964: A similar„ al- ttiough perhaps somewhat less dramatic; increase occurred among women,,from 0:2:per 100;000 in 1950,to 1-6 in 1964. Death rates from chronic bronchitis rose less preeipit'ously, doubling during the same period' (69,.70).. How much of this increase is the result of improved diagnosis of these diseases and how much the result of a true change in mortality patterns cannot be determined at the.present time,.Asso- ciations have been demonstrated between these conditions and smoking.. PopcmaTror. SmanMs Included in this broad category are investigations that collected information from a group or groups of persons either by a series of questions, bl* some form of physicall examination, or by a review of recarded.data such as hospital records and.death.certificates. PROSPECTIVE STUDIES In. the Surgeon GeneralFs 1564!Report, findings fromi seven prospec- ti se studies were presented. Additional data have beeni reported from four of these investigations in the past 3 years. Information relevant to smoking and chronic respiratory disease will be summarized here. The study of mortality among policyholders of U.S. G'overnment Life Insurance policies available to persons who served in the Armed Forces between 1917 and 1940 was initiated in 1952. -Almost all the 393,6'58 policyholders; were white males. Recently Kahn (44) pub. lished a report that inclhded all deatlis from~ Juhy 1954 through De- rember 1962,, a period of 8i/2years: 1Plie relation of cigarette smoking to death from bronchitis and emphysema ispresented by mortality ratios in table 2 and by specific risk of mortality in table 2A. Given the definitions previously cited, t'hese tables also illustrate the difficulties iiu separating these,diseases. The first row of table 2 gives combined, mortality ratios and'the next two rows give the same data in an.att.empt to delineate the specific dis- eases,. Mbrtality ratios are.given by the number of cigarettes smoked per day at the time the, men were enrolled in the study. Mortality from these diseases is much higher among cigarette smokers than among those who never smoked and rises witlh the number of ciga- rettes smoked' dai [y. The ratioss aree much higher for emphysemaa alonee than for chronic bronchitis with or without mention of'emphysema. A similar study of'veterans was begunn in Canada,in 1955. Answered'd questionnaires were returned by nearly 78,000 men whose subsequent mortality for a period of 6 years was recent.ly analyzed by Best aml' 91

pair never smoked and the otber either had smoked or still smoked at the time of the survey. The findings are presented in table 12. TkacE 12. Prevale7ace of "cough" and "b'ron,cliitea" amang smokers and no7usmokers in smoktingd'iscordand'twin: pairs Cuugh. Bncnebitie Numbmo7 ya4n 6muim Nonemoker~ emok¢r Nommaker \(onoz}tgotic:. Siem-----_ 14.6 i 7..7~ 6.6 1.1 274 Nomen-------------- 1316 ~. 7..6~. 3.0 2'.3 264 Dizygotic:: lten----------------- 12:.3 5.,5, 4.5 1..8 733 Women-------------- 14.5 5..7~ 5.5 1.,8 653 SoC].CE: CederPo(r E...eGa]'. (19). Tllis table shows that the prevalence of respiratory symptoms was much higher among the smokers in twin pairs than the nonsmokers. The authors concluded that this hypermorbidity "speaks in favor of a causal interpretation.7'Tn a further analysis of the data from monozygotiotwin pairs with discordant smoking habits, Cederlof and his coworkers (15) divided the series intoo a"low riskk group" in which thenonsmokinge twin clid not have "°cough," and' a"hiigh risk group"' in which the non- smoking twin had "cough."' The two groups of smoking co-twins corresponding to the two nonsmoking risk groups had higher than ex- pected prevalence rat'es: The observed value for smokers. in the low risk group„}mwever, was only half that expected'for nonsmokers.in the high risk group; This suggests that for some andividuals the geneticc inflnence may be more important than smoking im the devel- opment.of cougli, , But:, becauseany high risk group, is only a small part of the population, the total genetic effect will be mtuch smaller than the effect of tlobacco. Lundman (53)' made a. detailhd study of twin pairs in Sweden.. Of 247 twin pairs asked too participate„ 190paias were. examined (80 percent)y of. which 92 were monozygotic and.104 dizygotic. All par- ticipants were interviewed and examined without knowledge of their smoking habits. All twin pairs were concordant with respectto urban/ rural residence and discordant. in smoking habits: After estimation of.lifetime exposure to smoki'ngy 30 pairs were considered.concordant, thus.limiting analysis to77monozygotia and.89 dizygptic pairs. The smokersins both: groups of twins, hadd signi~ficantl}r higher frequencies of.some.respiratorysynnptoms, such as persistentlcough and morning phlegmy but not of other symptoms such as dyspnea, "day cough", and "day phlegm". Smokersalso had "an increase in the unevenness of 271-394. 0-87-8: 103

The: fourth of the prospective studies is the largest. More than 1 million men and womenn living in 25 States were enrolled in this investigation in late 1959: and earlly 1960. A report of the first 4 years of observation was publishedi recently by Hammond (36) and mor- tal5ty from emphysema and chronic bronchitis as related to smoking is given in table 5.. A slight dcpart'ure from the usual assignment of cause of deat'h should be mentioned. When the cause of dcath was listed as chronic bronchitis with. emphysema, it was aombined with emphy- sema alone. For this reason, the cause.of death in table 5 is not quite groups fi' with, emphysema for ci.garet'le sntokers--nen and women in 2 age TABLE 5.-1Y2ori¢lity ratios for deaths dtiz Co emphysema andd brortchtitia_ the same as any of the causes listed in the other tables. Againy, it is elearr that;,mortlality fiom tliese entities is related to~smoking for both men and women. This was the only one of the four studies with enough women enrolled to provide meaningfull data. C9use nf death Emphysema and brnnchitis with cmphy- eem(5DZ, 527.1)_________________-__ (£'9„ 30), it was possible too estimate the numlber of. years aa man con-~ tinned smoking afiter he had answered the initial questionnaire. Fora chronic bronchitis the mortality rates at first increased' after cessation of smoking and' Iater fell well below the rate for men who continued' to smoke.. Thedeath rate from, chronic bronchitis, per 100,000, tions, two further poi:nt~s, should be made. Excessive mortality was largely confined to cigarette smokers. The mortality ratio for chronic bronchitis and' emphysemay for pipe and cigar smokers combined, in the U.S. vet'erans study, was only 0:99; in t,'heCanadian study it.was about 1.6 (based on only nine deaths),; in. the study of men from 25 States it was 1.37 ;: and' among British' doctors the standardi¢ed death rate was 15 (compared with five among nonsmokers). Whatever may'• be the relationship of p'ipe and cigar smoking to chronicbronehitis and emphysema, it is clear that it is substantially less important than~ the relationship of cigarette smoking. , Ln two of hhese studies; stopping cigarette smoking is seen to have an effect on subsequent mortality fiom chronic bronchitis and emphy- sema. In thecourse of' the followup of the British physicians 6..5, fi&79 11.4 4.d4' 4.9 tMdrtatityqrstioa'of'nonamokersintheabuvexategpriesme1.00BydeBnitien ,t ~ CateuTated trum~(aE). . socacx: nummandl E. C. (.16)1 -. Beforesummarising the data presented froru these four investiga.

525.CEEU&, G:,.HABTMA.TN, G„ WiDMEaj L. K:, GREENRrIER, ,A., BaEny.H., REBES; H.,,STevR, H:.KAVESreNN, L. Zur. Bezichung Zwischen Liptden, Blutdruk und Gewicht bet Rauchern-Basler Studle. 4'erhundiungen der Deutschen GesellsohaftfRrKreislaufCorscbumg (Darmstadt) 28: 259-262, 1963. S?fi;. CROasaN;, E., Cam-rmr, J. Inflaenceof smoking on mortality from various diseases in Strotland and Sn.England.and,wales..An analysis by colmrta: Brittslu Medical Journal (London) 2: 1161-1164, November 9, 19631 '. 527.. CRosETrrr, L.,. Raa¢aeo, G. F.,. PP.TTIaeTI, L. Osservazioni: In tema di d'etossicazione dell'' emoglobtna nell'uomo, esposto aa risehio prolungata dkossido dl carbonio.. Minerva I41'edica (Torino) 57:288-269,.1966; ' 828. CvBrneY;,T. J., HBoq L. P. L., PRaxrxsi.N. M. Carboshemogiobiii In rela, tion to airpollution and smoking. Archives of. Environmentul Health. (Chicago) 10: 179:-185,.February106n. 529.. I)AHLBiRO1S, H'.,.NbRDRTROM-C)HRBEaG, ('.., RorABQHILD, A. The influence of tobaccosmoking„and increased initial carbon monoxide concentration on results of Sjostrand's method of total hemoglobin determination. Acta Physioligica. Scandinavlea (Stockholm)I 42: 174-18f, 1958. '539. DAWBeR, T. R~, KANVEL,.{^f1. B., LaELL, L. P:.An appiwachto longitudinal studies tn.a cummunity :..The Framinghamstudy. Annals of the?r'ewYorkAeademFof Sciences 107: 539-556, May 22;19631 531. Dwwaea, T.. R:,. KANNEL, W. B'., DicNaMeaA, P. Nf, The predictian: of coro:- nary heart disease,. Transactionsof the Associhtion of Life Insurance Medical Direetorsof America (New York) 47::70-105, 1964. 532. DAwRER, T. R., KANNEL, W.. B., %nvoTSKIE, N., KacaN, A.. The epidemi- ology of coronary heart disease-the Framingham enquiry. Proceedingss off the Royal Society of Medicine (Londom) 55:, 265-271, April 1962. 833. DEaoILLE, H., TRUa£ERT,.II., LEHBM, J., PARENT. Sur L'o%ycarhonftledes fumeurs; Archivesdes Maladies Professionneles, de Medecine du Travail et de Securite Sociale (Paris)'. 23'.(9) : 579-582, September 1962. 834. DocE„ 1P.. Ballistocardiographic patterns and'nicotine:. Types of ballisto- cardiographic patterns evoked by nicotine and tbe relation of the most frequent pattern to:effects.of niuotine.on respiration,.not on.the heart. Arehivesof Iaterna111Iedicine (Chicago) 112(4) c467-475, October 1963. 535. DoaMAn+os,. T.L.. Abnormal oaygen-dissociation curves. (letter),. Lancet (London) 2 ::81?-PI, Julp10, 5965: 530. IJaYLR, J. T:.Tobacco:andthecircttlationapparatus. National Conference on.CardiovascularPTiseases (WashingCon) 2'..301ti'62„1964:, . 837. DvNN, J. E.,. JR.,. LLNDENy. G.,. BsESnow;. L. Lung cancer mortality esperi- encee off men incertain occupations in California. American Journal of Public Health and. the Nation's Health (New York)50(10) : 1475-1!E87; October 1960.' , 8.38. EuaLrcrl, S: P., Ja: Seal Beach StrolieStudy.. November 1966. [,Utupublishedii' 8 pp. S39. Eraxrq b1: E. Coesistencee ofthromboangiitis obliteransand.s arterio- sclerosls.:: Relat~ionship: to smoking. J6urnal' of the American Geriatrics Society (IDaltimore)14'48) : 84G8581968. 840: ELIOr, R. 5.,,MiEUKAMr, H. Oxygen affinity of hemoglobin ih persons with acutemyocardial infarctionn and.in smokers. Circu7ation ;: Journal of the American. Heart.Association (New York) 34: 331338,.August 1066. S41. EBSTEIN, F.. H,,. GRTRAINDER; L. D.,. JR., JOFrNSON;, B. C., PAYNE',. 1tiI.{P.,. HASVER, N. S'., KEr:LEa, J. B„ FRescrs,. T., JR. Epidetniological studiess of cardiovascular disease In al totall communlty-Tecumseh;. Mich.. Annals of Internal bfedicine(Philadelphia).62(6),: 1170-1187, June 1965. 78

dispositions to smoking and respiratory disease mayhave a common in tabl'e 11. on the twin registry) is considered as a random, popudation, the as- sociation observed between smoking and respiratorysymptoms is given If the group comprrising only one of each twin pair (the first twin "bronchstis." subject checked' more than 3 months, he was regarded. as having how many consecutive months a year do you have a cougha;" the A subject who answered "Si es" to~ the question,. "Do you regularly have a eough P"' was regarded as having "cough." If, whem asked, "For 9,319 pai¢s-another ~response~~of . about 85 ~~pereent. ~ naire with medical questions were received from both members of received from 10;947 pairs (85 percent). Replies to a second question- tionnaire dealing with~ smoking habits and residential history were various causes among 12;889, pai6s of twins. Replies to a mailed qpes- (16;, 17)~ in Sweden studied smoking in relation to morbidity fnom and the other is not; an excess morbidity does not appear among the smoking twins, it wouYd.seem that the exposure to tobacco smolte was insufficient to result in greater morbidity. Ced'erlof and his associates pairs of twins, paarticularlyidentical (monozygotie) twins. If, when one twin in.each.pair of monozygotie and dizygotic twins is a smoker constitutional factors is to study the effect of tobaccolsmoking, among One method of tirying to. estimate the importance of heredity and genetic basis; TABLE 11. Prevalence of "cough"' and'"bTonch;itis'" among smokers and nonsmokers by sex aatd age Sex and biith ryeer biew 1886-95__.__ 1896-1905~________________ I906'-15_________._________ 1916-25__________________ Women: 188rr95__________.________ 1'89fr1905________________ 1906-t5__________________ 1910-25 CougL Slnuker I Nunsmuk. ' 17.7 15.5 . 15.0 13.8 17:8 6:.6 5.5 3.5 9.7 7.0 5, 5 3,8 Bronchlps Smoker I Nomm 7.4 6.7 6.3 4.9 ' 8.3 8.0 4.8 2. 0 Socncx: Cederlot R., ePal. (1'n. ' These findings are similar to those previously reported for various populations,. These respiratory symptoms were then analyzed among t vin pairs wit6 discordant smoking habits, that is, one twin of the 102 ;W A

568. HEIxe, H:, ScxMrnT„ H.,,AxDEas, G.. KliniscHes Bl[d und Therapieresultate bei PatSentea.mit Endangltis obliterans und peripherer Arteriosklerose. Angiologica. (Basel) 2: 195-211. 1963.. 559. HerneN-STUCax,. S. EpidemioIogie des Herzinfarktes. (196u). 8chweize- rische Medieinisehe Wochenschrift (Basei)~ 95(45).:1a3,'r1a$0i Novem. ber'6,196i. 560.. HrxxLe, L. E., JR. The use of. a large industrial population too study the effects of social and behavioral factors'.omcoronary heart.disease. Amer- ican Journal of Public Healthh and the Fation'sHealth (New York) 56'. (9)e 1470-1475, September 1966'. 561. H1Nisr.E, n.., E.,. Js,. BErr;raMrer B., OHSreTExsox,. W. N:, Utr.ssANx„ D. S'. Coronary beart disease. 30-yearesperience of 1,160 men. Archives of Euvironmental Health (Chicago). 13: 312-321„ September 1966. 862. . HOLLAttD; W. W., RAFTEBY; E. B., MCPn:ERRO.\', P., $TONE, R.. AV. A OflrdiO-' vascular survey of Amerioan East Coast.telephoneworliers. American Journal.of Epidemiology (Baltimore) &i(1).:61~-71,1967. 563. JoaxnxeaNZ.,. PaExalsz, J. B'ezposredni Wplyw Palenia Papierosow naSpiiogram u Zdrowyoh i Chorych a Rodzedma Pluc ii Przewlesklym ~ Niezytem Oskrzeli. Polskie ArchiwumBiedycynyWewnetrznej~ (Warszawa):36(6).: 783-796, 19661 564. KACax, A.,.KANNEL; W. B., DawEaa, T:.R., Revorsxse; N. The coronary; prodle.. Annals of theNesv York Academy of Sciences 97: 883-891, ~Aug., 29; 1963.. S6'o. KASmex, W. R:,. Epidemiologgof cerebrovascular disease: An epidemiologicl study of ceretirovascular disease. In:,Cerebral Vascular Diseases.. New York: Gruue & Stratton, 1966. Pp.o,3-66. 566. KANsEL, W. B., Habits and'd coronary heart disease:. The Framingham~ Heart Study. Betiiesda,. National: Heart Iirstitute. U.S. Public Health Service Publication No.1513,.1966.. Unpaged. 867. KasNcc, W. BS, KAGAN, A., DAWHER, T. R:, RES'oTSxn-s; N. Epidemiology ofil coronary heart disease. Implications for the practicing physielan.'~ Geriatrics. (]iinneapolis )17 (10) : 675-690, October 1962. Ili568. Kesnx;. T., Poncnx, 0~ JL. Action off cigarettesmoke on rabbits' cardio-" vascular cells in. vitsn: Tohoku. Journal of Experimental lfedicine(Sendai.) 8.3:.2Vfr252, 1964:.. ~ 569. KasaceN,. A., Foassraou;. J. Estingg and smoking habits of'. patientswitlt, myocardial infarction. Annalpa nfedeclnae Pbternae bienniae (Helslnki)a5(1).: 7-11, 1986:. . S7R KaDan,.)I.,,Dmowsxx;.G. The inHuence of.tobaccosmokingomthedevelop.f meat of atherosclerosis and on the compositiom of blbod' Iipids. Polish~ilediaal Journal ( Wurszawa:), 5: 37-43, 19661 571. KEDRA, Jfi, Koaoxxo; A Palenie tytonlu a. Krzez pniecie Krwl. Polski Tygndnik Lekarski. (Warszawa) 21 44-46, 1966; S7'L KERSnnwum A BECeET, S., KaoasnnrAw, R. Elevation of serum cholesterol after administration nff nieotine.. Americau Heart Journal (St:. Louis)',; 69:,2(ICr210. February196L 71: 573. KESSneevM„ A.,, J1MENEZ;. J.,. BecLET, S., ZasvrTrur, DL Sflixlificationn of~; nicotine-induced hyperlipidemia by antiadrenerglc agent5. Journall of'. A therosel'erosis Researeh( A'msterds m ) 6: II24-5a0, 1'966. 71 S7i. Kars;. A., BLACnaca:r, H~. Background of the patient with coronary heart.t disease. Progress in Cardiovascular Diseases (New York) . 6(1) : 14-44, July 1963. . 1 573, KxaKCar, K. Blood Iibids, lipoproteins, and proteins inn vegetarians. Aeta~~\fedica Seandiiiavica (Stockholm) Supplement tio..443;.. 1-84, 1966. , 80 1

CHAPTER 3' Smoking and Cancer CONTENTS. Page General Chemical. and Experimentall Data on Carcinogenesis and Tobacco Smoke----------------------------------- 127 In Vitro Cellular Changes by Tobacco Smoke----------- 129 In Vivo: Tumor Formationn by Tobacco Smoke _-- _--- _--. 9. 129 Thmor-Promoting.Agents in Tobacco Products---------- 130 Lung Cancer------------------------------------------- 1311 Mortality Data------------------------------------- 131 hTistopathologyof~Lung~Tumors~~---------------------- _- 140 ~ Esperimental. PUlmonary Caccinogenesis--------------- -- AdditionaI Evidence Concerning Experimentall Carcino- 144 genesis -------------------------------------------- 144 Cancer of the Buccal Cavity and! Pharynx (Lip;. Mouth, Throat).---------------------------------------------- 145 ~ CancerofltheLarynx------------------------------------ 148'. Cancer ofthe Esophag-as--------------------------------- 149' Cancer of the Urinary Bladder___ ---------------------------- 153 Cancer of'the Stomach----------------------------------- . 157 Cancer of the Pancreas---------------------------------- 158 Cited References---------------------------------------- 161 SupplementaP References--------------------------------- 167 125

I . repo: 1nt sin ective mit.ea mg oi 1 Th, #re a, cB additio followe ies that to the Center fi June 19 bronchi 2 of 42, ~rmg q Sehoid, t ~,A stroi C presen esented in another study of the epidemiology of persistent cough, Wynder (8(1) and his associates: evaluated the smoking habits, occupation, and residence (urban or rural) in a malle population comprised of 315 hospital patients in. Now York, and 315 in. California, and of 239 Seventh-Day Adventists liiving in C'alifornia, who were not hospital patients. Persistent cough was reported from 23 percent of the Ad- oentists (who do not smoke), 45 percent of the New York pat.ients,. .nd 53 percent of the California patients. Coughing wasmore fre- quently report'ed by cigarette smokers than by those who smoked pipes or cigars, as shown in table 8, Inhalers also had ahigher rate of persistent cough and the rate of'cough increased with smokingin each age group:. Wynder found no, correlation between urban or rural resi- dence and persistent cough:. Analysis of the California group showed a higher rate of'pcrsist'ent cough that.was independenti of the number of cigarettes smokedl, T:knLE, 8.-Peraent af Tnen. -urith persisient cough as related to smoking, habits Non, smoke.r `G6w York pstiants C;diforniu patientsL ___________-.-_- Frrnth-Dag. Adcentists----_ _ _ _ _ _ _ 14 22 23 Pipes/ eigan 33 30. Cigarettes ooly 1-lU. 11-YO II POi" 45. 45 46 74 67 74 Anxed smoker 51 66' EOraCS: Wynder, B. L. et:al. (8U/. Deane and her associates (28) studied symptoms in.relation to smok- ing iii a group ofl about 500 outside telephone. workers. over age 40. working in the San Francisco and Los Angeles areas. Symptoms were reported on amodified version of'the British~Biedical Research Council questionnaires Regardless of tlhe definition of the respiratory symp- tom-persistent cough. and phlegm, persistent cough, phlegm, and shortness of breath-it was consistently experienced by a greater pro- portlion of those who currently smoked cigarettes than those who. did not. Coates and his coworkers (20) also found among 1,584 postal work- ers aged. 40 or more (all employees of the Detroit Main Post Office),, that. for every symptom-coug)1 and phlegm, chronic phlegm alone, wheezing, shortness of breath-the prevalence was two.to three times greater among moderate (15-24 cigarettes per day).and heavy (25 orr more), smokers than among,those who did not smoke: These diifferences in symptom. prevalence were observed for both men. and women but `chronicbronchitis"' wasreporteds more oftenn by men„ which Coates ascribes to their. being heavier smokers. The prevalence of chronic.

acid, trther iliary lative .nt iddi- ;tated ained stem. f©N that li em ondi- okeis ecog nt of May trned eady 31op junc- ~tox- rure i nflu- ade New .hers' II of , uong. i ~ ; ,~ Rore': kory, ok- en i the~; has ~~the us I Climatic an& meteorologic variations involved with differences in quantity andl quality of specific ai'r pollutants make investigations of atmospheric pollution very complex. There liave been. many studies, however,.attempt'ing to examine tihe association of air pollution with chronic respiratory disease. Often com parisons of'mortality and'' mor- bidity are made between urban and rural areas, assuming a.difference in air pollution but not measuring it directly. Wicken (76) in his retrospective study of mortality from chronic bronchitis in Northern Ireland found higher mortality rates with greater degrees of urbaniza- tion.. Air pollution was suggested as a factor. H'olland and'. Reid (42) compared the prevalence of respiratory symptoms, sputum production, and lung function in Londom and in three county towns. TheS6ondom mem had more~ and severer symptoms, produced more sputum and had poorer lung function test results. Smoking, habits were shawn to be closely related to respiratory dis- turbance but urban-rural differences in these habits could not explain the greater frequency of respiratory symptoms in London:. A Canadian study reported by Bates et all. (11) indicates that among four cities studied, the city with the lowest amount of' industrial dust- fall and sulfur dioside.leveis had the study group with the lowest prevalence of chronic bronchitis. Preliminary results also indicate that this group had the lowest decline of pulmonary function. The groups of males in each, city were approximately concordant for other factors,,including.the influence.of cigarette smokimg:Ferris.and associat'es. (3, l, 33) . studied.air polllutionn and its effect on respiratory symptoms andl functions in two: separate tlowns-Chilli- wack, British Columbia„ and Berlin, N.H. After standardizing the «ataa for age and cigarette smoking,, they observed acorrelatiian be- tween symptoms of chronic bronchitis and the level of air pollution as.measured by,the mean sulfation rate. They also found'pulknonary fttnction tests to be betterin Chiltiwack when controlled for smoking habits and age. This may be associated with the lower level of air pol- lution in Chilliwack.. Studies of populations of twins.are.especiallly valuable in assessing the influences of constitutional factors and environmental' considera- tions, such asciga.ret'te smoking and airpollhrtion. Cederl'of(1/y), using interview techniques on a large population of'twins in Sweden, found that compared with smoking, air pollution was, of secondary im- partance in causing respiratory symptoms indicative of clironiebron- chitis and/or emphysema. In both the monoaygotio andld dizygotic twins, again using the co-twin control method, individual variations suggested thatthe propensity todev.elop cough.from smoking also may well be pertinent with re tg}trd to air pollution but that, when considering. the total population, , individual variations appear to be of minor influence (16). 109

soa / 9nn / /i~ ! L an -aglea eaffi7- [OxGRl OF RMOD OF FLYLIEE eINIM F....... - 19'ef-1929 e .......... 12.112. . c....._......... ,919-191e o ... Is19-rsl. e ..........waa-19u F . ......... 19D0.19. W. 6 .. . . . 199l-1999 890-199. I ._ I9ef-19e9 ! . . . 1990-1ee. e - . ,es-ler9 1 e.mnle/9 eo I 04 zs9Vs4eo I I y, f0 e9 9¢ f 60 69 10 - - .9[ Ie1E1e9 Fiovau 2.-Cancer of the lung among women, by birth cohort and age at death : 1949, 1954, 1969, and 1964. o.l

t nlta eroe we122 vea d 9' thi Amer ^k)51 I I D. 8 Yes d ardioa 3riCaa J /w na sklym :rznef Jnary L-893, alogic New gham' ealtli; gy of t }Cian, 4 dlo- IbineI with nki). a elop-~ Aish ~ plskl !erol vis) ht of' l of. Siasatara; N., SAOe,.H. J., Smxi+H;,W. J:,.Krasaraes$ A. G.Releaseof.cate-cholamines and.speci8cprotein from adrenal glands. Science (Washing- ton) 154: $29,53L Oct. 28,1966. S:7L I£nevscn:, H: Die. Reaktivatat desKr•eislaufes. bei Gesunden undKoronar- kranken. nacli dem Rauchen~einer Zigarette: (Neue Drgebnissemit elnem quantitativeruBKG-Rauchtest). Archiv fiir Kreislaufforschung:'. Belllefte. zur. Zeitschriftl fiir Rreislaufforsehung (Darmatadt). 41: 1-26,.July 1963., 878 . Kosrresex„ A. Cigarette smoking, and serumlipids in young men. British Sledical Journal (D:ondbn) 1(5285) :, 11115-1116';, Apr..21, 1962. 5,;1. KavnnER, D:.EI„Wmt.rAxs,.J. L,, Pesf•enaARnEa, R: S., Ja.7hrends.indeath~ ratesfeom cerebrovasculardiseaser in' Memphis, 7rennessee, 1920-60.Journai of Chronic D)seases. (S'tl Louis) 20: 129-137,. 1967. «n. KwAAN; H. C., Asraur, T. Aortic.arteriosclerosisin rabbits. Archives of. Pathology ( Chicago ) 7B'::'.474-482; November 1964.. e<l. LANDERHOLM, \V'.., HRUssevs, A., HASS, G. ]f. An experimental inquirginta', nicotine-induced thromtiarteritis: Federation Proceedings'. (Baltimore)26(2'): 359, March-April 1967. s*'1. BtcttrMwx; . \f. A., Woons, J. W. C9teeholamine excretion ih, young white andd negromaieswdth~ normal and elevatedl blood pressure. Journal of Chronic Diseases (St. Imuis), 20::119-128,196'7. +ti3. Iiieaea, I. IL., Goi:osTele:, B., GAUeAKO, J. C., SrelIsrAN;.J., Bsuso;. E., IIzR- szxawroz, A., SleacIT, J. B. Posible: atenuaeldn biocataiitica de los efeetas nocicos de Pa nicotina en' fumadores conn afeeeionescardiovascu- iares. Fnndamentacibn.qufmiea y esperimental..Revi6ta oto-neuro.oftal- molGglca y de cirugla neurolLgiea sud-americana (Buenos.Aires) 41(7/ 12) : u~-56, July 1966. :?,4. Li'as, E. D., Cous.w;, A.,.. ZALESxI, E:, ZtisvaE,. V.,., BINb, R.. J. Die. Bestiat- mung der. Koronardurchflussmengebeim Idensctien mit dem Isotop Rabid- ium-84 und einem Koinzidenzmesssystem und ibre' diagnostische. Aus- ,rertlnng,.Zeitsrhrifitf6e.Kreislaufforsehung (Darmstadt) . 54(12): 1117'- 1^28~, 196:i. "'..5. tireas,. F... C.ones, A.,. ZAnESSt„ E. J., Btso,. R. J:. Effect of Ntroglyeerlni intensalh, isoptin andi papaverinc om coronary blbod flowin man meas- ured by the coincitlencee countingg technic and rnbidium. Amerdaan. Jour- nal'l of Cardiology (New York) 17: 53sr541', April 1966. S`+;. Lvrr, N. G., Porescv, I:,. Ec:escu, V".. Ttieaction of smoking on the cardim , ascularr apparatus. iu'edicina Interna(Bucuresti): 13: 347-351,, 1361. 857. \IcDOSar-q J. C., LIDweuL,. 0. M., WnraHr, E. A. Serum cholesterol, smok- ingand.bodybuild.,A eurvey in the Royal Air Force, British Journal of'. Preventive andlSocial.3fedicine (London) 19: 111-114, July 19Ri. SbR. 3CCDoNOLGIr, •P. R., HAdfEB, C. GI.,, GARRI6ON; G. E., S!rIILa, S. C., LICHT- xAx, 3L A.,. Heeanprxuea, D C. Therelationstiig af' hematocrit tocar- diovascular states.of healthin the.negro and white.population.of Evans CountR. Georgia..Journal of'Chronic Diseases(St... Louis). 1R(3): 243'- 25T March 1965. 550, SIACx;, B. E, NacTIrca, D. D:, HooAxcAacP, C. EJ,. BH;o', BL J. Myocardiall extraction ofAb9° in the rabbit. American Journal of.Physiology (Wash- ington) 197(e'):: 1175-1177, 1959, . S90. \IwRxcsa, R. E,,. SCHAAF, W. E:.Cigarettesmokingandmedicai attendance prior to.deathi Archives of.Encironmental Health (Chicago) 13(1).:.66- 71, ,Tuly1966. 891. Slsms, J. W. Epidemiology of! coronary disease in industrial workers, III. Absentee: rates andd parental disease histories. Archives of' Environmen~tal Health (Chicago) 13: 63u-6611 riovember4966, 81

F »m 104C L~~F Y f eon o ` . ~ no ~ ~ wo f ' LOxpii Oi pER10° [! xnlfF inix °pf00 E • Mf) 9E9 Ym ° IefO ~9Y• L 91) 919 6 KO : aa )1. -0 19/Il OD eo r 0 60 E 19 9W 0 'f ! 90 .iBO. 60 b ~ / 4 -.iesl-1ees _ "° /Ix iew ua. .o /ees ieaa Ea / mx] ie» n xn ° /.L. .. 9aHf /U] -- i 6] . IA Of °) 20 xf 30 J] .0 .e )° e] 6° ee x° x] e0 )S.M 1EE IR S n•) ances of the lung among men, by birth cobort and aee at death Hlma n n i f ° ;•° -': • ' . d--0 ~ p ~p . ~ ~, ~ yj~ y , -'~Sa69..anQ1691 14ao ), `; a:':~ " 11"~I!B. ... ~' I- ti

cough and phlegm among ex-smokers was no greater than in' nonsmokers. I Very few studies have been carried out to estimate the association of morbidity and smoking'in.young people. Paters andlFerris (60) retro= spect'ively tallied' the number of visits to the clinic at the IIniversity` of'Health Services for 1,623 Harvard students and 404! RadEliffe stu-. dents.. SSnoking information had beem gathered on these students in; their freshman and senior years. Smokers made significantly more. visits to the clini'c ini total " for respiratory diseases in particular.. There was a.positive correlation between years smokedi and the num- ber of respiratory. disease visits. . In. contrastl.to most studies which select population groups, Huhti (43) studiedivirtilallythe entire popul'ation, age.40-64, in a commune in western Finland. Although it was a.mostly rural!population,,some industrial workers were included.. More than 95'percent.oE the men and women invited responded.to the survey. Questionnaires (based on that of the British 1Vfedicall Research 't,`buncil) and medicall eaamina- tionswere completed for 730 men and1.890. women. Only 18.7 percent of the men were nonsmokers and 21.6 percent ex-smokers, compared withi 86.11 percent nonsmokers and 3.6 percent es-smokeis' among women. Prevalence of both cough and phlegm production was sigpifi- cantly higher among smokers than nonsmokers as seen in table 9. TxnnE 9l-P'eraentt of'vnen, and'women with cougk (3 months in the year) and' euit7ih piilegm (3 monihs in the year), related to sm.oking, habits Ciganettes amukediper dey ffi24. Cough: Mell_____________________ Women.___._.______________ PSlegm: Men_____________________ Wamen__________________ enuxce: Hotiti, EI (4J): 31.5 10.41 ' 38.0 10.4 T6} 40. 8'. ~ 42.4 (3'.3 of7women. smoking 15+ cigarettes/dhy). 42.9~1 42.4 (4'. of 7 women. smoking 15i- cigarettesfday) RFSUME Nun- smokers 10.7 5.9. Et- smokoxs 8.5 13..3 17.7 13.3 In: all the prevalence studiest71at ha¢e.been identi'fi'edlandd reviewed, significantly more cigarette smokers. consistently reported having symptoms related to chronic respiratory disease. This was true for cough, production of phlegm, wheezing, and shorthess of breath:. It 98 0 L5i ~ ~ tp ~n >`•'F70.. 41

SI21.. Wrxnaa, E. L.,. %AaFxen, P:, L.,, LEaeaa, H. L. A sliort-term followup stVdy an es-cigarettee smakers.. With speciall emphasison perreisten ~. - cough and weight gain. (In pr+ess.). American. Review of Respirato . Diseases (Baltimore).:.February1987.. S122i ~9ssnaa;.E. L.,.LEMO~N,. F. R.,. Mazrrec, N. La.epidemiologlade Ia tasper;~ ~ alstente.. Falls Ciinica.internacional' (Barcelona) 15(2),: 7L~88, Febra- . : ary 19fi:i'.; (3): 123-130, March 1985; (4) : 201-210, April 19H6L S123. 2amae~aa„ L. D., HoaxoN,. R'. J. M., Lcttnso, E: ~'heNashville air poliU~~ ~ Sonn study: V. MortalityfEom diseases of the respiratory system lu~ reiation~ to air pollution. U:S.. Public HealtHService, Division of Aie ~ Pollution. Contract No: SAph 89828and PH566586:-05-157: Presented'~ before.the Epidemiology Section of the American Public Health Assoa4 ciation at the 91st Annual Meeting in Hansaa City,.5la:, Nov:.12; 1p93:~ [Unpublished.] 19&pp, 9124, .. 2emaeso;. L. D~, Parsnrx,. R: A.,. LANDAV, El. The. Nashville airr pollutlon.:- study. III.. Morbidityf in relation to air pollhtion. American Jorunai . of Public Health and the.Natffon's Health (New York.). 54(1.):.85-97, ; January 1964: C 1

ing and mortality from bronchitis and emphysema. All repor consistent associations that might be expected if there were a can smokers than among men who smoked pipes or cigars. These a tion.of death rate& M'ortality was consistently higher among,cigare and'.the retrospectivestudg included enough.women to permit calculb This was also true among women although only one prospective stu increasing gradient of mortality with an increasing amount smok relatibn.between cigarette smoking and these diseases. In addition, i such a relationship exists; cessation of smoking'should be followed bg These data, then, strongly support the conclusion that. cigarette aluded information on changes in smoking habits. a rediuction in mortality.. This did' occur in the two studies that in=t smoking is at least one of. the causes of chronic bronchitis am emphysema.. CBfRONIIC. BRONCI!IOPULMONARY DISEASE MORBIDITY table 7. of chronic bronchitis or emphysema, or both. This is presented in lespondent was asked questions about their smoking habits; A strong relationship was found between smoking habitsand the presence; tions about health for himself'and othermembers of the household, th househoids containing about 1434,000 persons.. After answering,ques= andd emphysema (7$). Tlus was askedl ln a, nat;onall sample of 42,000,t asked about cert'ain chronic conditions including chronic bronehitis,# Health Statistics, hofi+ever, in interviews from July 1964 to June 1965 quency of signs or symptoms of disease: The National Center fors Most surveys of' chronic respiratory disease are confinedl to the fre-' S'rIIDIES RELkTINn .SMOIIZNO 1'ORESPIRwTORY' SFMrDOmS status-number of cigarettes per day (Acaviest amount) emphysema~ pcer~ 100~0 persons. 17~ years~~s and~d over, by sex, and smok2ng TABLE 7. Ageadjusted' prevalence rates of chronic bronch;itis and/or Nesnr. Former Pmaent emotera smoked smokers 1-10. I 11-2f! I 21+ T I61en.------------------------- _ 1.0 5.8. 1.1 2:3', 3.3 .. Nomen---------------------- 1.2 2.6~ 1..6~ 4.0 B~E 9ocnce: NaSonet centtr.Wr neelth 9tattsaes (7S;,F1g. a). 96 a q C 4 00 C11 ' . U

Of the group of 179 individuals„54 had mucous gland hyperplasia: epithelial cells were found in six (13 percent)., This compares to. 26. (45'percent) of the 58 students who had been smoking 10 or more the ages of 17 and'24: Of the 45 who had never smoked, atypical' history. Robbins (63) studied a~ group of 103 colSege students between bronchial epithelial cells in living persons iscompared with smoking Onlyone study has been.found in which the frequency of abnormal were essentially nonsmokers- previous pulmonary disease. In contrastJ, approximately one-third of thee remaining139men„ who had either very mild or noemphysema, deep-seated lung infections or other demonstrable relationships with Of the54 persons involvedy 511 hadl smoked more than 20 pack-years, and the remaining three were essentially nonsmokers. In contrast, approximately one-third of the 125 men in whom mucous gland hyper- plasia was not found were essentially nonsmokers: When the total group of 2'53 men was studied for evidence of'pullnonaryemphysema,, 114 were found to,have moderats or severe pulmonary emphysema. Of the 114, 98 had'smoked more than 20 pack-yeais., The other six, who essentially were nonsmokers, hadl either asthma, previous tuberculosis, cigarettes dhily for 1 to 8 years. Gyt,olbgicul examination was don without knowledge of whether the specimen came from a smoker o nonsmoker. ANWlAL EXPERIMENTS of the~l'ung~parenchyma.-.e dogs that were exposed longer showed signifCcantly greater disruption knowledge of the source of the lung specimen. Lung damage among chyma was assessed macroscopically by comparison with. preselected, standards graded in severity from 0 to 3. Assessment was made without alinostl 15 months of smoke inhadation. Disruption of the llung paren proximately 5 months and the remaining eight were sacrificed aftec in wooden inhalation chamlbers. Seven animals were exposed for ap- higp eoncentrations ofl cigarette smoke for 30-45' minutQs.twice daily Results of t vo experimentall studies relating smoke inhalation toi lung parenchymal changesin dogs have been published in the last 3 years. Hernandez and his coworkers (39) used 23. healthy greyhounds retired' from racing:. Eight served as controls andi 15' were exposedl to, :luerbacL and his.associates (5,6) .. tracheostomized 10 adult bea.gles and, im an attemptt to~ approximate human smoking more closelyA ;~ sacrificedl after approximately 14 months of expmsurre. Other beagles Five dogs died during this experiment and the remaining five wer® exposed them to eiga.rette smoke through the tracheostomy tube 106 lli I~r tk r 1

with female nonsmokers; similar to the relationship noted' between' male e.x-smokers and male nonsmokers. Coates (Q0) observed no, relation between smoking habits; and vital capacity or FEV;,a. He did find, however, that the ratio of FEV,.o/' VC was significantly lower among heavy smokers (25' or more ciga- rettes per day)' than.nonsmokers. This was found for a16 but the old- est group of workers; but here the number of'subjects was small'. Peters and Ferris (59) askedi 133' Harvard College seniors to com- plete a questionnaire on respiratory symptoms and to perform some sample tests of pulmonary functions. Of these„124 responded. When classified by smoking history,.the smokers were found to record more frequent cougiy phllegm productiony breathlessness, and wheezing with or apart from colds:. There was no d'ufference in vital capacity be- tween~ smokers and nonsmokers. Alt'hough~ tlhe forced expiratory vol- ume in 1 second (FEVi.o) was less for heavy smokers than nonsmok- ers, this was not significant' by itself. As a ratio of'vitali capacity this did show a sigpificantt decrease., The air flow rat.ee using the Wright peak-flow meter and other$ow rates determinedi from tracings of the Stead-Wells spirometer (FR;,n, FR.es, FR,,%, FR,a%) did show statistically significant reductions in heavy smokers as compared to nonsmokers. These data show that relatively young,cigarette smokers have some impairments of ventilatory function, in turn suggesting the possibility of a: rather immediate effect of cigarette smoking on respiratory symptoms and ventilatory function. A series of experiments has been done by Krumholz andi his asso- ciates (49, 50, 51) to evaluate cardiopulmonary function in young apparently healthy persons. The first experiment (Yr9)) involved 1'fl'8 house staff physicians ranging in age from 24 to 37 years. Nine had smoked at least one pack of'cigarettes a day forthe preceding, 5 years and nine had not.smoked for at least the.same time period. Extensive: pulmonary function studies were done at rest and after exercise. The& smokers were found to have a greater oxygen debt after exerc.ise„de- creased diffusing, capacity at rest and with exercise, and decreased total lung capacity and vital capac.ity. In the second Krumholz experiment (50), 10 young staff physicians,all'ofl whom had smoked at least one pack a day for 5years, were given pulmonary function tests immediately after and again 33 weeks after abstinence from smoking. Six physicians refrained from smoking for 6 weeks and were testedl again. After 6' weeks of no smoking; expira- tory peak flow and' pulmonary diffusing capacity weresignificantlyincreasedl. Heart rate and.oxygen debt.aftert exercise were decreased. After 8weeks functional residual capacity was decreased andl inspira.tory reservee volume and' maximal voluntary ventilation were increasedL 100

ventilat'ion. measured by nitrogen washout, and an increase in aivwu; resistance as measured by dynamia spiromeUry."' Rr"sunre Two recent studies (l7, 53)) of popuSations of identical and fraternal twins show that for some individuals in the populations studied a genetic element appears to. be of.some importance for the development of cough. However; the effect of smoking was clearly shown to he' much more important for most of the,indnviduals in the total popula- tions studied. One study (53) also clearly showed that smoking twins more often had reduced ventilatory function tests as compared to their respective nonsmoking twins. These dat'e, provide strong confirmatory evidence that cigarette smoking can cause chronic bronchitis; however, no, inferences with respect to pulmonary emphysema can be based on these datn. Studies such as these, when specifically designed to provide additionalliin- formation aboutpulmonary flunction, may be helpful in evaluating the relationship between cigarette smoking and'pulmonary emphysema. PATHOLOGY STUDIES Very few papersrelating the gross.and's microscopic appearance o the trachea, bronchi, and lung parenchyma to tobacco smoking have appeared in the last 3 years. Auerbach andl his coworkers have con. tinued theiranalysig of bronchiaLtissues.taken frdm 758 subjects (7) andi lung parenchymaI tissue taken from 1,340 men (8).. They pub- lished a report (9) correlating findings in the bronchial tree with findings in the Ihng parenchyma of 267 men who were included in both previous studies. They reported a high correlation between fibrosi's in the lung parenchyn¢a and different abnormalities of the bronchial epitheliumy such as hyperactive glands„increasedl nuunberof cell rows iia~ the ciliated epitheltium,and increasedl frequency of cells with atypical nuclei..As reported previously by and summarized in t'he Surgeon GeneraI's1964 Report'y, more frequent and more severe ab- normalitieswere observed among cigarette smokers.. Seetions of the bronchial tree among ex-smokers were more like those of nonsmokers while fibrotic changes in tlie, lung parenchyma were more like those observ.edd amongsmokers.. Changes in the bronchial tree similar tlo those.described by Aue bach and his; coworkers were reported inn a.series of 100 random adult autopsies by Hernandez,and Anderson and. their associates (38). They reported a.higher frequencyof abnormal epithelial hyperplasia,.goblet cell hyperpi'asiay round! cell infiltration, congestion, and edemaa in 104

(;). AsTavr, P: VariatSonert.oksltiaemoglobinets..dissociationskurve:Ugeek for Laeger(S:obenhavn) 128(24).: 695-70141900. (5). Asrevr,. P. Haemmet iltafgift' fra blodet agudviklingen af obLtererend arteriesygdomme: Ugeskrift for Laeger (Kobenhavn) 128(24) : 701-700. 1`.mu. (6)ABTBIIP, PL, H6LLAN6-LARSEY, P:,. KJELnsEN, K.,. M!OLLEMOAAanI K. Th effect of'tobaccosmoking on tlie.dissoclation.curveof osyhemoglobin: Investigationss in patients Ici th occlusive arteriall diseases,ia normaLsub+l jects. Scandinavian Journai of Clinieal and Laboratory Investigation (Oslo) I8(4)c. 4.ril-157;.1908L (7). AUEanACIr,. OL, HAMMOSn; E., C.,. GeaazxsEn, L. Smoking in relation atlieroselerosis of.the.corunary arteries. New England Journal of Medi cine(Boston): 273(15).:. 775-779;. Oct 7,. 1905. (8) AclAno, D. 3f., SAwAqES„M., FOLLE, L. E. Cardiopulmonary effertsof ta' bacco and relatedd substances.. I. The release of'histamineduriag inhala tion.of'cigaret!te.smoke and.anosemia.in.the heart-lungand intact dog preparation.. Archives of Environmental. Health. (Chicago), . 12(6): 705-724; J!une.1960.. (9)timEs,. S:.M. Personal Communicat'lan. Nerv. York, St. Vincent's Hospital and Medical. Center. [Unpublished.] June1907: (10) Axxes;. S:, bL„ GIANnEtr,L, S., Js., Aaxamaosa;. R. G. Carbosyhemoglbbin: hemodynamic and'd respiratory responses too small concentrations. Science (SVashington) 149:.193-194, July9i 1905. (11) B~aoEaox;. L. M„ Ja:, EanrsE, D., GoxLuBoL, F., CASrmaAlvos, F:. A.,,; Smoea., A'., BLSC„ Rl J.. Effect of cigarettee smokingon coronary bloodd florvand myocardial metabolism. Circulation ; Journal of the American.. Heart Association. (New York) 15: 251-257, 1957. ('12) BSLLL•r, S., WEST, J: N.,, Mtha.zn, 0~ . F., MANZoLn; U. C..Effect of nicotine ow the coronary blood flolvand relatedcireulatory parameters. Correla- tivestud8 in~normal dogs and dogs with coronary insulBciency+. Circula- tion.Research 10(1) :27-34„January 1962. (13) BENSON, H., COaTAS, H., JR.,, G98eIA-PAL3[IERI, M. R., FELraERTI; ArsALd, R:, BLAxToN,.J. HL,. Couon, A. A. Coronary heart diseaserisk faetors:. A comparison of two Puerto Rican populations. Amerir_an. Journal! of Public Healtlih andd the Nation's Health (iCew. York)~ 50(7) .: 1057-1060; JulyQ906:.. (1¢) BEST} E. W. R. A Canadiann study o8 smoking andlnealth. Otfawa~. Depart- ment of National Health and {VeLfare,. 1906.' 137pp:. (15) Brso,. R. J:,,B~miisa,. A~.,.BLuenmaeta, G., Couxre,. A.,,GwlasGxeR, J..P.,. F.ALMxr, E. J. The determination of coronary flow equivalent with eo- inciilence . eounting technic. Circulation ,. Journall of the American Heart Association (New York). 29:883-84G, June 1909. (16) Basa; R: J~, CosEre„A., B'LCES[caEm;,G. Tobacco alkaloids and.circulation. In: Tobacco Alkaloids and Related, Compounds. Proceedings of the 4th International.Symposium.helfl at the.{Tenner-Greu Center,. Stookbolm, February 1984 : 1905; Pp,, 241-251.. (17) BosuANi, N. O;, HECICTEe, H. H., BaESLOW„ R'. Reportt of a 10-year fol- lonvp study of the San Francisco longshoremen. Mortality from'coronary keart disease and fromm all. causes; Journal! of Chronic Diseases (St. Isouis). 10-1251-1208, 1903. f18) BaecnrnLn, N.,.BozEe;.J.,. GoaLrv, R..Action ofnittoglycerih on coronary circulation in, normal.and in mild cardiac subjects.,Cireulatlon; Journal of the.AmericamHeart Association.. (Nen•York) 19: 097; 1952.

to emphasize the Iack of progress in.defuling the two conditions' fo' monaryemphysema are then.provided.. animal experiments.. Additional considerations pertinent to pul report but are grottped 1n populatlon studles„ patihology studles, andY search findings on both diseases are not considered separately in t'his' i tory disease published sinee'the Surgeon General's 1964 Report. Re- to record the research findings related to smoking andlchronic respira- searchers are limited to describing symptoms andisigns observedn in t;he? populations under investigation. It may also explain why it is diH'i..~' cult to dist.inguish these conditions in the present report which seels` This statement may help to explain some of the.difficulties encoun! tered by research workers in studying these:diseases and why the re= "Chronicbronehitis and emphysema coexistinm-tany patients ' ' * physiologic abnormalities are similar in both~ diseases. sema, the' array of symptoms,. physical' findings, and pulmonar,j more cough and sputum than do those having only pul'monary emphy; "Although patients having only chronic bronchitis tend to ha has hampered medical research and, exchange of information. P'.113.SL. N.T:A, task force report states further: IInabilitiy to' distinguish between chronic bronchitis and emptiysema ly identical definitions'willi be foundi, erence' may be' mad'e to the Surgeon General's 1964 Repor6t where nea purposes of differentiating tliemi from other diseases of the lung. Ref as can be seen ini table'1. conclusions cited ini the Surgeon General's,1964 Report. Deaths in the United States from emphysema or chronic bronchitiss orbotlir have risen steadily fcom about 3;0000 in 1950 too more than 20,000 in 1964, the upaYardd trend well established at the time of. publication of tlie' Mort':alit'y fronl chronic broncliopuImonary diseases has cont'inued CHRONIC BR4A1\'GHpPULltiO'NARY DISEA'SEMORTALITY r codes.601, 502, 527:1) TAB'aE 1.-DMortndit9y,' front emphysema' a.nd'/or chronic hronchitis (riSC Year Number of deaths' Year Number' of deaths 1964___.______ 20, 208 10; 433 1963I____._____ 19,443 1958 9, 328' 1962'_________ 15,915 1957__._______ 8;. 136 1961 13,302 1056L_.___-__ 6,535 1960 12,426 1955~__._______. 5,616 6arrace:. Vital Statlst'ks of the United Btetes,14§4ID644 (70). Vear 1954_________ 1953_________ i1952________. 1951___.______ 1950________. 4, 877. 4,.657 3,846 3,6(50 3, 157 '.Yll death ratess throughout this chapter aren per 100,000 population„ unless otherwiseihdicated. 90

maldehyde, crotonaldehyde, formic acid, acetic acid, proprionic aciX andi some phenols are also cilfiatosic (25, /t6, .48, 73, 77; 79)~. F~~'urtharl information may be obtained from a special symposium on ciliary activity held in 1965 (48)~ A recent study (h) suggests that osidativa enzymes such as adenosine triphosphatase, apparently important to ciliary activity, may be adversely affected by cigarette smoke. Add~y tional research is necessary before precise conclusions can be stat~ concerning which, if any; of the identified ciliatoxic agents contain in tobacco smoke are.most damaging to the human respiratory system4 OTHER FACTORS ASSOCIA'Il'EIYi WITH CHRONIC BRON- CHITIS OR EMPHYSEMA O1t BOTH 4 It is not the purpose of this report to, discuss all the factors that may play a rolie in the development of chronic bronchitis and emm physema. It is important, however, to recognize thatl these condi- tions;do exist among people who do not smoke and that many smokers apparently escape all. signs of affliction. It is also important to recog-. nize that other factors have been associated with the development of ' chronic respiratory disease, or chronic bronchitis and emphysema{ ' as we have defined chronic respiratory disease. We must be concern with~ the multiple etiology of biological proce_sses..One factor alre•ady ' cited is the role of heredit.'ary or eonstitutionali factors in the develop-, mentt of respiratory symptoms, either operating alonee or in conjunc-- tion with other factors such as smoking:. Aside from the personal pulmonary pollution, inherent in smok- ing, occupational exposures (a wider fiorm.of pollution) and exposure to various pollutants in the atmosphere have both been shown to influ- ence the prevalence of'respiratory signs and symptoms. Studies made in someispeeific industries-for example„ puIp mill workers in New England (3$):, coal miners in West Virginia. (31):, and gold miners in South Africa (66, 67)-have shown an increased frequency af respiratory symptoms or of diminished pulmonary function among men exposed to certain dusts and fumes. t These studies indicate that cigarette smoking is generally more important than the oecupational.eaposures in producing respiratory dflsease in the workers. These studies also suggest that cigarette smok- ing may interact with some occupational. exposures T.o produce even greater deleterious effects. Cigarette smokers outnumber by far the workers subjected.tonnusual environmental exposures. Also„there has been a general. improvement in many occupational environments„in the continuing effort to remove or reduce the exposure to specifia'undus- trial airpollutants: , 108. 0 I I

SA27.Smokingand atherosclerosis, Bri:tish Medical Journal (London.). 1: 75 756, Mar. 26,1966. S128,. Smoking and Ibloodl clotting. British Medical Journal. (London), 1: 833'-, &34, Mar. 30,1963. 5129. SbIIEErt, A., HOIISSSY, 11. E. . J., BAaaoasE, A., RmoxDAE, D. G. C., CEacL'vo~' 0. A. Accldnn dell fumar sabre la circulaci6n menor. Prensa Mddlica Ar ~ gentina (Bnenos Aires) 52: 1547-1850;,Aug..27;,19651 5130., SPanavE, Hi B. Environment inrelation to~coronaryartery ddsease.. Archives of Env-unonmentali Health. (Chicago), . 13(1) :4-12, July 1966. 5131., STAr-EaxES, R.. A. V.. Prospectivee epidemiologicstudiies ofcerebrovascu- lar disease:. In: U.S. Publir. HealthService. Cerebrovascular disease,, , epidemiology, a workshop..1R'ashington, U.S. Government Printing Public Health Monograph No. 76. Public Health Service Publlcation No.1441,.1900i Pp:,51-55. 5132. Saeax„S.,.Baevs, K. Effect of ebemo+eceptor stimulation on the.pulmonary, veins. American Journal of Physiology (WasHington!) 210(3) :535-539,' 1966; .1 5133. TALSOxT, G: D.. Influence of environmental fuetors.on llpid-response curves,y Cigarette smoking,. salt, alcohol, and liigh-fat't diett effecting healthy males. Geriatrics (Minneapolis) 19(8): 570-584, August 196i:. 4 5134. THOMAS, C. B.,..MUaenY, E! As Circulatory responses to smoking in heaithy~ young men... Annals : of'the ti ew York. Academy of Sclences 90~:, 266-276;, 1960. 71 5135. TnoreAS, C. B.,, Ross,D~ C., Hiatsaorxroy, C. Ql, Precursors of' hyperten; sion.and coronary-diseaseamongy healthy medieall students:. Dlscrimi-' nantfunction¢nalysis: 1. tisingsmoking habits as thecriterion.. Bulletinn of the John.sHopkins . Hospital (Baltimore) 115: 174-194'„ 1964. 8130. TStJixoTO;. A.,. TAN¢so,.. S., Kvaaaocnr, Y. Effect of nicotine on seru ~ potassium and'.blood glucose. Japanese Journal of Pharmaeology(Ky.; otb) 15:. 415-422, December 1965~. 9137. U:S. PUnaxc.HuAt.xrz SERvrce:.Framingham, Mass. Duration of cigarette smokinghabit. Jlyocardial: infaretiann oncoronary mortality. Heart Disease Epidemiology Study, b'ramingbam,. Mass. Apr. 21{ 1966. [Unpub lisbed.] '4 pp. 9128. U,S. Puar:re HEAaTIP Seuszcn National. Centerfor Health Statistice. I Cigarette smoking, and health characteristics, Unltedl States July 1964- June 1968. Washington,. U.S. Departmentt of Health, Ediucatlon, and Welfare, Vitall andHealthi Statistics Series 10; No. 34, Public Health' Service. PttbIication. No.1000,.3Yay1967. 64 pp. ~ S139. ViswxvArxax,,R Acuteeffectsofcigarettesmokingon.pulmonaryartery' pressures. Indian Journal ofbledicallResearch (Calcutta) 53'.(5) : 421? 427„ May 1965: 5140. 1uACxEa, A- R. P. (I7ditorial).. The preventionn ofcorouary keart.disease_, American. Heart Journal (St. Louls)', 72(6) : 721-724, December 196&~5141. 1C'Ar.xea, W. J:, GaECoanros„ G. Myocardial infaretion in young men. American..7ournal of Cardiology (New York) 19: 339-343, March 1967a 5142. R'e.rxgxex:r, B. T., Easnrx; F. H. Comparability of criteria andi methods in the epidemiology of cardiovascular disease. Repart.of a.survey:.Cir-' culation; Journal of the American Heart. Association (NewYork)y 30(5)~: 643-653; November 1964 11. 5143. IVENxEt:, D;,G.,. STARa,. L. G: Effect of nicotiue.on cardiac necrosis induced by isoproterenol. American Heart' Journal. (St. Louis) 71(3) :. 865.370,' March 1966. I) 84 41

GENERAL CHEMICAL AND, EXPERIMENTAL DATA ON CARCINOCMENESIS AND: TOBACCO SMOKE PolynuclearArom¢tic Hydroearbons As criteriafor the presence of polynuclear aromatic hydrocarbons in tobacco smoke, the list of J. W. Cook (20) has been lvidely accepted by tobacco chemists. The Surgeon General's 1964 Report and Cook's paper are in agree- ment.with respect ta:thepresence.ofbenzo(a)pyrene.(3:4'-benzopy- rene):, dil.iena(a,h)-anthracene (1,2: 6,6-dibenzanthracene),' benzo(c) phenanthrene (3:4-benzophenant4mene),, and dibenzo(ayi)pyrene (8J: 9,1I0-dibenzopyrene)y.all having:carcinogenic.aetivity. Cook considers,furthermore;asidentified': Benz(a)anthracene (1,2- )benzanthracene)marginall carcinogenic activity; chrysene,,benzo(e); pyrene (1,2abenzopyrene)y questionable carcinogenic activity;: benzo (_c,h,i)-perylene (1,J:2-lienzoperylene),2 benzo(b),flboranthene (3,4- kienzofluoranthene) carcinogenic (o9,:1I6),.and benzo(j)flhoranthene (19,11-benzofluoranthene)~ careinogenic. (106). Indeno (1.213'-cd)pyrene:(2;3-phenylenepyrene) has sincebeen iso- lated from tobacco smoke: (4'.5). Tihis polynuclear aromatic hydrocar- boa was found to be carcinogenic (44, 69). The following carcinogens, or questionable carccinogens, were isolated by Kiryu and Kuratsune (55) in thesmoke of' cigarettes smoked by human volunteers:: benz (a) anthracene, chry,sene; benzo(a)pyrene„benPo(e)pyrene, benzo (b) fluoranthene and benzo (k) fluoranthene. The carcinogenic polynuclear aromatic hydrocarbons areregnrdede ass the: major initiatingg car- cinogensintobaccosmoke: :1'-Heterocyclzc A'romatie Hydroaaraons The Surgeon General's 1964 Report lists as carcinogenic compounds three NI-het'erocyalics, dihenz(a,j)acridine,, dibenz(a,h)acridine andl7 II-dfibenzo-(c;g)earbazole. An independent imvestigation has con- firmed the presence of the first named compound in cigarette smoke (107). R'-A?i'trosamdm,es N-nitrosa¢nituss are among the most powerful known animall car- cinogens.. Since tobaccoo smoke contains secondary amines, (67; 71) 'Dibenzo (a,h)unthracene.in the Surgeon General's 1964 Report.should be repl6ced by dibenz(a,h)antbracene(E4',):.. 'Benzo(E,h;i)peryleuewasnot tested'for carcinogenicity until 1966 nnd then was.found to be.inactive (i44) . 127

es-smokers of 5' years or more was 37 compared with a rat'e of 59 for ill other smokers. Similarly, in the study of U.SL. veterans, the mor- tality ratio' for chronic bronchitis and emphysema was 10.1 for all' >nale,current digarette smokers.but only 7.6 for men who had stopped sTnokiilg far reasons other than "Doctor's orders:" ga- I was !oniio 4, in iwa iI 25 Cat 01la itis than have Phy- pians con For ~tloni aued I,000 RETROSYECTIkE STIIDIEB Wicken (75) made a study of lung cancer and bronchitis mortality in Nortlhern Ireland. During the3 yearsi.1960-6L„a totall of 1,262 men and 680 women, aged 35 years or more, were certified as having died of! bronchitis. For each of these persons a. control was selected-the next het on in the Register of the same sex and 5-year agee group who la~t resided in'the same area and who died of a nonrespiratory illness.. Pcrsonal interviews with relatives of the decedents were carried out for about 94 percent of the subjects and controls to determine the dccedents' smoking habits., Iu addition, a random sample' of about 1.J(i0, lh.ouseholds'ih Northern Ireland was selected and one member of each household was interviewed to obtain dl'ta'ilsof the age, sex, smok- ii1, h:cbitsy, and other information on all adult members. This informa- tion on all adult members was used to define the adult population of N'ortihern Ireland in order to calculat'e death rates: Bronchitis mortalityfoc both men and women was associart.edi with sniohuig and directly related to the number of cigarettes smoked daily, as-cenintable6: ' TABLE 6.-Age-standardized deatfirates per 1'00,0Q0 popuLa.tion.from bronch'itis for adirlts 35 years old and:oaer as related'to smoking habits I I I Numberrof cigarettes smoked'daay I 6mnker uL 1-10 (245): 189 (57) 77' k"w00): 220 (20). 118'. 23+ I t~ii§arBLt9br I Plpesor'' P'pes!ur eigers cl®p25 (P68) 284 ~ (62) 99 ~'(289) 118 (1'S) 201 1__-------- (2) V65 , Figures'.in pacenthesav show the number of desths uLwn which theaataa ere based. eouxcs.:.wdcku study (7s). I7 ing these data, Wicken applied the bronchitis death rates observed among male non-smokers to all the male population of Northern Ire- land and estimated that had these rates prevailed, only 45 percent of tltee male deathss from brohchitis would have'e occurred.. I~l:`FIBIIDfE Recent data from the four prospective studies and the one ret.rospec- tiv.e study all reveall, for men, an association betcveen cigarette smok- 95 ,«:

: 96-97 ,q.coagu- )hicago) ~ reciewy Ist 19&.., ecumseti if 5fedi•~ 3 1 nd per= May 14, +ts of.to-; ~igarette ;hicago), ¢ascular 731-746, rdiallih- ncidence ;hicago) :al iaso- Circula- 4: 1022- mronary nference. ' lssaaia. 'tgarett 87e po Jour-N I ? .glyaerin s:. Circu- 19: 700, 'n: Dow, hington, patterns „ Educa- lth S'erv- lion men es to the Ith Serv- :966. Pp. (}Pq Hrccnrs, M., Kaeceasaa, M., MerzNEA H.Characteristi:cs of smokers and nonsmokers in Tecumsehi Mich. I:.The distribution of smoking babltsliu persons and families.aud their.relationship~to social characteristics. (In press), American Journal of' Epidemiology (Baltimore) :1967. i~TO)HIOCrNs, M., Kascseeao, ML . Characteristics of smokerss and nonsmokers in Tecumseb, Mich.. II:. The distribution of selectedd physical measure- mentsand.physiolagicall variablesand the prevalence.of certaiadiseases in smokersands nonsmokers. (In pness:). American Journal of Epidemi- olog.e ( B'altimore) : 1667; 27 pp: 1.711 Tosxrss, C. D. Personal! eommunieatiom TheUniversitiy of North Caro- ]ina, Chapel Hill, Apr. 16; 1967. n~?i KAnu, . H.. A. The Dornsbadyofsmolting and mortality among U.S. veterans: report on.S1/2 years of.observation-In:rHaenszel,.W'., editor. Epidemiologieai.approaches to.the study of cancer and ottier diseases. Bethesda,. U.S,. Public Health Service, National CancerInstitute3fono- graph.' N a: 19, January 1966. Pp. 1-125. ~-'.:7~ IC.nssnr, W.. B. Cigarette smoking andl coronaryheart disease (editorial). .lnnals of In2ernal. Medicine (Philadelphia), 60!(6) : 1103-1106i June 1944. r Iiassen, {4C B., DAwaxa, T.' R„COans,'_1'i. E., McNAaresa, P:.M. Vascular disease ofthef brain-epidemiologic aspects: The Framinghamm study. .a'merican. Journal of PublicHealth and the Nation's Health (New York) M (9) : 13a+-1366; September 1965. .;:r) I<~..cs}m., W. B., DAwana,. T. R'., MaNAnresa, Pl. M:. Detection of the carm- nary-prone adult: The Frnmingham.study. Journal of'the Iowa..Jledical Society (IDes Maines) 56(1) :, 26-34, January/196li1 ~?: i KEOaay \I.. Koaor:xo;, A. Tobaccosmoking and blood clotting-.. BulIetinn of Polishliedical Sciencee and History (Chicago~). 8: 145-148,October IOBa. Peasna.irvr, A.,,Bxr.r:e.T, S. Cigarette.smokingandhlood lipids. Journal of the American Medieal' Association (t<"hicago)'. 187(:E) : 3Z-36, Jam 4, 1964. Iieasaexuyr,. A.,. BEar.er,, S. Smoking as a factor in atherosclerosis_ Geriatrios; (]Linneapolis). 21(12): 153r170;. December 1966. Iieasnnerx, A.,. BE=, S.,. JrxEaEZ; J., Fraamesa, L.. J. IDifferencesin effects of eigar andd cigarette smokingg on free fatty aeld:. Mobilization andd catecholamiueescretion.. Journal of the American Medical Asso- ciation (Chicago) 195(1'3) .: 10S:r1098, Mar. 28, Ri66. i;9:) Iiauuuorz, R. A. Pulmonargmembrane diffusing eapacity and pul- monary capillary Illoodd volume: An appraisal of theli clinicall useful- ness; American~ Revieww of Respiratory Diseases(Baltimore)94(2): 195-200, August 10(36i !G1.). IfatAnmr.z;. R. A., Cnavnrs:ea, R. B., Ross, J. C. Cardflopulmonarp func- tiouin. Toung.g smokers. A comparison of pulmonary function measare- ments and some eardiopulmonaryresponses to eaercisee betweenn a group of young smokers and a comparable grompof nonsmokers. Annals of Internal 3iedicine(Philadelpliia) B0(4).:6tY3-610;. Apri1. 1964. 'N2)Karxxrorz;, R. A,, CHxrar.rea, R. B„ Ross, J!:. C. Changes in, cardiopul- mona.ry functions retated to abstinence fromsmokiing. Studies in. young cigarette smokers att rest and ezercisee at 33 and 6 weeks of abstinence. AnnalsofInternal. Medicine (Philadelphia): 62(2) : 197-20'ft February 1965.

S3}, 11ESIinaxers, G:.A. Themeteorolugsassociated with New Orleans asthma, Axchives.ofEnvironmental Health (Chicago) 11I(8) .: 787-79C;,December 1965. 53:i; DoawANor, T. L.. Abnormal: osygen-dissoeiation curves (letter). Lancet (London) 2(7402) : 80-81, July 1% 1965. 536:Eowaaos, G. Acute hronchitis-aetiology,. diagnosis, and. management. British Medical Journal (7.andon) 1(5493) : 963-966, Apr; 18, 19661. 537.. ENrERLINe, P. E.,, LAINHAaT,. W. Si The relationshipbetween coal mining and chronicc nonspecific respiratory disease. American Journall of. Public Healthandh theriation'sHeaIth(wew York)I 57(3) : 4&1-495, Marck. 1967. 538I Thee ethnid distribution of disease In the United.States:.Journal of Chronic Diseases (St. Louis).20(3).r,115-1L8; March 1967. 539. FrcEEr, G. F.. Emphysema and chroniec bronchitis;: Clinical manifestations. andd their physiologie significance. Medical Clinicss ofl North America. (Philadelphia) 51i(2): 283-292,. March 1967. 840: FLETCHER, C. M.. Some.recent.advances in the prevention and treatment of'f chronic.bronchitisand relat'ed: disorders. Witte special.reference to theeffectse of cigarette smoking~. Proceedings of the. Royal Society' of il9edicine . (London) 58 No:,11, pt. 1):918-928, November 1965, 5!1. FOROTEaj, R. E.,. RotiOHTOS, J. W., CAransR, L., BBIBCOE, . W. A., ICBEIIZEB, F:t kpparent pulmonary' diffusing capacity for 00 at varying, alveolar Oi ten- sions. Journal of Applied Physiology (Washington) 11(2).: 277-289;. September 1957:. 8-F2. GERnea,. P. An infeetiouss deoayribonucleie acidl derived fromm vacuolatingg virus (SVr,).. VirGlogy(New Ybrk). 16(1) : 9C-97, 19G2:, S13. GLASSER, M., GRSENBUaG„ L:,. FxEin; F. Morbidity andd mortality during ann episode of'f hi6h air Iwllution,. New York City, . Nov: 23-25, 1966. April 1967. [Unpublished.] 92.pp:. 594. GOLDSMITH, J. It. Air pollution, medical research. Science (Washington) 154(3756) : 1588'-1591,, Dec. 23', 196C:. Sd+i. GanusxxrH, JL R:. Epidemiology of' bronchitis and emphysema. I. Factors influeneingg prevalencean& a criterion for testing their interaction. SSedicina Thoramlis(Baselq 22(1 ):1-23,1965. 8-16. GOLU9YITH, J. R„ t~1REE9BUEG, L., ALTeHIIt.IRaj A. P., SFICEa;, W. S., JR., CASaEi.n, E.. J., Lx~,asBEao;. H. E, Air pollution and health. A statement bythe.Committee.onair pollution. American Review of Respiratory Dis- eases(Baltimore) 93.(2) .:. 302-312;. February 196C~. 547. GREEN, H. L. Respiratory protection againsrpartinulates-problemssolved and unsoll-ed. American.Industrial Hygiene. Association Journal (De- troit ) 26( 3): 203-211,. May-June 1905. 548. GREao, I. Chronic bronchitis and occupation (letter). British MedicaTJour- nal (London) 1(5488) : 675~i6, Mar. 12, 1966. 549: Hacaraox., R.. ]f.,, SPRAauE, H. A.,. LANOau, E. The Nashville air pollution study :, VIL.}lortaiity th'om.cancer in.relation.to.aikpollution.. U.S: Public Health. Service, Divisionn ofAii• Pollution;. Conttact No, . SAph 69628 and Contract PH86ti5--15.7. [Uhpublished.] 17 pp:. S.1Ui HAU,exT,. W;.Y. Effect.of azone.and cigarette smoke on Iung function. An- chivesof Environmental Health (Chicago) 10(2').: 295•-302;. February 1965. 551.. Hk.vnosu, E.,C. Smoking in reiatiomto mortality and.morbidity. Fiudings infirst.3fl months of followupp in a prospective study,started in 1959. Journal of the. National Cancer Institute (Washington) 32i(5):1161- 1188,.'.UayI961. 271~a9a 0--67-9

In the. female population the greatest percentage increase (1116 per- eent) over the 15-year period, 1949-64,: occurred in the 35-14 year age relation to cigarette-smoking hist'ory as presented by mortality rati and.by death rates per 100,000 person-years. (Tabl'e 1).. about the lung cancer mortality experience of both men and. womem in f-Ia.mmond's (4d) prospective stmdy provides extensive informat"son continued to increase for eac4 cohortto the end of the life span. group 45-54 years. The death rate from lung cancer among women, 25 years: and over, rose steadily with advance in age for each year during 1950-64,, andd the cohort experiencesliows that these death rates group. The next highest percentage increase wasnoted in the age Tenr.E 1.-Lung cancer mortttllity ratios and death rates' of amokers by sex an.d specific age groups 4frdt Years h3orta3itv~ ratios---- - - -------.-- Deathrates--_--______-._-_---_ remeles z.. 17 r (7)15 Melae 7.84 r (11)87 Cf74'Aean~~. Females 11.76 s(17)30 Meles 11.59 r(E3)262 ~ I CumVuted hnm epp. t8b]e 19. r Numtlersin permntheseslndirate death rate.e br nonsmoke[s. 9ouscz: Hammandl E..C. Itahles 2f:end 28.:app+ table 19 (4077. Tables 2 and 3 below show the relationships of number of'cigarettes smoked per day, degree of inhalation, and age smoking began, to lhng, cancer mortality ratios and death rates for malesand females,, respectively., t`ienerallyy, mortality ratios and death rates increase with increasing amount of cigarettessmoked and degree of inhalation, and' with a longer liifetime history of smoking. Table 3 shows the relatively lower lung cancer mortality among wotmenn as contrasted' to men„ but reveal9, for the most part, the same relationship to amount smoked, degree of inhalation, and age when smoking began. Table 4 illustrates the fact. that cessation of cigarette smoking is associated with a decline in long cancer death rates: • The mortality ratio is the ratio of the death rate of'smokers'to that oLnon smokers-the mortality ratio of nonsmokers alwayss being one;, bydeanition 134

m) 1: 75 tn) 1: C., CaaVISP MLd1ha se. Archi ~6: !rebravasc lar di'sea ating Of6 Publicatio f' hypert : Discri o. Bulle 964. on Seru alogy($ f cigaret ity. Hea G; [Uapa Statisti July 1964,-' etion, a rli'e Heal flry arte +{5) : Iut dise acber 1 bung m ~arcli 196' l metbaE prvey.. C erv Yo Ils indu p 368-37 I 514A= WEFzzL,.D. GI,. Su, J..L: Interactlonsof nicotine and.tyraminewitlu adte- nergic.blockingagents aa ventricle strips. Archives LnternationaIes.de Pbarmacadynamie et deTherapie (Gand) 162(1) :. 180~185" July1966. 8145. 19zwzzc, ID. (4., Tvavza;. Ji. A., Joanex, S. W., SiFaa, J. Cardiovascular interaction of nicotiue, ergonavtneand hypereholesterolemia.in the rab- bit. Cirrulation.Aesearch. (New York) 9:. 694-699,May 1961.514G. NnmzsL, D. G., Tvvusa, J. A.,, Sxsarn, D. Effect of nic.otineon chol'asterol'- indueed atheroseferosis in the.rabbit. Circulation Research (NewYork) 7: 256-261,.19ii9: ?117. 11'aivzzl„ D.. G'„ 1PArrexeporvosrm, A., Vsoaaz,. D:Nicotine. and renal hypertension inn the rat. Journal ofPtiarmacologg and Experimental Therapeutics(Baltimore).145(ti3) : 315-316, September 1964.. S1fa,, WEST, J: W.,. GAZxerr,. SI V:,. Baa.ET;.S. Cardiac effeetsof intracoronary arterial injections ofnicotine.. Citeulatiun Research (New York) 6: 389-395, May1953; S1-1D: R'ESrenrs:,. Tl. O. Tobacco alkaloids and the release ofeatecliolaminesf iir: TobaccoAlkaloids.and Related.Compounds. Proceedingsof the 4th. Internatdonal Symposinm.lield at the Wenner-Gren Center, Stockholm, February 1963 : .1965, PD. 170--209. Wur, W., PFALrz;, Cl R.. Sehiidigungesder Sclileimhaut.d'er oberen luft- und Speisewegee durch. tabar... Prasis (Bern) 55: 182-184,. February1966. Si --1. R'nrTE, H., J.,. GOas;, I., LARKEY, B. J. The antagonism between nicotinee and mucopolysaaeharide activity. Bioehimica e BSologiu Sperimentaln. 3(4):, 107-11_'6,1964. SS:,2i lYice_~is, S. L. Relation of tobacco smoking to cardiovascular disease. National Conference on Cardiovascular Diseases (Washington) 24. 360.361,.1964.. $1:,'i. \cxrr,as„ S. Ik, PtAra,. C. Sf. (Yigarette smoking and arteriosclerosis.. Science (Washington) .138: : 875-877, Ilovember.1962: 54:,+, R'TLcrAMrOLSSOY, L. Rokningoch.blodsocken Lakartidningen (Btoekholm) 029: 381G-3811, November 1965.. Sl :;. WrvxErszers, \L'.,. Jn. Study of blood pressure in. Buffalo, N.Y.. Annals of the NewYork Academy oPSciences,107: 576~-575J.May22i1963'.. 1FitifiELSTe[N~ \V.,. Jr. IV. Same retrospective studies of' cerebrovascular disease.. In:, U:S: Public Health Service. Cerebrovaseular disease, epldemiologS:, a workshop:IS'ashington,. U.S,. Government PtintingOlilce, Public Health Sprvice. Publication Na. 1551, 1966: Pp. 4'1'-491. ti167: 6'vxv, A„ The recognition of coronary proneness. Medical Journal of:4ustralia (Sydney) 1,:350-853, February9967. Y:rxAMOxo, 5.,, Mrnnxt,, T.,. Fvxr;r,. 1. Determinatflon of inhibitors of urokinase-actiiat'ed 8brinolytic enzyme sFstem by means of' gell flitraw tiow inn human serum.. Reio Journal of Medicine(~Tokyo) 15(2).: 63-66, June 1966. Znaciar., E. V. Pharmacoiogical study of the central nieotine-sensitive etiolina-receptors. Actibitas. Nervosa Superior (Praha)8(1): 6G-67, 1966. 85

vol~ aiok- ~ii gh~ Ethe fh'ow uW Vkers mgl lung' 18° ~ad~ ars ive1 The ~de- ised I ~"s'' l pen: (ter ~ for a- t1y j Hed• I t ira i re The final study (51) again used 20 young medical persons divided among 10 smokers and 10 nonsmokers. The mean puhnonary com- pliance was siglt'ificantly greater for the. nonsmokers than for the smokers.. Since cigarettesmokers have a chronically elevated carboxy- hemoglobinn level~ usually greater than B2 percent and occasionally exceeding 10 percent, a study (19) was performed having nonsmokers inhale enough carbon monox.ide to raise their earboxyhemoglobin levels to the range seen in acontrol group of'cigarette smokers. This maneuver caused the development, im the study group of nonsmokers, of an increased oxygen debtwit,lt exercise and a reduced pulmonary ditfusing capaeity at rest. These changesafter carbon monoxide in- halation were similbtr to those found without carbon monoxide in- halation when comparing cigarette smokers to nonsmokers:. (Further (Iat:cconcerning smoking and carbon monoxid'e is presented and dfis- cu,sed in the chapter on cardiovascular diseases i'¢i this report.) Rlksu3~d Findings from various studies relating,smokingto pulmonary func- ttorlare less consistent for certain criteria of measurement than from those reloting smoking to respiratory symptoms. They are, however, "onsistent ircthat they all report some form of diminished pulmonary function among cigarette smokers„even when relativ.elyy young smokers %cene studied. This is trueof the studies outllined here as well aaothers that have not been included (18, 40„ 56, 58, 81). 'Phee usual measure- ment found to lie loxcer among smokers is the 1-second forced, expira- torti volume (FEV ,,q) either alone or as a ratio of the vital capacity (FEV'„o/VC). Vital capacity allene was generally not fnund to he oeiated with.smoking butl.diminished flow rates, such as FR;9, FR,o and the peak expiratory flow (PEF)., were often observed. In these studies, distinct quantitative relatlionships, were not observed between impairment of pulmonary fun.ctiom and the number of cigarettes smokedi daily. ItELA'IPIOti OF SMOKING TO HEREDIT'Y' OR TO COiG- STIlTUTIONAIL FACTORS Although various surveys and studies,consistently show an assacia- tion betweenn smoking and respiratory symptoms and. mortality from respiratory disease, there have.e been objiectionss to interpreting thiss relb.tion as causal. Arguments have been made that smokers and non- smokers may differ im some respects, perhaps. biologicall, that are relevant to the occurrence of disease,. Others have suggested that pre- 101 ® r; ;,,

(96) HAMmaxn;, E., C. Smoking in relation to thee death rat'es of 1 million men and women. In: Haenszel, Wl, editor.. Epid:emiologlcal Approaches to the. Study of Cancer and Other Diseases. B'ethesda, U.S.. Public Heal(fid^ Service, National Cancer Institute Monograph No. 19,. January 19f16.7 Pp. 127-204. (37) HARers, H; W., Mexeecx;. G• R;,. RsxzErrr, A. D„Ja., Sr~r.a;,J•.D:, Wrdrr;, J. P. Definitions andd classification ofl chronic bronchitis, asthma and ~ pulmonary emphysema., American Review of RespiiatoryDdseases~" (Baltimore) 85(5)~: 762-768, May 1962. ?] ($8) HERNANDEZ, J•A., Aaneasoic, A. El,. Fonnxna, A.,G. Imterrelationships be- tween tween bronchial alterations,, emphysemaa in lungmacrosectflons, and smoking. Presented atthe62d Annual Meeting.of bheAmerican Associa~ tiom of Pathologists and Bacteriologists, Philadelphia,. Pa.,. Mar: 5-7..'1965: [Unpublished.] 2.pp. A (39). HEasernsz, J. A., A:vnessor, A. E., Js., HacUae;, W. L.,. Foaaxes;,A. G..Pullnonary parenchymal defects in dogs followingprolongedg cigarette" smoke exposure. American. Review of. Respiratory Diseases (Baltimore)I ~ 93(D) :', 78-83, January1966i. Ai (40) Hmmxs„ 1. T. T. Airpollution and chronicc respiratory disease. ASHRAE Journal (vewYark) S~(B) :37-45,.August 1966. -4(41) HocE;.B. V.,. WASSeiaacwN,.%. Familial empbysema. Annals of Internal bledi- , cine (Pbiiadelphia)'63(6) :1(109-1017~ . December 19656 (42)Hour•s.Nn, W. W., Rran, D. D:,Theurban factor in.chronic.bronchitis• Lan«cet (Iandon) 1(7383): 445'-448r Feb. 27, 1965. A (4E). Hva•cr, E:. Prevalance of.respiiatory symptoms, chronic bronchitis and pul- monary emphysema iha Finnishrurai population.. Fieldd survey of age 40:-f,1 in the Harlavalta.area. Acta Tuberculosea et Pneumologica.Scan-dinavica (Eobenhavn). Supplementum~811:. 1965. 1I1 pp. (4+y). KAxxy. H..A.-The Dorn.studyof smoking and mortality among U.S.. veter-ansc Report on 81J'a years of observation..In: Haenseel, W., editor.. Ep1- demiologicab Approaches to the Study o8. Cancer.,and other Diseases:. Bethesda, U.S, Public.Health Service,.Natflonal Cancer Institute Mono-graph No: 19,. January 1988:, Pp: 1-125. (45) EERSZea,.C. J. Cigarette smoke and ciliastasis. Archives ofEnPironmental Health (Chicago) 14(2):: 371-372;,February1967. DenaatsN;.T.,.RYSacrosa,R. (Replyto.Eensll:r) Cigarette.smokeandcilia- stasls. Archives, of Environmental Health (Chicago) 14(2): 372-373;. February1967: , (46) &ExszEn; C. J., Bsarsrsrg, S,. P.. Cbemical andd physical factors affectingmammaliang c[9iary activity.. Amerlcan Review of Respiratory Ddseases. (Baltiinare)i 93(3, pt. 2) : 93-102', March196C, f. (47) &u.nusN;.%. H. Cilia.and mucus tS•ansport as determinants of the response ofllungto airpollutants. Archives of'.Environmental Health(Chieago) 14 (1) : 77-91„ January 1967., (§8). ElzacnN;.1C. H:,.SACZnvo;,J:.V., editors.. Symposlumi an structure, function,' andl measurement of'respiratory cilia.. Duke University Medical Center, Durham;. N•C., Feb, .18-19, 1965.. AmericanReview of Respiratory Diseases (Baltimore), 93 (No.,3;.pt:.2) :1t.4 pp., Marcb1966:. (q9). %RUUemx, If. A.,.CnEVwnns;,R. B., Ross, J. C. Cardiopulmonary function Inn youngg smokers. A comparison of pulmonary functionn measurements and some cardiopulmonaryreespomsesto exercise.between a.group of young smokers and a comparable. group ofl nonsmokers> Annals of Internal Medicihe. (Philadelphia) 60(4).: 603-810;.. April 1964. _ 114 ( i^ 8~c .~ Attiee'.,

rvith airway abnormalities. Damage too thee puhnonary arterial eapil 1'arie, has. frequently been noted on autopsy examination of smokers. This damage may be a direct effect'of smoke inhalation andy function- ally, may impair the vascular perfusion of the alveolar tissue, thus leadiag,to further deficiencies in alveolar tissue funetion. The possibility must also be considered that the accelerated in vitro thcombus formation. (discussed in the cardiovascular chapter of this report), associated with cigarette smoking, may be the basis for mul'- tiple small thromboses in the pulmonary arterial capillaries. Sdclitionall research is also needed to answer questions concerning other factors that may account for the apparent increased suscepti- bility of'some indfividuals'to cigarette smoke, such that they have a marked excess mortality from this disease: Genetic and': constitutional fac,tors may be important to some individuals"devel'opment of pulmm- uary emphysema, just as these factors appear to be import'ant in the development of cough in smokers„ as reported by Cederlof and his assnciates (17t, 15, 16, 17). An increased susceptibility of some indi- viduadss to the emphysemaa associated with cigarette smokinghasg been suggested, but not proved, by the occasional reports of "familial" emphysema (41, EQ)', Oeher probable causes of pulmonary emphysemay such as allergic' or in fectious disease processes, also should be investigated for iin:teraetions ticitlr and without smoking. Other apparent causes of pulmonary emphysema,,such as possibly atmospheric air pollution,. may be inter- :utiing withcigaaette smoking to prodtlce effects.even more deleterious to hnmamhealth, , The observation that other probable causesof pulmonary emphy- sema may exist should not detract ftrom the strong relationship that h:LS.been shown to egistt betlweem cigarette smoking and pulmonary emphysema.lN'urtiier investigations of the mechanisms of injury to t4ie cellular and subeellular structures ofYhe lung tissue are recommended (r3,)),. Also, clari'fieation of'diagnostic nomenclature and criterix would be ]telpful, as indicated in the earlier discussion of definitions in this chapter. CITED REFERENCES (1) Axnsasoa, A.,E.,,Ja:, HenHwnaez, J. A.,. Ecar.aT,.P., Foawr.ES, A..G. Emphy- sema in lbng macrosections correlatedd wlttih smoking hatiits.. Science ('FFashingtun) 19i1(3621).: 1025-1026, 33ay22,1964.. (l). A.nr.asos, A. E.,. Ja.,. Hnn.vxsoe¢, J. A.,.Honars, 1P: L., Foaesaa, A. G. Pulmonary emphysema. Prevalence, severity,, andi anatomical patterns in, macroseetlons, with respect. to smoking habits: Archuvess of Environ- mentat Health ( Chicago)12'(5 ) i: 560-577;, SSay1968~. (8) Arrnmtsox, D. 0., Feanrs, B. G., Ja. Air pollution.levels and chronir.respira- tary disease: Archives of' Environmental Health (Chicago) 10(2): 307- 311, February 1965. 1111

and most tobaccos, certainly Burley and Marylandi varieties, contain nitrates (64),toliacco.smoke can be considered as a potentialenviron- ' ment for the formation. of N-nitrosaRnines. The major nitrat'es i~nn tobacco are alkaline nitrates. Neurath, et al'., isolated three alipbatic N-nitrosamines from the smoke of' a cigarette rich in volatile basic components and high nitrate content. One of them tentatively has been id'entiffed'as methy- ,, m~butyl-nitrosamine (73). When the particulate matter, °`t'ar,',' was collected from cigarettas - not enriched with basic components or when the smoke particulate l matter was collected without aging and not in cold traps,, N-nitros- : amines couldl not bo isoiated' fromi cigarette smoke (7°~).. Since th® ;_. only other pukilication eoncerned with the isolation of nitrosamines ` in cigarette smoke' was based on cold trap collection of "tar;" the positive finding of three N-nitrosamines appears questionable (86) ~ In summary, tobacco smoke can be regarded as a. potentiall environ' 'I mentfor the formation, of N-nitrosamines. Howevery additional infor ' mation is needed to substantitute their presence. in tobacco smoke. Polonium 210 Several investigat,ors(33, 35, 50 76, 92,.9."3 112) have found' trace - , 1 amounts of Po'1° in tobacco leaf and cigarette smoke. The eoncentrat'~ 6ion of Po210 in lung tissue is relatively high (33, 67). as compared to ~T other body tissues and is higher inn smokers than in nonsmokers (,Y3, i 43,65,66). Lung tumors have been induced experimentally by intratraeheaI,; implantat:Yon of various radioactive substances. These radioactive sub- stances must, however, be present in the respiratory environment above 7 : a certain threshold level and must be in contact withthe target organ : longg enough to beedective (68, 77, 88,107) .. B eaausePo21tl emits alpha ~ particles,, it has been implicated as a lung cancer initiator (43, 68, 76), 72). More research is needed beforedefinitive conclusions can be made_.~ Uhttill such: tiine, hovvever; Po2'" should be considered as; a potential~ tumor initiatorinr tobacco smoke~ Selenium A Selenium has beenn mentioned aspossibly being' important in thi pathogenesis ofhuman lung cancer (100):. Preliminary reports suggest that selenium may be present in some cigarette papers. Because earlier reports (17, 34, 97) indicated the ingestion of selenium caused camcer' of the liver in. mice; a recent investigation (101) by the National C'an- cer Institute was condkieted, with negative results. So far the earlier reportsof t'he cnrciivogenicity of selenium have not been substantiated Additional information: is needed on the possible carcinogenicity of selenium and its presence in cigttrettesmoke before selenium can be indicted as an.agent indmman cancer. 129 Piem Tot of the high( initiat ILa: on cti fract In 3i bronc Thes, _llth, some point the s orgal hydr hydr have singl In path be if hydi have P ledd mct: the lrov, inh:: can to 1 vini cha cvet seea to exF

distress. AmericamJournal of Pathology (New York) 47(5) e877-889, November 1965:.. 569... KnsvxN, K. H. 3fucooiliary clearance from bullfrog (Rana eatesbeiana) lung, U.S,. Public Health. Service, National.InstiUSte of Allergy and In- fectious Diseases. Researcb. Grant Al 07617:, [Unpublished.] 21 pla 570: Krtnuam, K. H. Pathogenesis and treatment of chronic bronchitis: Medical Times (Manhasset) 95 (2) : 161~476, February 1967. 571. Kalns;, P. Opportunities in environmental and occupationall pathology. Laboratory Investigation (New York.)13(6) :. 619-623, June1964. 872. . Kooamssx, R., Baa.ue,. D., Haara, M. J. Etude statistiquc de laa relation entre le tahac et las bronchfte eltronique.. Bulletin de 1'Academie Nationale de SLedecine (Paris).15Q(17-18): 318-329„Efay24, 1966. 573:. Lwssoy, R.. K.,. FUKUnA, P.,, Mvaaex,. J. Fl. Systemicandl pulmonary vascular eHectss off nicotine I'n anesthetized dogs. American, Reviewi of Respiratory Diseases (Baltimore). 91(4):. 556-564, Aprll.19651 574. LaCr.em, R: A. Recovery of.f cuStiurahle tohaccomosaic vitrusfromsputum andd thoraoentesis 8hids obtained from cigarette.smokers with a history of pulmonarydisease: American Revlewof R'espiratoryDiseases. (BaRi- more), 95(3) :510-511, March 1967. ST1 Lamov; F. R:, R'nwE:v,.R..T. Death from respiratory system disease among Seventh-Day Adventist mem Journal of theAmerican.Medfcal. Assocla- tion (Chicago) P98(?) :117-126, Oct. 10,.1966,. y76. Becnare.vnnnoen, C., Lm-carENaEaoea, R. Kumulative R'irkung von 2igarettenrnuch-Inhalation und. Infimenza-Virus-Infektion bei der Entstehung vonn atypischen Froliferationenn im Bronchiaiepithel von /sIausen.Oncologia (Basel) 19(1).:81-104, 1965. 977. :. Lcw[s„C. E., Keans, G: R: Anepidemic of polymenfume fever. Journal'of the American Medical A'ssaciation. (Chieago) 191(5) : 375-378, February 1,. 19Gi. 878. Lowm.}., F:. C., FnasKszv;, W., lllicaeusos, A.. L., Scarxaes, I. 1V. Chronic obstructive pulmonary emphysema: a disease off smokers. Annalss of Internal Medicine (Philadelphia) 45(2').: 268-274, August.1956. S79: IRBAS; A. J. Carbonn monoxide poisoning. New England Journall of Medicine (Boston), 272(5): 252-253, February 4,.1965. 580. 3lcIir.aeexa, F.. J., CoaeN6 . Bl ]1. VentilatorSperformance of American physicians. A pilot study. American Journal of the. Medical Sciences (Philadelphia)i252(1) : 1-8, July1966:. S81'1. bfasssao; D„ Botrrosrs, L. Epiklemiologyof chronic bronchitis. Medical Times(rifanhassetl). 95(2).: 121-128~, February 1967., 582: SlacaaEq G... E. The role of smokiugg im chronic bronchitis inEgyptlans. Royal.Egyptian Medical Associatibn Journal (Cai'¢ro). 4'9(5/8) : 313-328, 1966 583. ]Jkr:c.es, \V. F. Rehabilitation off patients with chronic obstructive lung disease. 9fedieall Clinics.of North America (Philadelphia) 51(2').: 349- 381, March 1967. S84• 5ffimaEr.u, R: S., Rxasy. S. F., Perrz,. T. L., Fn.r.ex,. G. F. The signilicanee of morphologic chronicc hyperplastic bronch.itis: American. Review of Respiratory Diseases (I3'alti'miore)93(5) : 720-729, May 1066. 585:.3flrrcnncc, R. S., VxercFisi, 7C N:,, Fa.nez, G. F:.Cigarette smoking,chronic bronchitis,, and emphysema., Journal of'the Ameriican. Medical Associa- tion. (Chicago.).188 (1) ; .162-138, Apr. 6,1964 • 886, JirrcaEr.r„ R. 81, R'ana; N. C., Ficr.Ex, G. F. Chronic obstructivebroncho- pulmonary disease. IZI. Factors influencing prognosis.. American Review of Respiratory+.Diseases. (Baltimore) 89(6).:878-896, June 1964. 121

(4) Arroeaaoy, D..0:, FEnats, B. G., Ja, ZICaMANSEi, R. The ChillHwack. R piratory Surrey,. 1963~ Part. I V:. Thee effect of tobacco smoking on the prevalence of respiratory disease.. Canadian Medical Association. Jou nal (Toronto) 92(20) ::1t166.-1076,.May15,1966. (5) AUEanwcu„ 0., HAMM•ovn,. E. C., KtaxAN, D~, Ge.ai'INxEL,. L. Ehiphysema producedin dogs.bycigarette smoking..Journal of the American Medical Association (Chieago ).199(4) . : 241-246, Jan: 23,.1967.. (6) AUEBEACH„ 0.,. HAMMOND, E. C., KIRMAN, D.,. GAR@INHEL, L., STOIIT,. A. P. Histological changes in bronchial tubes of cigarette.smokingdogs. East Orange,. N.J., U.S. Veterans Administration Hospitaq March1967: [Un- published.] 8:pp. (7) AnEaseca, 0.,, SaovT„ A., P., HAasvoND;. E. C., GADelxxac, L. Changes ih~ bronchiall epithelium in relation too sex, age, residence;, smoking and pneumonia. New Ehgland.Dournal.of Medicine (:Boston) 267(3)~: 111-119, July 19;1962. (8) AvEaascx, 0, STOCT, A..P., HAMMOND, E. C., GASFINxm, L. Slnokinghabit's and age iin relation to pulmonarychanges. Rupture of alveolar septums, 8brosis and thic6ening, of walls of small arteries and arterioles. New F.nt,Hand J'ournal of Medicine ( Boston )2161)(20) t 104o--1054,. Nov. 14;:1963: (9) Aveanacn,. 0.,. Sxova; A. P., IIAe.camso,. E. 0.,, GemaNxES, L.. Interrelation• ships among various histologic changes Inn bronchial tubes and in lung T _ parenchyma. Ameniham Reriewof Respiratory Diseases. (Baltimore) ~ 90 (6) . : 867-876 December 1964. ((10) BsI,LeNGne; J. J., DAWeON,. F W., DERUYTes''tS. G'., H'AeDINO, H..B Effects ~ ' ' of nLcotdneon ciliary activity invailro. Annals af Otology;.6h niologpand 7; Laryngology (St. Louis) 74(2) .: 39.9-311i June 1965~ (11) R'eTes, D:. V., GosDON, C. A., PACn„ G. L, PLACE, R. E. G., SNIDer, D. P:, Woonr, C:. R'. Chronic bronchitis. Report on the thirdd andd fourth stages of the eoordinated..study of chronicbronchits.s in the Department of Veterans:Affairs,. Canada. Medical Services Journal;. Canada. (Ottawa) 22(iZ),: 1-59, Jauuary 1,966. (12) BEST,. E. R?.. R., A Canadian study off smoking and health. Ottawa, Depart', ment af.National Health and,Welfare,1966..137 pp• (13:) CAR60N, S., GOLDIIAJfER, R., CASiPESTER,.R. Responses Of Ciliated.Nptt]1C1tUn1 ~, to irritants. Mncustransporti in the respiratory tract. American: Revlew af 4~ Respiratory Diseases (B'altimore). 93 (No. 3,. Part 2) : 86-92, March1966. (44'.) C§.oEaDoe, R: Utban~ factor and prevalence of respiratory symptoms and-* "angina pectoris." A study of 9,188 twin pairss with theaid of mailed! questionnaires. Arch ives of Environmental Healtti. ( Ch icago ) 13 (8 ): 743~ 748; December 1966:. (15) ChDEevot,. R:, EDaoas, M-L., FareEno; L., JoxssoNy E. Hereditary factors, "spontaneous cough" and "smoker's cough." A study of 7,800: tlwimpairs • with the aid of mailed questlonnaites. Archives of Ebvironmental Health (Chicago) 14(3) :401J10G, March.1967. (I6) CEOesr.oe,. R., Faiscac„ L:,, JosssoN, E., SAia, L. Morbidity among monozy gotiec twins. Archives of Emvironmental Health (Chicago) 10(2) : 346'- 350i,Fehruary190.5. (17) CeDeatioF„R., BRISEao~ L,,.Jovssos, E., KAta„L. Respiratory symptoms an& "angina.pectorls" intwins with reference to.smoking babita.. Ann epidemioalogical study- Icith mailed questionnaire. Archii-esof Environmental' Health (Chicago) 13'.(6):: 726-737.December.1966. (18) CkaeacAN;.D. T:.Theacuteeffect of cigarette smoking on pulmonary functioa..Journal of theIrish.MedicaliAssociation (Dublin) 564333): 72-74, March 1965. . ( f f

The mortality ratios of the Dorn (49) study cann be compared with those of the Canadian veterans study;,in table 6: TAe1,E' fi,-Lung cancer mortality ratios for Canadian veterarts by age, type, and arnounG.ofsmoking: Numbm of cfgarettec(dey. 1-8 10.91 Cturentcigarette.emokers only: Age.30 tu~49L-- -__----- 1. 00 2.47 t 15 Age50ta~.69---------------------- 1.00 10.71 26:92 Age.70 pl'as_------------'-----'--- 1.00 12. 15 9:43 Totid--------------------------- 1. 00 10.00 16:,41 Ex-cigarette smokers onUy total-----_ 6. 06, 5uuxce: Csnadien Pensionere study [(e), Tsbleel and 8.21. From the data shown in table 2.mortal[ty ratios of 17.47 and 29:84 may be noted for smokers of 40+ cigarettes per dhy, age 55-69 and 70-84, respectively. The,Dorn (49) study (seetablle5) simillarlyshows mortality ratios:of 33,80and. 2320 for smokers of 40+ cigarettes per dayy.age 55-64 and 65-74, respectiicely: The. Canadian study (see table 6): shows mortality ratiosofl 26.83 andl24'.53 for smokers 56-69aud 70 years of age.and older respectively who smoked over 20 cigarettes per day. There is rather ¢lose agreement among the three large prospee• tive studies for the general range of mortadityy ratios observed in heavy smokers: Ftom the dat'a supplied by the Doll and Hill survey of Britishh physicians (2$, 2cJ)i a mortality ratioo of 31.86, . can: bee calcu- lated for alll smokers of more than 25 cigarettes per day, as com- pared t'oo a mortality ratio of approximately 8, for smokers of 1-14 cigarettes per day (see table 8). There is relatively little risk of lung cancer associated with pipe or cigar smoking, probably because. smoke from these sources is rarely inhaled.. "lltiked smokers„" ii.e., smokers of cigarettes,. pipes, and/or cigars, have less risk than do smokers of cigarettes'onSy; al5o suggest- ing that they may smoke fewer cigarettes or inhale less tobacco smoke than do smokers of cigarettes only (see tables 7 and 8):.

miners and nonminera inn a. Witwatersrand town. British Journal o. Industrial!Medicihe(London) 24(1) r.13-25; January 1967: (~68) D7LS. Punuo'.HnAiTa SEavrcE.. $hiokingand Health. Reporti o2 the Adlvl~soq~ Committee totheSurgeon General of the Public Health Service. [~Rash.. ~ ington.] U.S. Department of Health„ Education, aud Welfare, Public ~ Health Service.Tublication No. 1103, 1964. 387 gp. (69) [,':S.,PVal,rcHe.rcma SnRVrcn. \'ationalCenterfor.Health~Statistics:.Slor-- tality trends in the United States: Ma1-63. Was'hingtion, U.S. Departimentt of Health, Education, and Welfare, Vitall and. Health Statistics Series~. ~ 20,. No. 2;. Public HealtL, Service Publication. No. 1000, June.196Q. 57pp. . (70 ) U:S.. Pvazrc Hesr.rrr SeavzoE:, National Center forHeaIth. Statistics,. ]ior-~~~ tality. Vital Statistics of.the.Uni2ed States. washigton, U.S. Department l of Health;.Education, and [Welfare:.1950-1904. (71) 17:S. IDtrm.ICHieanTa. Seavice Chronic Respiratory DdsensesControl. Pro-~ gram. R:epurt.of tbe.Task Force.on Chronic.Broncbitis and Emphysema.11 Natnonal. Tuberculosis Association. Bulletin (Mount Siorris) 53(;5) : 1~23; 3fay 1907: (72) U.S. Poauc~~ H2bzrfr. SEawrcE. National! Center f'orHealth Statisttcs. Cig~`_-: arette smoking, and health ebaraeteristics„ United States July. 1961-June'~196a. Washington, U.S. Department of Health, Educationl and welY°are,~ Vitall andHRalth Statistics Series 10, Noi. 3Y',. Public Health Service ~ Publication No. 1000; May 1967. 64 pp. (73~) \'4'ALaes, T. R'.,. %rascn,. J. E. Ciliastaticcompon,entsin the gass phase oti cigarette smoke. Science . (R'ashington). 153 (3741) ': 1248-1250, September~9,1006. (74') Wena, R'. &l. COOK, W. A., LANIUS, J.. W., Sanw; R. I{. Cigarette smoke y` and surfactant. American Reriew ofRespirator,v Diseases(IDaltimore) 95(2):241-247 Februa.ry1967 ~. (7S) N[esux A.. J. Environmental andd personal! factors iu lung eancer and brenchitis mortahty in Northerm Ireland, London, England ~ ToriaccoResearch Council, Research Paper.9, 1968. 84pp ,`$$, (76) D'rsxEnsxax, W., Ja.,. IiANraa,. S,. DAvis, E. W.,. 1texEar, C: S,,, Mosaeq.4 W. H. The retationsbip of air pollution and economic statuss too total.~ mortality and!selected respiratory system mortality in men., I. Suspended!~ particulates. Archives ofEnvironmental Healttr. (Chieago)14(1) :102- ° 171,.January 1967. (77) 1WZrrnen, E. L.,, Goomirsta„ D. A., Hoeeuasx~. D. Ciliatoaic components in~.~n cigarettesmoke. 1!L.Carbosylic acids.and!aldehydes. Cancer (Philadel-. phia) 18(rl) : 305-509, April 196"a. (78) WYNDER, E. L.,, GoomarAx, D. A., Hot~eMUxrr, ll). Ciliatosic components in. ~ cigarettesmoke, III. lavitroeomparison of different.smoke.componentai Cancer (Philadelphla), 18(12).: 18i2-1E58, December 1965. . (79) W'vxosR, E. L.,.KArean, H. E., Gbonar~eN,.D. A., HosaxAtvN, DL A method fon i determining ciliastatic com~ponents in cigarette smoke. Cancer (!PhtlodelF•- ~ phia) 10(9) :..1222-1225;,September1903:. (80) R'rvnea, E. L.,,Lexox,. F. R, Memrey N. Epidemiology of persistent cough.. AmericamReview of.Respiratory Diseases(Baltimore) 91(5): 079r700,3faP1085. (i81) 2w•r, S., Gocnnras; H. I., Lzszx, A. Cigarette smoking and pulmonary funrtionn in healthy young adults. American Review of Respiratory Diseases(Saltimore) 89(1)'.:73-81,.Tanunry1904! , 116 h

5103: SALATA, J.. R. Air pollution. Rocky Mountain Medical Journal (Denver)'. 63(10) :47-.51, October1966: 5104: SAUANEIC, Jll,. Avznno;. D. ril., PEsxi:v-, G. W. Bronehopuimonary effects of tobacco and related substances. IIb:. Axon reflexes elicited from thevisceral.pleura. Archives oflEnviFonmental Health (Chicago) 11(2)'.:166-1B6;. August.1965: 5105: Scava[ACr,. L. M. Epidemiologic approaches and problems in. the assess-ment.of causalifacturs ia chronio.respitatory disease. Journal of the Kentucky Medical Association (Louisville) 64(4) : 311-316; April 1966, 5106: SESIaR,.R: DR:,,FlsanraN, A. P'. Disturbances of alveolar ventilation. Medi- cal Clinlcsof North America ( Philadelphia ) 51(2) :.403-425, blareii1967.. 5107.. SHAne, J. T: PAVr:, 0:,, LIreeR, M. H:,. :1ticKEAN; H., SAXTON, G.. A., JR. Prevalence of chronic bronchitisim an American male urban industrial population. American Review of Respiratory Diseases (Baltimore)91(4).: 510-:i19; April 1965: 5108: Snsovssan, B. G:. Clinical and physiological studies on clironicbronchitis: III. Bronehial reactivity to ivhaledacetylcholine: Aeta Allergologica ( &obenhavn ) 20(5) : : 325:-348;,1965. S109.. SPICnR, W'.. S., JR.,R'elation of'.air.pollution to disease:.Archives of Environ. mental Health (Chicago) 9'(5):: 600-605i,ti'ovember.1964. S110.. Sronsrx, M. 1, CcsauAr, G.. D.,,KEaR, D. H., BLmE,. R. W., SexceE; W. Sl, Ja: Efferts of environment on respiratory function. Weekly studies on young male adults. Archives of.Environmental flealth (~Chicago) 13(2) : 243-254, August 1966, . 5111. STANEK, V., FOnOR,. J., HEJL, Z... WIIII][RKY'. J... CHiARFAT,, P.r. SAN'LRUCEx, bC., Zkaw,.F., VArmx,.3I: A contribution.to the epidemiology of chronic bronchitis. Actw :Iledicai Scandinavica. (Stockholm) 179(6) : 737-746, June 1906iti11`S. STEOMAN,. R. L., MILLER, R: tiL. Alkylating activity of cigarette.smoke con- densate. Chemistry Rndi IndnstYy(London) 1(14) : 618-619, Apr. 15, 1967: 9I13I Tnvxcsecx, W. M., ANavs;. G. E:. A distribution curve for chronic bron- chitis.. Thorax ( London )19: 436-442, September 1964. 8114.. ToxASaEFSxIy. J.. F:, PRATT, P. C.. Pultnonaly emphysema: Pathology and pathogenesis. Medical Clinics of Narth~ America (Philadelphia), 51(2).: 269-281, 9tiarch.1067. 8115, VISwArvATnArv; R. Acute effects of cigarette smoking on.pulmonargartery pressures, Indian Journal of.3Sedflcal Research (ICalcutta). 53(5)i: 421- 427, :Vfay1965. S116. VlswwNATIeAV, Ii:, Mons,. R. K., PRAeao„ S. S., SkxaA; S. P: Branchial asthmaa and chronic bronchitis. A. pilot.survey. Journal of the.Indian ilIedical Association (Calcutta) 45(9).: 480-483, Nov. 1, 1965. 5117: WhanELC, J: A. Bmonchitisand emphysema. Britisti. Journal of Clinical Practice (Iwndvn) 20(9).:.477-180, September1906:, 5118:. WksB, W: Rr, Coax, W. A.PAaxus, JC. W., SHAw, R. R:. Cigarettesmoke and surfactant. American Review of RespiratoryDiseases' (Baltimore) 95 (2 ').: .244-2474 Fehruary 1I96RL 5119:. WEiss;, W. Cigarette smoking and diffuse pullnonary fibrosis. AA prelim- znary report. Archives af.Environmental Health (Chicago). 1A(4).: 561- 568, . April 1967. 5120. W.u.HEL:usnrv,.. L.,.TISSUIN, G.. Tobaccuo smoking in 50-year-old men: I. Iles- piratory symptoms and ventilatory function tests.. Scandinaciam Journal of Respiratory Diseases (Kobenhavn) 47(2).: 121-130, 1966. 123 Y :l. ~ r ~f~lli~a. ~k:

S92L Bfems, J. W., Acnarasy $1.. J.. Epidemiology of: coronary disease in indus- trial workers,. II. Absenteeratese and' serum lipids. Archives ofEn- vironmental Health (Chieago) 13: : 045-6:"', November 1966. 593. lFI¢n'rox,. A. S. The effect of nicotine an blood glucose levels and plasma non- . esteri$ed fatty acid levels ihn theIhtact. and adrenalectomized.cat. B'rib~~ ish Jburnall of Pharmaeotogy and Chemotherapy (London) 20: 258•-263, 1960. 594. )fbansorr„ A. )yL:,, Paasosa, 0. A. The coronary personality: A critique.~ Psychomatic .\fedicine (New York ). 29 (1) : 1=14, January-February 1967.. 595. Bfosars;d. N., HennY; J. A.,,RAnI~, P. A. B. Physique of.London. busmen. Epidemiology'of uniforms. Lancet (London) 2:569-.i70, Sept. 15, 1956. 59B:. Bioams„J. N.,,KAOem„A., PATi-rsoN, D:.C.,,GAaunea;,hl. J., RgrFCE;,I4 A,.B. '7ncidenceand.predictionoffschaemlcheart-disease in:London.busmen. , Lancet (London) 2: 5a:'-559i. September 1960: 597:. Dloats, ID. C., Pbweas,.D., Soaorrn, L. A. Glucose blockage of the increase in strokee volume produced by smoking. Circul'ation..;l Journal of the ~~ American Heart Associatiom (New York) 29(6): 820-fl29',. June 1064. S9&. Dfcnenar, R.,. Hroxar,. N. Cigarettesmoking habits of patients with caro- naryheartdisease: British Heart Journal (London) 28: 401-408, 1966. . S9U. ilror.cenr, R,,, Hfexer, N. The role off cigarette smokingg in the eausat¢an- ofatherosclerosis. Geriatrics(hlinneapolis). 22(2): 1&i-174, F`pbruauy ', 1907: SI00. Mh'menr, R:, BIDxer;. N,.. J., illAVaea, B,. J. The aetiology of coronary ' !ieart.disease in women. Journal of the.Iizisti.lfedical Association (Dub- 15h.) 00': 23-29;. January 1907.. S10I-. \tuaenz„ E. A., MUSTARD, J. F. Coagulation tests and platelett economy in attieroscleroticc andi control. subjects:. Citculation;: Journal off theAmeri- can HeartAssociatton (New York) 25:114-125,.January 1962. 5102: NArcuu, L. H. Smoking and thrombosis:, Connecticut Medicine (&ew4 Haven ) 29(12) :&5&354, December1965, 5103. Npconrov, J. Assessment of physical performance of middle-agedlAmeri- can men. EfedicaI Times(Manhasset) 95(2).:220~227,. February 1967. 5104,. Newstudies: eitee multiplee factors in: heartt disease:. Lung cancer age not atfecteidlbyrsmoking, Southern Tobacco Journal (Winston Salem). 80(1): 5, January 1A66: 5105: Oasauw,v;. A.,. DoLC„ R: K, GRAYSrer„ A. Interdependence among some fac- . tars associated withcoronary heart disease. Pensacola, Fla.,, U.S. Naval Aviatiun ]3'edica[ Center, iiIlS. Naval.School oF.Aviation ]Sedihine.ltlae,5, 1964. ['IInpublished.]i15pp. 5106: OLrvea,. Sf: F. Arterial disease and.hypertension: Presymptomatie diagnosis .. of.ischaemic.heart d]sease:.Proceedings of the.Royal Society of Medicine (London) 592 1180-1184; November1966. S107, OLrvmr, 7f. F.,.SrueaT-Haasrs, C. IL Present position.concerningprevention nfheart.disease. Briti9h Medical Journal fLondon). 2(5472).: 1203r1208,. Nov.20,19&ii 8108: OsrFEr.o;,A. 31. Arestrokes:preven[ablee Medical Clinics of' North Americs (Philhdl>lphia) 51I(1): 105-1'11', January 1967. 8109:. OsxansoeR, L. D.,,Ja. Bnndle-branch block. Au epidemiologic study-Cirou- lation; JourrmLof'.ttie:American.Heart Association (New York) 30(6i r 872-881, Decembet 1961. 5110; PAa7evuxacsa,. R. S., JS;,.Norxi.r, dl., KRUeaee, D;.E., 1;'ocF, P..A., Tt[oaxe, 3I. C., LeBa,una, E, J.. Wauwsss, .7. L. Chronioc disease inn formerr collegestudents. II. hlethods of study andd observationss onn mortality from ~ 82 P.~ ~ ~ ~ ~ rA

0376491'7 r~

airwg, ,atern s'tudi ® 3pmen l to lopula ;tw 'red t I ;aret s wit Itudies tal in ng the ; seme Loe of ha e COn (7) pub- i with d iio. (Ceen Si the er of cells ~the I ab- a,e ke hose uer- 3ult bey blet in bronchi from smokers than nonsmokers. There was, however, no evi- dence of more bronchial gland hyperplasia. Thesesame workers also studiedmaeroscopic sections.of single lungs from 211 routine autopsies on adults (,l, 2). Analysis was limited to 165 of t:hese cases on whom smoking histories.were obtained, usually from relatives. Withoutt knowing the identity of the subject or his smoking history, each lung section was classified on a scale from 0 to 6 by severity of emphysemm.tous changes. The type of emphysema, was also described as panlobular (changes throughout the secondary pul- monary ldbu7es)„ centrilobul'ar (ehanges located around the centers of the secondary lobules), or mixed. The severity of emphysematous changas was about the same for men and women„ but for each sex, changes were more severe among smokers than nonsmokers, as seen in table 13. TABLE 13.-Me¢nn severity, ofemPh;ysema etassified by nwcrosections by sex mnd smokingg history 2iumbar ''Meev de- lgreenrem. Number Meen de. gree.ofem- ' Physema PLyeema MOnC I wOmen! smakers-------- 96, '~ 2.1 Smokerei_______ 1$'. 2. 1 Nonsmokcra____ 11 I 1.1 Nonsmokers!__- 40 S Socu[c: Anderson,. A. E., Jr., et al..(C). Perhaps more' important was the observatiion that the type of pa- thology seemed strongly related to smoking ($)'. Of 48 subjects whose lung macrosections were classified as having mainly centrilbbular emphysemay 45 persons had been smokers. In contrast, the 62 subjects judged to have panlobular emphysema.were divided in.theespected proportions, 38 smokers and 24 nonsmokers. Pettyy andl his associates (61) also studied postSnortem findingsin the lungss of' a series of 253 men overage.40, unselected'r for smoking, n$o died' in. two Denver hospitals during a 6-year lueriod' from 1959 to 1965. The presence and severity of emphysema was estimated and graded in four categories; from 0 to 3+. During, the last 3 years of the study bmnchi' of 179 men were examined for mucous gland hyper- plasia. Independent of the morphological studies; smoking histories were obtained for each person, apparentDy by questioning relatives; although this is mot clearly stated. 34en were grouped according to the amountt of cigarettess smoked duriingtheir lifetimes by calculating pack-years of smoking. (One pack-year is.the' number of cigarettes 4moked if a~ person smoked one pack per day for a year. A pack-year couldl also mean smoking, two packs a.day for 6 months, one-hallf pack a day for2 yeacs, or any equivalent amount.) 105 0

:;' s th PIX Phenaas Tobacco smoke contains a large number of phenoll (107). Several of them are known to be tumor promoting agents: when applied in high concentrations to mouse skin previously treated with a tumor initiator (,1h). IN VrrRO'CELLDLAR CIH.1NGE5. By TOBXCCOSETOHE ~g Lasnitzki (60) extended her studies with tobacco smoke condensate a}~ , am cultured human fetal lung tissue to include a "highly purified ~ fraction of hydrocarbons"' isolated from cigarette smoke condensate., hey In 33 out of 50 treated lung tissue explants, the epithelium of the es bronchi was hyperplastic and sometimes showed squamous changes., ye7 1 These~ changes were not observed with the untreated controls. _Ylthough a,hydroearbon-free fraction was weakly active by producing some squamous metaplasia.in these explants, these tissue culture tests: pointt strongly to, carcinogenic hydrocarbons as the active group in the. smoke: The findfings with purified carcinogenic hydrocarbons in organ culture (21), support the finding that polynuclear aromatic hydrocarbons are one group of active smoke constituents. Carainogenic ee hydrocarbons are also the only group of chemical eomponents that a have been demonstrated in vitra to induce malignant conversion of' t1O _einglece.lls ('.7,13). 13, In summary, tobacco.smoke has been demonstratedim, viLro toindhae patholbgic:al changes in tissue explants..Although such changes,may al - be induced by different smoke constituents, as yet the carcinogenic ]ttidrocurbons arethe only agents identifiedd in tobacco smoke which. e- have liceit shown to induce malignant changes in'ntisstte cultures. A In Viceo. 'Il'uxou. FonxATIoN Br Toane;co SMOKE Passive inhalation experiments with tobacco smoke have not yet led to fully established squamouss carcinoma in mice (109). This method of' application has resulted only in papillomatous growth in. the tracheobronchial mucosa of a few hamsters. None of the tumors, However, was found to be invasive (90;.111)I. Itt appears that passive inhallttiommay not lead to the induction of sqpamous cell bronchogenic cancer in experimental animals.. This conclusion can also be applied to' passiveniliailat'ion studies im which the animals are infected by a. virusbefore long;term smoke etposure(62', 110). The'.pathologieale changes seen in the mice weree ieversiblewhether ornotr the animals lvere prev.iouslginfectedl with avirus.. The hyperplasia.and.tnetaplasiaseen in miceand' rats after passive inhalation. appears, , af least in part, too besecondar3r to viral or bacterial infectionn that is enhanced by exposure to tobacco smoke. The relatively negative findings with pas- 129 9 a LA s I

TABLE 7.-Lung cancer mortality ralioa, byy type and' amount amoked 12. 14 Current'' smokere of <tgeretteranlyw saoxce: V.6..vstuepssthdy[epp..tahleA({B)1. TABLE 8.-Lung cancer death rates by type of smoker and amownat smoked C.Igarettasmahers 'Vansmnkers All smoke+s _ Alfammnnts 1-It15-24 25} l1lx~vp rJearette amokln®. Nflad smakers Ptye or ct@6r ---- PerdaA - , I r - - - - 7 71 120, 57129 ', 2 23 24 52 43 Soraca: StudyofBtltishphyslAisus[ta61ea29andI4'(t8)]j TABLE 9.-Lungcaneer deatlih rates for ex-amokersof cigarettesby length of time stoppedsmoking Eaamukers Lcssthun 5 years~ 67 5:e yeers 49 sou~ce: Study af BFitish Physiclensitable 25 (a9)]: where there was no general decrease in amount of smoking. This can be thought of as a controlled aessation eaperiment and the Iheneficial physician group, is involved in thesefigu..res, we can compare thiss population group to the entire population of England and Wales that for. the physician group decreased 7' percent. Since the total vVhile the overall lung cancer mortality of men over age 25 in I England and Wales had increased 22 percent over this 10-yea;r period', and/or cigars.. cantly decreased (one-half pack cigarettes or more) their smoking (in- cluding those who stopped) and 5', percent had switched to pipes interest in respect to es-smokers. Over the 10-year period of the study (~1!951-61)29. percent of the smokers off cigarettesonly,: had'i signifi- The Doll and Hill study (28) of British physicians is of particular (see tables 4„5i 6, 7„8t 9). This llower risk is evident irrespective of the quantity of cigarettes formerly smoked'.& death rates from lbng cancer with the cessation of cigarette smoking 18 The preceding studies show appreciably lower mortality ratios and 139

velopment of invasive carcinoma.. Auerbach (5) has more recently reported.on astudy oflthe patholbgy of thetracheobronchialtrees of 339, men who died feom.causes other than lung cancer and of 63 men who died from llungeancer. Il7p to 55 cross-sectilans of the tracheo- bronehial tissue were studied in each case. The 339 non-lung, cancer cases included 65 men who had never. smoked cigarettes and 274 men who, had smoked in various amount. Figure 3 shows that only 1.3 percent of the slides from those who never smoked regularly have GO percent or more atypical cells„whereas 76 percent of the slides of those smoking more than two packs a day had 60 percent or more atypical'cellk. (See figs. 3'and4). PERCENT OF SLIDES WITH LESIONS SJfOW!'NYd 60% OR MORE ATYPICAL CELLS 92.1 34~s 3.11 4.7 F--1 F__1 Rurec 5makeU GV2Patl. 1/2-11PneY. I-2 Packn 24 Paek. Requlorly. A. Day A DayADay A Day Lunp; Cqac.r FmTTae3-Perceut of'®lides with lesiionsshowing 60 percent or more atypical. cells Source: Auerbac>r,.O:, et al. [Table 1(5)„updated.1967] Auerbach (4) has also studied the bronchopulmonary autopsy ma- terial from 255 men and three women who died of lung carcinoma, of varyingg histolbgicad types, ranginging t,hee spectrum of the WHOclassification (IZ09) from the highly differentiated to the undiffer- entiated squamous cell carcinoma, with others being oat.cell; polygonal'' cell,, acinar, and adenocarcinoma. A search for double primaries was made, and by using striet criteria, multiple primary invasive carci- noma wmss found in 3.5 percent of the autopsies. studiedL When. less 141

PERCENT' OF SL/QES' fk°ITN CARCIN'OdlA-FN- SlFU' 17.0 Lunq. 6anaer 11.4 0.0 0.3' 0.8 ' 4.3 F71 NeverSmoteE <I/ZPael 1/2-IlPach I-2Packe 2?Poeta fle9ularlt' A Da, A DaYA,OapADup Ftutac9.-Pemeut of alidf:s with mrMauma in titu. S'ource:. Auerbach, Ol, et al. [Tabie 2(5 ), updated 1967]. strict criteria were used, but.very, doubtful cases excluded, up to 12.5 percent double primaries were found. This study suggests that muTti- plee primarybronchiad carcinomasin thee samepatiente may be more frequent than previously suspect'ed. Further studies are necessary in this area, since therapeutic implications arealso ine*olved'.. The differentiation of' tumor types as relhted' to smoking habits in various groups with clinically diagnosed lung cancer has again been incestigated.in several recent studies. In one study (I9)y of'417cases of IiistologicaIly'pror.en lung cancer, 87 percent were smokers. Among the squamous'cell cancer cases 89 percent were smokers; among the undifferentiated cell cancer cases90 percent were smokers, and among those widh adenocarcihomas; 60 percent were smokers.,A study (99) dealing specifically with alveolar cell cancer of the lung reports that 91 percent of the 180 males in.whom this,tumor type was diagnosed were smokerss and~ simillurly, that. 65'5 percent of th'i e 85 females with this.type.tutnorwere:smokers..Anotherstudy (10!~~)~wasmadeof lung cancer cases in nonsmokers, defined as persons.smoking,notmore than oneeigarette.a day for '10 years: This study group included eight.males and.26females.. Ofthisf gronp,.only fourpatients had epidpxmoid carcinoma (tiwo males andi two, females). Both males had a history of occupationaIl exposu',re to respiratory irritmits,. Ofthef two women, one had an unusual history of'.circinoma, including multiplebasal celll skin.cancersand.in si dw carcinomaa of the.cervi x. A study (1) was made.of.666histologicall'y provem cases of lung cancer. A smoking history was recorded on 442 of the men in this 142'. a yr; seri Tatc ade TA] Un Sql Ad 8 Yr th m OF lil ci be h sl n n r c r

o:ter than ~ association cis (60) rett Ihe LJniversi Radcliffe st oe students'; ficantly mo1 in partienla Lnd the nun ~oups, Hvh ln a Gommun Ilation, son of'the m es (ibased o al examina-' 18.7 percen >, compa cers among was signjfj,~e ntable9'. in the yea 2g 1ea8at8 Ex- smokers 8.5 131.3, I 17.7, 13.3 . 'evieWedy I having true for 'eath_ It was also true when the respondent'swere asked. not about symptoms liut about disease, that is, chronic bronchitis' and emphysema, andl in. one instance was reflbcted in the number of clinic vistiths for respiratory diseases. Prevalence of t.hesesymptoms increased with the amount.of cig,u-ettes smoked. Ilt.cas less among pipe and cigar smokersi and ex- oig2rett'e smokers among whom the prevalence,, in some reports;, ap- proached that of nonsmokers. STUDIESRELATIIr G S SSOKING TO PtZ'JIO\.1RY FUNCTiON \Iany afYhe surveysoutI'uned in the previous section on respiratory synlptomsalso~included lungfuncti'on tests aspart of the.esamintione liuliti (f3)', for example, in his.Finnish study took chest X-rays.andl collected information on vital capacityy, 1-second forced expiratory cntunle. (FEO;n) and peak expiratory fibw (PEF) as: sho vn in table 1U: T.tR LE 10''.-M'e¢n values of letng fiu,net7on . tests among men and women by smoking habiis Cfgaeettes snnokeA per day Lf. 15-24 25+ Nbn. amukers FEVi,e (liters): Slen_____________________ 3:.17 3: 30 3.08 3146 139 ' Wamen.__________________ 21.74 (') (1) 2: 42: 2: 32' FL'C (1(ters): 3fen 4:40 451 4,26 ' 4.40 4':51 Wamcn.__________________ 3153 (a) (a) 3: 19 3. 19: PF.F Bien_____________________ 518 537 517 569' ! 551 Wamen.__________________ 431 (z) (a) 4'10. 403'. i '.Slthougli this:tabtePresents data for all agesicombined, the esme daference1.were ap~rent In each. Syear a5re.grouping. "Only 7 women smaked 15 or more cigorettes per day. Sacecm nu]it1, E: (4d). Among men the FE'4?,.e value was Iower for smokers than nonsmok- ers. The PEF value.was-sl,ightly7ower, but the vital capac.ity. Was.un- related to smokinga In this study none of the values seemed to be clear- ly relatedl to the number of cigarettes smoked. Among the relatively small number of female smokers in this study, most of whom.smoked between one and 14 cigarettes per day, almost all the lungfunetiong values werebetter'than in.the femalenonsmokers. Femalesmokers. rvere slightly taller inn heig]it and sliglrtly lighter in wezghtlthan: fe-male. nonsmokers, Which may account for this finding. Hon-ever, fe- male ox-smokers had slightly redbced FEV,.e and PEF when compared 99 Bx. amokers ~--- I A, ~ _. ~ tJ1 - .~ QD

587. bforeer,. ]I. A. J., SvrHEnunw: J. A.. W: Persistence of viralantibodies.in S11 patients with chronicc bronchitisi. BritishMed'ical Journal (London):, 1(5540) ::601-603; Man 11, 1967. 51i S88. MOLHO, M.,, RAZ:, I., Kae[s[.EE„ BL. A basis for. different(ating' between pri-, ' mary empbysema andd pulmonary obstruction disease due to cbronlC~- bronchitis. ProceedingsTel-Hashomer Hospitall (Tel-A~viv) , 5(2) : 29-36, June:1966; 1 589. Mosox.v, W. K. C. Chronicbronchit"s. The"Englishdisease."Postgraduate~~.: ~ Medicine (Minneapolis) 41.(2) : 190-194, February 1967. 590. ~fiavxx; Q:.. N., EvANS, D: G. Metabolic and immunalbgic activities of ~ alveolar macropbages:. Archdvesof Environmental Health (Chicago) 14 (1) : 92-96, January 1967: Sl S7 591. .\'ASH, E. 51, BaxscaE, W.. A., Co¢axxao, A, The relationshipp between .~ clinical and physiolbgical Sndings in chronic obstructive disease of the lungs. bfedieina Thoracalis(Basel) 22: 305-327, 196-3. 592. PAaN~um., Ji L.,.AvnessoN, ID. OO :, Krsxle,. C. Clgarette smoking and respira-~, tory infections in a class of studentt nurses. New Englamd Journal of ': Medicine: (Boston:). 274(18) :.979'-984„3fay'5,1966: 4 593. PEtzea,. A. M.,. Txomsox, M. L. Effectt of age, sex, stature, andi smoking / habits onn humam airway conductance. Journal of Applied Ptiysiolbgy '` (1Pashington), 21(12): 469-176„ 1966L, ~ 594. PExnearo:v,. J. Occupational lung disease (letter). British MedicapJournal (London),1(5487):,009;,Mar.5,1966.. 505. PEanccrr,. S. Pulmonary sm+factaat.: its depletion and regeneration in ;! excised lungs. Baltimore, The Johns Hopkins Scbool of Hygiene: and Public Health, Department of Environmentall Medicine, Supported by . U.S. Public. Health ServiceGrants HE01929, AP0020S (Division of. Alr ~ Pollution, Bureauu of Stnte. Services)) and TG-HTS ;r453;., and byNavy ; Contract NR102-101. [Unpublished.] 16 ppi. '~..' S96.. Rs'nna D. D., ArDEasoN,. D! 0:,. Fnusis,. B; G:,, EtexcnEa, C:. M.. An A'nglo- , American comparison of the prevalenee of bronchitis. British. Medical -Journal. (London) 2(&I23) : 1487,1491, Dec. 12, 1964. ~u .Df97.. Ri:in D.. D., CORNFIELD, J., MAaR:II9H, R. E., SEIDEL,. D., PEDFIEBES, E., HwESSZeL, W. Studies of disease amongg migrants and native popule lations in Great Britain, Norway, and the 6'nitedi States. III P[eva ~ lence ofcardm respiratory symptaomss among migrants and native-bonn_~ in theIInited States. In: Haenszel,. W,,, editor, Epidemiologicall Ap,~ proachess to theStudS ofCancer-and Other Diseases. Bethesda, II.S:I Public Health Service,. National Cancer Institute Monograph No: 19,, January 1966:M pp..321-3'4G.. 598. REZaavx.,.H. A_ Acute respiratorgtract infections in: the aged. Geriatrics (Minneapolis) 22(3) ;.160-167, Marclu1967: S99: RExzErrl;.A.IDI, Pragnosis(n.ahronic obstructive pulmonary disease. MeW cafClinics of North Ameriea. (Philadelphia) . 51(2) : 363-371, March 1967~ ' 5100: REVxEi-rr, A D.,.Ja:,. McCEEmnNr, Ji. H.,,Lrrr; B. D. The Veterans Admin•sa Iestratlon cooperativestudy ofl pulmonary function• III. Mortality in relation to. respiratoryfunationy in chronic obstructivepulmonary dis-iS 129 1L~' 41 1 Y k r ( ): or ) ease. American. Journal of Medicine (New. ,AL July 1966. ' 810LR'xcclmxut, M; L. Modern•concepts in the management of emphysema irt theaged and.inHnn, Journal of the Ameri;tan. Geriatrics Society (iBaltl'il more )I 14 (5,)0497:-504„]iay 19661 5102: SAm,. S. I. Role of pulhmnary surfactant in. health and disease. Medic Clinicss of North America (Philadelphia): 51(2) : 39!11102, March1967 122 S S

TnsLE, 2'. Lung cancer (men)..1Vumber of'deatA:s, and age-standardized death',rates and 7northd'ity ratias, by current number of cigarettes s7n.oked per d¢y, degree of inhalation, a7td' age began smoking, by age at' start of study ` N umber aP.cigarettes a day, degree Age 3.7-54 Age 55-69 Age 70-84 All eges, 35-84 oi lnhalation,, and age 6egann smvking Num- Death Num- Death Num- Death Num- Death r her ol' rate tier of rate beeot rate ber of' rate deaths deaths deaths deaths Current number ot'dgarettCs aday: UOn9 . 10to 14i __---- .._________________ 201o 39l__-.____________________ 4l Plus.._._._..__._.___._..__. Degree otinhalatihn: Sone oi.slight___________________ Noderate_.._._._________.____.._____ Dcep ............................ Agz began cigarett9 smomng: 3 or older---------- _ ___. 2 20 to 24_____________________________ 15 tb 19 :............_._...._..____. Less ttlgn 151____________________ bccer smoked regularly-__..____.. Current numberm6ctgarettes a day: 14o9_----- _____ ______._..__.__ lOtb l9---- _--------------- ___- 90 to 3&--------- __.____....____ 4U.plus'~.__._.______..______.....____ De3ree ai inhWation: 51ane or slight-_.. ____-_.. _._.__ 5'loderate__-____________.._.____ Deep-- ------- --_--- _ _._ _._... .1 ge began cigaretto smoHUg: 25 or oider--__-_--___-_'.____-_ 29 tu 24._._._.__._.___.._.._.._____. r5 to 19-_ __ Less than15_.__...___----- -__ 9 36 12 69 5 134 26 SB 15' 24 57 103 10 2/3 82 90 138' 86 216 2&1' 2P 446 391' 159 26 47 SO 334' 6 754 82 201 19 29 87 203 I4 193 l29 103 114 62 m 224'. 20 401 311 1EB 53 5S 73 266 13 638 141 173 17 12 65 3 65 20 39 31 36 72 212 7 2ds 110 1S8 112 54 176 250 27 490 315 Iss 3E 79 57 30¢ 9 424' 101. 183 11 6 27 19 lt 25 49 12 Lung canter mortality ratios (men) -------- 6.17 -------- 3.53 -------- g.32 -------- 4!6f ---- .___ 3.90 -------- &77 -------- 9.82 -------- - __..__ 9:37 _______. 13.82 ...____ 17.62 ..___._.. 3.11 -------- 7.67 . -------- 17.47 -------- 29.84 -------- 16.61 __.__._. 4175 -------- . 10.80~ -------- ' L__.___ 8 .C __.____ &4B ._______. 1I.72 __...____ &88 -------- 11.1t ___---- 9.OD -------- . 13.93 -------- 26.26 ..._--- f 14.31 -------- Z n - - - - --------. a 39 ------- 3.88' I h------- 3.2i 8~83 - - B.T. 12.81 _-_-- 12,so 18.70 _----- la.L I Mortalityratios are based on death rates carrled out tbi more signifieantEgure thsu shown. Savnce! Hammand. E'. C. ItaDle 20: ({0)1. 271-3940-67-10 185 a.)

9onrnal Adviso e- (Was p;. Pub) tlics. Moi part®ea es Seria 57 pp; ~ :Ice. ]So); parimenl tzol Pro;=~W ,'hysema,3e ies. Clg;. 64-,Tune -' Yelfare,~ Servicc t baseof "itemDei ~ smokeg imore),, s and~ igland'.~enea, ~ total ended I 162 its in~ ikdel, ,~ ta iw STJPPUEbENTAL REFERENCES SiL AsBOrr;, O.. A., HorsxNS, W. A.,. YAic Ft.err; W. E.,, RoanesoN, J. S.. A new approachh to pulmonary empbysema. Thoraz: (London) 8(2) :: 116-132, 1953: 52:.AOncMAN, Jt U. Areview, and reappraisal of emphysema. Diseases~ofthe Chest' (Chicago) 51(2) : 156-161, February 1967. $3.. ANDEasos, A.. E1,..Ja,. Azevr„ A., BATCaztiaea, T. L., Foeasza;. A. G:, Eaper- imental analysisin.dogsof the relatiovshiphetween pulmonary emptiy- sema„alveolitis, andbypperinflatian..Thoraa (London) 19(5):.420-432, 1964. 34. AxaeasoN, D;, O: Observatiiuns on the classifleatlon and distributdonn of pulmonary emphysema im Canada: Canadian Medical Associadoa Jour- nal (Toronto) 89(14).: 709r746;.Oct:5,1963. 55.. AmnnesoN, D. 0.,. Feears, B:,G., Jn: Community studies of the:8ealtmeffects of air poRution-a critique. Canadian Journal of Public Health (Toronto )I 57 (5)', : 209-220, May 1966. 50: ANDERSON, D:. 0.,.2rc8neANasr:, R.,. FESars;,B. G., Ja: Response to a.Tespiia- tory survey: Canadian Medical Association Journal (Toronto) 8g(12).: 596-602, 'Atac 23;,1963: S7. AsonnsoN, R. J., Epidemiolqgic studies of airpolliutiom. Diseases's of the Chest (Chicago) 42(5): 474-481„Novemfier 1962:. Sff.:txoosea, J. R. The incidence of. smokingg and the smoking habits in 5000 registrantas for mil'itaryserv3ce. Journal of' the American Geriatrics Society (Baltimore) .14 (8) : 631'-G32, June:1966: R9. AL-EflBACB, 0'., 51C1UT;, A. P., HAMMOND, E:. ().,, GAHFIN%EL„ L.. Emphysema and otherpulmonarg ehangesin: amokers. Histologic evidence. Post- graduate Medicine (iMinneapolis): 4Q(1).:, 9t-r100;, July1966: 110, AN]dUo,, D. M., SAMANEn, M. Br9nChepnlmonary effects off tobacco and related substances. I.. Bronchoconstriction and.bronchodilatation: Influ- ence of'1ung, denervation. ArChiress of Ehvironmental Health. (Chicago0 11(2) :.141-1514 August 196.i. Sii. AVznno, D. M., BxxASEnc,. 3I., Founn, L. E. Cardiapulmonaryeffeetsy of tobacco and' r,elatedsubstances. L The. release of histamineduring inhalationn of cigarette smokeand, anosemia in the heart-lung and intact dog preparatlon. Archives of Environmental Health (Chicago) 12'(6) :. 70ir711, June.1966. S1Q: BAeraea, A.,bi., BATE®;,L. M. EfCects.of environmental temperature and vapor pressure on eilia-muruaclearance:rates. In:: Proceedings.of the International Congress on lReupationall Health, Vienna, Austrin;. Sept. 19-2;,1966. pp. 673-676. 513, Be¢caxANS, J..11t:. The:depositlon off aerosols inn thee respiratory tract ID: Deposition In cigarette smoking. Canadian J!ournnl of Physiology and Pharmacology (Ottawa) 1 43(5).: 707-714, September 1965. 814., Bi.Aexavax, H., T4sr.oa, H. L., PAm.rx; R. W'. &rncntmo, J. BNre, A..Phys- ical activity of occupation and cigarette smoking. R,elationship to ventilatory functionn and respiratory symptoms. Arcbives of Environ- mental.Health (Chiiago)~ 10(2) : 312-328', Februa.ry19tYo. BoATat-uN;. EI.S„ MaRrnr, H: B. Electron microseopy ln pulmonary emph,v- sema.of'rabbits, American Revlewof RespiratorgDiseasea (iBaltimore), 91(2) ::197-20.i; February 1905. S16.. BoauN, H.. G:. Esirerimental emphysema. Basisn revlew, and critique. The American Reviesv of. Respiratory Diseases (Baltimore) 92(1):: 1-15,. Jalq 1965. 117

las ea ltras rppe 0 4Pmai i la ma iking ween nlcah F u 28 mors done ar or to ast inds to~ ~ily ap- ter f yen- ptecl but long I ion Wles aly; ~be. ere rles rsere.kept as controls; two had tracheostamy openings. These control dogs were sacrificed at the time the last five smoking dbgs were sacri- 6ced. Lungs of the dogs exposed to cigarette smoke showed microscop- ically the presence of dilated air spaces especially beneath the pleural surface. Here the albeolas septa showed a fibrous thiickening, of the walls with areas of rupture and dilated ain'sacs. Padlike attachments to alveolar septa were found. These zones of connective tissue sur- rounding dilated air sacs were also visible macroscopically as white areas on the lung surface. There was no thickening of the walls of small arteriesand.art'eriolleswithin the lung-'Il'he lungs of.t'he control dogs were normal in appearance with none of these changas: These abnormalities approximate '1Sut are not fully concordant with some of the typical pathological findings in human emphysema. This es- pcriment does indicate that inhaledl cigarette smoke apparently can damago the pulmonary parenchyma of dogs. Other findings (6) as yet. unpublished,indicate that abnormalities of the bronchial epi- thelium resulted thatt approximate many of the histopathologic find- in,s of human chronic bronchitis. Rockey et al. (64;) have' noterl'' that cigarette smoke' produces bron- ehial andl parenchymal changes in dogs that approximate some of the histopatlmlbgic findings found in human smokers who have chronic I;ronchitis and/or pulmonary emphysema. Mouzalris (57)i has.noted similar changes in rabbits, and in dogs exposed to cigarette smoke through tracheostomies. RESCrMt:. Researchers carry.ingg out pathological studies have', consistently re- porte.d epithelial hyperplhsia of the bronchial tree associated with smoking:.lThey have also reported thatt fibrosis and emphysematous chamges in. thelung' parenchyma, although observed amongnon- smokers, occur much more frequently among men and women who have histories:of smoki'ng:. Chamges'in the lungg parenchyma„approxilmating some of the changes noted in human emphysema, have also been pro- dnced experimentally in dogs by exposure to cigarette'smoke. CILIATOXIC EFFECTS OF CIG?,RETTE SMOKE '17Setoxic effect of tobacco'e smoke on the.ciliary' defense.'mechanism of the respiratory system has been confirmed by additional espari- mentall studies (9, 10, 13, 93, 24, "6y 27;, !Y5; 47, 77, 78) which seek too determine more exactly the mode.of action of the ciliatoxic agents contained in tobacco.smoke., As, yet„ hydrogen cyanide and acrolein appear to havetlhee greatestl.ciliatoaic effects.of the agents that have been id'entified in the gaseous phase of tdbacco smoke„although for- 107

siive inhalation experiments probably relate to the relatively small'T amounts of smoke aerosols thatt bypass the nasal passages.. The defen~ sive nature of'the upper respiratory tract against airborne irritants'as has to be fully appreciated in the evalluation of any passive inhalationt study. A',ctive inhalation studies with tracheostomizedl dogs, ascarrted out, by Rockey, (79; 80) and Auerbach (Q),, suggest that this approacb may lead to the induction of bronchogenic carcinoma.. The cHange in the bronchial' epithelium after 1 year. of active smoking indlcates - early pathological changes thatmay, upon continued smoke esposure,~ lead to tumors in thebronchie rl_o~ So far, neither passive nor active i:nhalation studies have contributed k` to our knowledge about the nature.of the tobacco smoke carcinogens. Studies with the particulate maBter, tar;,of cigarette;, pipe, and cigar smoke;, however, have clearly demonstrated that at the site of applica-~ tian tumors can be induced. Tumors have been induced on the skin `' of mice and rabbits, the ears of rabbits; the. subcutaneous tissue. and hill m. of rats and the cervices of mice (9,11; 22, 31, 32, .48, 48; 61, 7¢,, ' 82; 83;,81y,.1D7,.108). ~. OnPy relatively few investigators have been concerned with the ` nature of chemical carcinogens in tobacco smoke (47, 84:, 107). tYl- thougJi the acidic and nicotine-free basic portions of'tobaeco~ tar had been fbund to have weak tumorigenic activity, the only fraction shown to have induced significant numbers of'tumors is fraction B'f of the ) neutral portion (2 percent of the whole condensate) (10A'). This S~ fiact'uon was further fractionatedi into three subfra.cNonsfrom which Lonl.y I3,, was shown to have tumorigenic activity (Q7),. The E, frac- : tion equals 0.6 percentt of the tar and combines all aromatic hydro- carbonss with threeee to seven riitgsincl'uding tfie carcinogenic ones. " 71his can be considered as evidence that in in vivo studies, the poly- T nuclear aromatic hydroc,arbonss are the major carcinogensins tobaeco smoke. Although these compounds albne can account for only a small ~ portion of. tlhe t'umorigenic activ.ity of tobaeco tar,. they are; neverthe ~ less, the onl!y identified carcinogens and tumor initiators in tobacca smoko shown by experimentation to be biologically active. Their ~, tumorigenic effect is enhanced by the presence of tumor-promoting agents in the smoke. TLmOR.-hRODSOTIING. -AGEVTS IN TOBACCO PnODUC18 ht the experimental sett-Ing, the tumorigenicity of toliaccoo smoke condensatee cannot be solely explained by thee presence offf known car- :~ cinogeus. In assays om mouse skin and'' rat subcutaneous tissue, the ~ knowm carein r a t b h b o~ ens mus e en anced yother componenth as .s's suc 4: tumor-promoting agents: In fact!, it has been demonstrated that to- 130 bac Inc pol tur pht pr nu de 16 ti4 no tr sr „

bacco extract and tobacco smoke condensate can act as promoters to, mouse. skin previously treated withl tumor-initiating carcinogenicc polycyclfi6 aromatic hydrocarbons. (1D; 12, 96, 107). Although somel tumor-promoting, activity of tobacco "tar" can be explained by somee phenols and carboxylic aucids; additional tumor promoters in tobacco~ products,remain to be isolatedland identifiedL It is important, however, that a significant decrease of'the polil9- nuclear aromatic hydrocarbons in tobacco "tar"7eads to a significant, decrease of the overall activity of the "tar" on mouse skin (9, 46;1108y, 109)- Itr summary, experimental studies have demonstrated that the par- ticu[ate matter of tobacco smoke, "tar," is tuunorigenic: Sbme poly- nuclealr aromatic hydrocarbon-careinogens have been identified ascon- tributingsignificantly totlla overall tumorigenic activity of tobaceo. -mokecondensates in the experimental setting. LUNG CA\CER' 1tfOxT.4LIT1 DAT,ti.' -  ~l,..... ,..n ~..,.,..1...,. ..L'.],...~h.. C-, ata.. TA.,)..,.n l_.._ . _ _Q ad~'j~ the lung, (Iliterlntional CllasaificaClon afDiseases, Codes 162, 163) rose. .,~ from 18,313 deaths in11950 to 45,838 in 1964 (9f). Iln this 15-year he ~ period, deadhs.from lung cancer totaled 467,442. During thts same timee period the death rate for cancer of the lung almost doubled, a rise from 12.2 dl'aths per 100;000 population.in 1950 to 24 deaths per 100,000 population.ial196.4., (The corresponding age-adjctsted.rate hass also nearly dbubled, therefore the increase in the deathl rateeannot be alttr,ibuted, to, the changing age compositionl of the population.) The R-htngg cancer mortality~ in the~e male population: increased fcom~. 19~.9~9 ~ co ~ deaths per 100,000 population in 1950 to41.4 in 1964,, while in the ' t_11~ a fe 1 1E ~th~d th~' df 4 1 0 0 ma e popu a lon eea s mcrease rom a to . per 100,00 0 population over the same time period. The mortality experience of the individual male cohorts during 119}9-64 (fng,1) shows that at any giken age the risk of dying froml lungg cancerwasr almostt always higher for the more recently borm cohort. Within each cohort, the death rate for lung cancer increasedl steadily to the end of the life span.. Figure 2 shows the death rate for women by cohort groups and age at death. One can see the increasing death rate slope for each more recently-bornn cohort, starting withh cohort F-thosee women whowere 2Cr30years old in.1930. This corre.spondss to the timewhen: smoking became increasingly popular among women. ' 911I death rates.throuqhout tllis ctlapterare per 100,000 population unless otherwise iladieatcd.. 131

effects of stopping or decreasing the amount of smoking become qpite evi:dent: Wicken (102), in a retrospective study of 1'ungcancer mort'ality in. Northern Ireland during the periodl1960-fi2 reported the following results (Tkb1e10)~: q enr.E 10.-Lung cancer mortality ratios and. deatli rates, 8y sex; age 35 andover; bytype and amount of smokang;.. Northern Ireland, 196tJ-62 Non• smokers ClgaratteemoSeus smount per dap _ Cigsrettav andpiPe Pipe snd cigsronly r snd elger 1-10 11-2@ 23+ Male: Mortality.ratins_------_ 1.,00 4.83'. 9.33I 21.2' . 5..22 2.27 Deathrates------------ 18'. 87 168 383 ' 94 41 Female: Mortality.ratios __ 1.00. 2;27" 8.72 Death rates . __ 11 25 74 216 __ __ -------- Soueet; W9cten„A. J. I(10d)„Ta61e 17]. tively moree frequent in: nousmokers„especially women. Changes in thebronehial mucosa resulting#eom the inhalation of cigarette smoke in- eluded loss of ciliiay basal cell liyperplksia, and the appearance of atypical cells withi:rregular hyperchromatic.nuclei. These:changes, itt was concluded,, were related to the prem.alignant process of the de- would have occurred if the lung cancer mortality rates of the least susceptible groups ]isdbeen applied to the whole.popuPation of North- ern Ireland, and found that males would have had only 18 percent of the lung cancer mortality if none smoked and that if they lived in truly rural areas they would liave only 10 percent of the mortality. 'll'.hus;; the difference-8 percent-may be attributable to the urban or suburban residence factor, possibly air pollution. If no females smoked, tliey woulid.have had only 6'5'.percent of the total.female 111ngg cancer mortality, and 53 percent if they lived in truly rurall areas. Thus;f'or females, the difference o4 12percentage: points ]mightt beattrlbuted' tlo the urban ensciironment_ The nlagniCude of these differ- ences depends on the prevalence of lung cancer in the various sub- groups of the particular poptulation studied. HISTOr.aTAOLOGY OF LT?iY0 TIIM oRB , Classification of lung cancer by histologic type was discussed in the Surgeon General's 12'J6'4 ReportWiththe.conclklsion that the squamous,undifferentiated, and oat-cell carcinomas were far more frequently found in smokers than in nonsmokers, while adenocarcinoma was rela- S~iJieken also analyzed.tlie proportion of lung cancer deaths mhich 140 velc repl 339 whc bro casc whr per 60 ~ th( ati !b

The search continues for an experimental animal system in which the inhalation of tobacco smoke will produce malignant tissue changes closely approximating those observed in human pulmonary cancer. VVlien dealing with passive inhalation of tobacco smoke,however, a problem of the defensive barrier of the nasallpassage is intToducedl So far; dogs inhaling cigarette smoke: through tra- cheostomies seem to be the most promising system, but there are problems in keeping the experiments going for the length of'time.nec- essary for lung cancer to develop. Additional research is needed using, cultured lung tissue together with autograft and homograft studies to determine in vivo results: Additional insight may thus be gained intio in vivo systems. It should be noted, however, that it may not be possible ever to achieve histologic ident'ity in pulknonary cancer production, not only because of difficulties in duplication of man's smoking action for reasons of anatomic and physiologic differences, but also because of inherent species' differences in cellular response. 0 CANCER OF THE. BUCCAL CAVITY AND PHARYNX (LIP', IvfOUTH, THROAT). The S'urgeon General's 1964 Report concluded that the causal re- lationship of pipe smoking to the development of cancer of the lip appeared to be established. Although there were suggestions of' a relat'ionship between cancer of'other specific sites of the oral cavity and the several forms of'tobacco use, their causal implications could not be stated at that time. The National Center for Health Statistics (94) reports that.dUring 1964, 28'female8 and 157 male deathsoecucred fromm cancerof the lip. Duringthe.period 1950-64, malemortalitp from this disease declined about 67 percent. This was partially doe to changes in thediagnost'iio classification. but was mainly due to increased early diagnosis and therapyr. Duringthe~ period.195S-64. whenn the: seventh revision of the International Classification of Diseases was in use,, total' mortality from cancer of the lip remained about the same, but when analyzed by age,,substantial decreases occurred in this death rate for each 10- year agegroup.from 55-84 years., As for cancer of't'he oral cavity, other than the Tip, the total death ratee showed no marked variation from 1950-64 (3.1 and. 3.3'3 deaths.per 1001000~population;..respectively)~In.196'4,t'he deathrate for cancer of these sites in the male populatiom was about three times the cor- responding rate in thee female. population (5.1 and 1.66 deaths per 100j000population,.respectikely).. 145 O b.7 ~ f~1 __:^~ O ~A

552: HAMbmsa: E. C: Some.preliminary findings on physical eomplaintsfroma prospectivee study of.1,0frS,004 menn and women. American Journal Public Health..and theNation'sHealth. (New York). 54(1I).: 11-23, Jan ~~ ary'1904: 853. Hexvoxn, F,. C., BERaLVND, L., Kwscow,R: Smokinghabits.andldisease' Minnesota. Ciinnesota biedicine. (St. Paul).48(p): 44 19, January 1965.' 554. HAUazosa,. E. C., EsxT, L. S„REEna D:. C., Wasos, J. L. Smoking habits~~ and.health in. Kancan and otherrrntrnl ctatnsi Im,rnol' nf thn Kanooa~, 4iedical. Society (Topeka) 65(12): 586-590, December 1964. 355., Han[Deonw, E.. C., GEnsna,. I. F: Smoking habits and disease in Ohio. Ohi State Medical.Journal. (Columbus) 61(2)1: 134-137,.February1965.. 'j 556.. HAStMoam, E.. C., MoaenB, R.,, Beaes, S.. Smoking, air pollution and healtli' tn. California: California Division~ of the American Cancer Societyand, • theStatistical. Research. Section,. Medical Affairs Department,. American. V ancer. Socieoy; 1904. 22 pp.. 557. HAMMuxn;. E. C., SraFSa,. E... C. Smoking habit's and~ disease in Illinole; Illinoishtedical Journai. (Chicago) 126(6) :: 661-46a, December 1964. S5H. HA1[YovDi.E..C., VsN GRIEfnnY6EM, T: H., DmrZER, J. B., SNEDDDN„A. M.,* : HAauowu, W'.. Smoking, habitss andi disease in New York State:, Newl. York State Journal of' Medicine (New York)~ 65(20):.2557-2561, Oct ` :. 15, 1965. 859. HAMMOND, , E. C'., Wu.som, O:. Smoking habits and disease in Missouri.~ Missouri Medicine (St:.Louis).62(2):. 109-112, 122, February 1965. :lk S60.. HwYCe:AFT,. R. G. Tokyo-Yokohama astlima.. A review and some current concepts:. California Medicine (San.Franciaco) 10a(2):.89-92, August~ 1966: 561.. HerssAC-N;. H.. Status of' air pollution healthresearch,. 1966. Archives of Environmental Health (Chicago) 14(3).: 488-503„ March 1967. S62. HesswnDEZ„ .P:. A., ANDSasoiv, A. E:, Ja,. Hocxse,. W.. L. FuseE:Es, A. G."Z P ulmonary parenehymal de(ects in dogs following prolongdigtte ssge care.i smoke eaposure. American Review of.Respiratory Diseases (Baltimore). 93 (1) : ..73-83i. January1!966. S63.. Hroanva, M'., E:rntsaEac, M. Charaeterlatics~of smokersand nonsmokers in" Tecumseb, Mich. II. The distribution of selected.physical measurements~ and physiolbgicnl variables. and! thee prevalencee of certain diseases in smokers and nonsmokers. (In press. ) American.Jlournal of Epidemiology;- (Baltimore)~: 1967. . 864. Hor.Dawer, M. D.,. Tuaa,. D: C. Capsulated: haemophilusinfluenzaean respiratory-tract, disease. Lancet ( Londom). 1(7486'),: 358,6Q Feb,. 18; 1967. 565.. Housno;.FV. 14.., R'Em, D. D., SeLrses, IL, SToae, R: W:.Respiratory disea in. England and the United States. Studies of' comparative prevalence: Archives of. Environmental. Health (Chiirago) 10(2) : 338-343, Febru- ary 1965,. S66. Homaxo;, W. W., SaoxE„ R.. W. Respiaatory disorders In United States east coast telephone men:American. Journall of Epidemiology (BaIU- more) 82(1):.92-101,.July1965: _ 867. HoNa; C. S, GenDIVle, B.,. LovELL, H. Ventilatory cvpacityin a series of male adultsand the effect.of respiratory, symptoms, productive cough, smoking habit and occupation. Medical J'ournal of Austtralia(Sydney)' 1(4) : 169-172, Jan..28,.1967. , 568. Ersxewe; Y.,. MoiornstiL, E. K., Caos, C.. D. The ultrastructure of the lungs of lambs. The relation of! osmiophilic inclusions and alveolar lin- ing layer tofetal'o maturation and experimentally produced respiratory 120 " Sfi S7 87 S7

. series. The chart. below takes into account smoking histories as. re- lated to three. histologic groups: undifferentiated, squamous, and adenocaacinoma (see table 11). TnBLE 11., Distribution. of lung cancer' deatbs by eellvlar tVpe. ¢nd' tyye of smo/cirny Celllilsr~.typei Nonamoker.. PiDe.moker Cigasette moker Uhdifferentiated------------------------- _ 1 4 ~ 14 124 Squamous------------------------------ - e. 24 211 AdPnocarciaoma.------------------------- -, 2. 1 56 9ovsc6: Axhley, DiJ. B., et aC [Q).Table C] Insufucient information is provided. in this study to specify in detaiD the past smoking,historiesy but the data suggest that cigarette smoking maybe related to adenoearcinoma in some instances. The preeeding studies indicate that squamous,.undifferentiated, and oat-ceil carcinoma rarely occur in nonsmokers. However, it appears that cigarette smoking may also be associated with. alveolar cell car- cinoma and glandular carcinoma of the bronchii. This'relationship has lieen previously suspected. In fact as early as 1950 Wynder and Gra- luam (105) demonstrated this relationship. This was also shown in the s3udy by Haenszel(.49) . Greaterstandardization and'.precisionof tiiag- noses are needed to establish how few cases of undifferentiated or squa- mous carcinoma occur in nonsmokers who have been established to have never smokedl.appreciable amount's during their lifetim.es. I'f 100 per- centaccurate.smoking histories were obtainable on. every case of' lung cancer, iit.is suspected thatvery few cases of undifferentiated or squa- mous cancer would be found in persons who hadi never smoked., A report (98) on lung cancer in uranium miners noted a. frequency of lung cancer, occurring almost entirely in the cigarette-smoking miners, greater thhan the frequency to be eapected'in a similar sized cigarette-smoking nonuranium mining, populktion. A recent report (85) on bronchogenic carcinoma in asbestos workers also noted an in- creased frequency of lung cancer, occurring entirely in the cigarette smoking asbestos workers. This fiequency was greater than the frer quency to be expected for a similar population of cigarette smokers who were not asbestos workers. These reports suggest that cigarette smoking may interact with certain other environmental exposures to increase the frequency of! lung cancer occurrence st'lll further. Analysis of occupation and other environmental exposures must be performed simultaneousljr to detect which interactions with smoking seem to be especially dangerous. 143

Other studies (55, 76) have suggested a relation between air pollhi- smoking and chronic respiratory disease."' disease and respiratory disability." All the recent evidence, however, does not alter the conclusion in the Surgeon General's 1964 RReport that "the dominant association in the United St'ates is between cigarette types of pollution areassociated with increasedd amounts of respirato cluded„as we must from.the available evidence, that all " * * three pollution have been summarized recently by Higgins (40). He con- The contributions of air pollution, industrial pollution, and personal tion and symptoms or mortality from chronic respiratory disease, although they were not controlled for differences in cigarette smoking. direct toxic effect oflcigarettesmoke. However, some of these abnormal-' it'iesare relatedlto t'he unevenness of'pulknonaryventilat.ion associated', diffusion noted in cigarette smokers, may; in part, be related to a smokers and nonsmokersalso indicate that abnormalities of pulknonary Studies. (lk9;,.50, 51, 620)of.the pulmonary function of relatively young: apparently reflecting damage in -vzvo. ently is important for maintaining tissue surfiace tension and thus the spatial configuration of'thealveolar walls (65). Im vitro abnormalities' have been noted inn surfactant as a result of cigarettee smoke (21, 7/y).~ A1~veollar macrophages (specialized cells t,hat incorporate and remove foreign material fi•om the affected Iung area) are reportedly damaged iin viGTo by cigaretlte smoke (35). Abnormalities of'the alveolar macro+ phages and lipophages with inhalation of cigarette smoke are aiso reported ('54) in cytological studies of'humanf bronchial washimgs„ S'urfactant, a, fluid suMstlancel'ining the alveolar cell walls, ap,par-1 the typical anatomic findings of human pulmonary emphysema. , Hon•ever,, inthese animal'studies there were also some differences feom, esist contributes to the rupture. and fibrosis of the alveolar tissue. on the pulmonary tissue. Possibly this direct toxic effect,, if proven to support the thes s that there Is a dlreet tos c effect ofi clgarette smoka The experiments of the Auerbach„ Hernandez, and Rockey groups tothe qpestion. made,.The available evidence that follbwshas only indirect pertinence a. strong association between cigarette smoking and many cases. of pulmonary emphysemaand' an inference of causation may validly be If future evidence supports such a finding ofi a direct togicc effect,, we will have the missing link to the present chain of evidence showing of pulmonary emphysema tAt present, it cannot be answered':, tissue in the lung parenchyma which is important in the pathogenesis Does inhaiecl tobacco smoke have a direct. toxic effect on the alveolar This crucial questionmustbe answered afHrmativelybefore an infer- ence can be made that smoking directly causes pulmonary emphysema : ADDITIONAL riONSIDERATI0N6 REGaaDING.r7MOHINn AND FiSiP1HY5E]LA 110

E$rERIME?rrAr: PIILMONARY' CARCINOnENE6iS. Experimental attempts to produce lung cancer involve the adinin= . Inousmetaplasia involved in the premalignant changes may explain. why cigarette smoke condensate most readily produces cancer in thee sqnamous epithelium of the skin of laboratoryy animals. istratibn of tobacco smoke condensates and of carcinogens known to be present. in. tobacco smoke, either in vitno to preparations: of ce11's or in vivo in experimental animals. Difficulties are encountered with,t'he viability of tissue cultures and experimental animals when subjected to these various substances.. Studies of human.tissue from lung cancer patients indicate that abnormalities of the tracheobronehial mucosa, such as loss.of cilia, basal cell hyperplasia, squamous metaplasia,, and cellular atypism are iimportantt in the pathogenesis of human lung cancer causedl by smoking. These changes have been experimentally produced in dogs exposed to cigarette smoke through a tracheostomy (2„79; 80). A large number of dogs is now being studied to determine if lung cancer can be experimentally produced by this technique;,if'the dogs continue.to.smoke for a longer time, malignant changes.may ap- pear subsequent to the already noted premalignant changes. The squa- butnot malignant cells(Q3). Inhalation (59, 78i 90), intratracheal administra..t.ion. (25;, 86y, 42, 54, 81),. subcutaneous; intraperitoneal and intravenous injection, oral administration, and skin painting, of car- cinogens have al I inducedd pultnonary tumors (87). .. exposed to cigarette smoke developed a small number of tumors m the I'- tracheobronchial epithelium (.90; 110). Cigarette smoke condensate ~ has been studied'.in.tissue culture preparations (38), and implantation #r° of'cigaret'tesmoke condensate exposed lung tissue subcutaneously has. ,~ been reported to cause malignant growths (26). Cigarette smoke con- ~ densate also causes skintumors when applied topically (9,11, 46. 48,611 ~ 74,82,107,108). This was conl a large-scale stud~ with about. 8;000 mice.by the Tobacco Ii,dustry Research, Council of England (22). - Repeated injections of' cigarette smoke condensate in rats produced. sarcomas (32„82, 88y.84~.)'.. Since.19fi3'. two studies have reported nega-tive results when cigarette smoke condensate was administered intra- tracheallyto rats and S}rrian.haRnsters. (Q5y4.2)y respectively: H3ronchoscopic painting of cigarette smoke condensate rapidly causes squamous metaplasia in dogss and may acceleratecareinogenesis (91).. '. Carcinogens, known to be present in tobacco smoke, have been applied to cells.in tissue culture.with the observation of malignant changes (7)~ and other effects (21), such as differential growth inhibition of'normal'. The inhalation of tobacco smoke by mice was. reported. to i¢Icrease t the frequency of glandular tlumors (37; 41, 6.9, 70). Syrian hamstzrs 'i ADDITLONAI:. F.E!IDENCE (~iONCERNINO E&HEmMENTAL. (i'ARCINOOENEBIs 144 p e c ~ c c c4

TABLE 114. Dpath rates from. ¢ancer of' upper reapiratory tract and digestive systemm byy sitee andd tyPeof smoker Non Atl. Cigsrette Mixed P/pe.or site ®okers smokers smakers mmokers tlqar emokers Mouth„pharynx,, or nose------- 0' 6 5 10 ~' 4 Larynx or.taaahea------------- _ 01 . 6 5 3 10 Esophagus-------------------- - 4,, 10 6 10 'I 8 9ooace: Btudyof British physicians, [table 12(Ee)J. Dataorv the relationship between amount of cigarettes smoked and. the death rates were also provided (seetablle 15). TABLE 15.-Deafh rates from cancer of upper respiratory tract and digestive system by site and amount smoked Amount of tobscrn smoked dslly(g.) I 8ite Non- smoking All nmOnnt9 1-n 1&-21 2} eeses- ttun Mouth, pharynx,. or nose--------- 7 4 1 211 6 Larynx~,or trrichea--------------- 6 2 2 15'. 5 Esophagus--.------------------- 12 8 14 20 2. L (g;) = 1 gm.=t ci®srette per dsy=;Q ox: tobeso per week. Savacs: 9tudy of Brinsh physimans (table 13 (28)J. Additional significant inf ormationi comes from a study (69): of' 102', cigarette smokers, all of whom were "cured"" ' of a primary mouth or throat cancer and remained asymptomatie for at least 3 years. Of these patients, 37 stopped smoking while 65. continued. Of the 3Z who stoppedl smoking, onlytwohad'y aa second! primary cancer develop in a different site in the buccal-pharyngeaI area,.whereas 14 of those who continued to smoke develbped a second cancer im a. different site in the buceal- pharyngeal area. I''.xPEmSfENTAL S74n)TEs In one study (56):, pipe smoke condensate was dissolved in sputum and applied behind the ear of'mice. Although no ear lesions were o'b- served, two animal developed scirrhous and planoceRular cancer, re- spectively;.of'tlie lower jaw, perhaps as a consequence of'licking the ears of othermice~ In.anotherexperiment (37),,,rats were placed.ind cliambersands exposedt.o cigarettesmoke. Five of 68 surviving rats developed tumors of the buccal mucosa, three of these animals hadl malignant invasive.lesi'ons. 147

TARr.E, 4.-Lung' cancer (men). Age-standardized death rates and 7n.or- tal'ity ratios for' ex-ctigarette smokers wrtlih a' history of cigarette smoking only, by former number of cigarettes. smoked per day, and years'since last cigarette smoking. Death rates for current cigarette sm:okers wiCh a history of cigarette smoking only.. Men. who never smoked regularly are shovre' for comparison. 1[den' aged 60-8'9. ,9mokedl-19dga[ettesadsy 8moked@04dgarettavaday Mortelityratiu, smoked- 8a<i arettesmakers(yesn slnce4ast cigarette smokffig) 'NUmAen Numben ~Death Nomber INwntler Death I-Ig 2d} of'. meu' uf8es[Ha rate of inen bldeeths rete Cnder.lyear------------ ..__ 740 3'. 1®. 2,244.. 83 4T! -------- . _._____. .ta4.years._______...._.___ 1,814. b' ®. 5,.435~ 33 180. -------- ________ ito9years~..______________ 1,TlU 1. 15 5,803: 22 10& -------- .__..._._ nplhsyears._._.....____._. 4.209 1. 6 8,142 5 18' ~ -------- _____.___ Totalex-smokers__.___. 3,588 10 gd 21'~,BPf. 93 118~. 12.0~ 7.9 =urrentcigaBtte:smokere.._. 22,808. 80 97 55;ffie 351 205~ d5 13.7 \evej.smokedregularlP----- SS,:28~ 32~ IS b5.T28 YL l6. -------- -------- I Computed from source. SoeaCe: Hammvud, E'. C.,Ikabie 2li(40)/. The Dorn stud'y (49) of U.S. veterans providesa'ddit,ional informa- tion on the relationshipp of dosage to mortality ratios andd deatlh rates for males who.smoked cigaret,tes'only (table 5). TABLE 5'.-Lung' cancer mortality ratios and death rates for fi7:S:. veterans byage,, type,, and'd amount of srdaking Numlier of cigeretteslday. Clurent cigarette smokera only: Age 45 ,to 81:..____ _.___.__ Age 55 to 84L.------ __. Age 0 to 74'_---- ----- __ Age9bplus, ______________ Tota1______..__.._.____ Ef ~aigarette smakers only_._ DR' MR? 14 MR DR, 10-20 DR MR 21-9. DR. 404 DR MR ~ 24 52: 7S 10'. 1.111 70 7:00 123 12.30 205' Zd.SU 388 e0 1:.0U 18S 4:b0 265 8.83 482'. 11L40 696 40' 1.00 1.00 b'.48 9.91 17.41 .95 3.49 pi28 L DR, Death mte; 11iR; Mort.aLLtyratla. Booecn: U.B:.ceteransstudylapD+tat/leA(48)). 28.80 23.20 23.83. 8.24 187 I I v

S17:, BoanN;.HL G:,. BaBEY„J. F.,,CuaPE;. R. F., Gkzsaowsxr; S., NEwereN, M. M Oaaxtvtcec„ A. B',, LEeren, \M1'.. Treatment of drug'-resistant tubercnlosiad a statement by'the Committee on TLerapy. American Revievof Respira. tory Diseases (Baltimore)94(I): 125-127, July 396g, 818, Boaer,. H. G,. DEr.AxaxT, A, B.,. STEH;NxEn, W., Jr. Reactionn off guines pig lhng too inJected lung, homogenates. Medicina. Thoracalis (Basel) 22(3)~:~.355-364,.1965i. 819:. Boa¢rv;,H. G:,.Koax, R. C., Sxvxa;,J. C: Ttie.Veterans Adminis6ration army cooperative study of pulmonary function. IL The lung volumee and'. Sts' sutidivisionsia,normal men. American Journal'.oBMedicine: (New York) 41(l):.9G-114„Ju1y19166, 520. BoaeN, H: G., Kae.nL, V:..E. ~~'entilatorys nettral,.and'other.factors ihfluenc- ing thee pulmonary microctrculatiom of the frog. B~ibliotheca Anatomic ( Basel )'. 7 ~: ~~ 86-91,.196fi. 821. Bsixxa[x., G. L., Bcocw, D: L. The prognosis in chronic bronchitis. Journal ~' ~ of theAmesrcan Medical Association ( Ctiicago ). 197 (1). :.1-7„July 4, 1966. • 522. Bttaoess, A. rif., Bunoass, S. B. Cbrontcobstruetime pulmonaryemphysema. ~AA review, withspeeial reference tb, ithretatfion to cigarette smoking.~i Rhode Island Medical Journal (Providence) 49.(8). 461-f6fi, 494', August ': S23t Bcans; ML W., MAY, J. H. IIaemophllusinfluenzae precipitins in the serum~ ofl patientss withh chronic bronchial dilsorders.. Lancet (LUndon) 11(7486) :~ 304-3.58, Feb..18;.1967.. 824. Buanows;. R,. Pulmonary diffusion and alveolar-capillary block. tifedicall~ Clihicss of lorthAmerica(i'hiladeiphia) 51(2) : 427=138,, March 1967. ~ S25: Buaaows;,B:, FLevcnaa; C;.M., Henan„ B. E., Jn.wES N. I.., WtorLU+t} J. S..,'~'.. The emphysematouss andd bronchial types of chronic airways' obstruction. AelinleopathologicaL study of patients ih London and Chicago., Lancet ~, (:London) 1i(7442) : 830-835, Apr.16,.1966'.. 520! CnEnrv[ecn,.N..S.,.DOwrsso;.H. F:,.Cenro.v; R. W., McBaroE, V. E. The rol0~;f s l oa acute ower nespiratory mfe.ctiaa in cauarng pnimonary insu®ciency s im branchiectasis:. Annals of Internal Hedicitie (IPhiladelphia). 66(3).: 489-497, ]larch 1967:. 827.. Ckronic bronchitiss and occupation. British Medical Journal. (London) j 1(5479), c 101-102, Jan. 8,1966. 528: CoHEN,. B! bT. Sympathomimetic amine aerosoll administration in chronicm obstructlivee ventilatory, disease: A one year trial in patients abstaining * ' from.cigareBtes andd a.matched.group who cuntiatted to,smoke. Medical Times(lianhasset) 94(3): 35:.359; March 1966. 529.. CooLErJL R:. T. HoLLAmSvw Social and enviro t nmen r n l' f t' i_1 ~ . ac o ,~ a. a respiratory disease.. AA preliminary report. Archives of Environmental-~- Healtli. (Ckicago). 14(1) : 157-161, January, 19674 , 530;. Corea, J. E., Rossr~: C. E., HmorNs, II:. T. T., GYLsosy. JL. C. Average normal; values for the forced expiratory volume in white Caucasian males. British Medical Journall (London) 1(319i): 1016-1019, Apr. 23, 1966 531. Caorro.w;.E. C..Acomparison.of'the mortality from~bronchitis.ln Scotland and ih.Engiandand{Rales. British Medical Journall (London) 1(5451)~: 1635-1639, June 26, I9G5. 532: CnLCEx, JL H'.,,KAra, 11: L.,.KAEx[e[mr:E.v, J:.T. Chronic diffuse pulmonary iafiitrationn and airway obstruction. American Reviewof. Respiratory Diseases (Baltimore) 92(5) :. 77ir780, November, I965: 333. DASCOS,. A. Negro-white.differeneesin pulmonaryfunction: (Vital capacity; timed.vltal capacity,, and eapiratoryflow rate.) Human Biology(De- troit) 38(4): 360-393;. December 1966': E18

The Dorn study (49) of U:S. veterans reports the following laryn- geal cancer mortality rat'ios related to amount of cigarettes smoked, and smoking of! pipes and cigars,, or cigars only. TABLE 17.-Zaryngeal' cancer mortality ratios and deatli: ra.tes for U:S• veterans, by age, type, and amount of smoking Numba of ei®erettka per.day Pipe I Ciear~ and ~ ooly 0. 1-9. 10-20 I 21-39i 4O+ aigar __ -- 43ortality.ratio--------- _ 1 3.27 8.45 13.62 18.85 7~.28~ 10:,33 Deathrates:h I I Age55 to.64------- 1 I------ . 4 5 20 4. 3 Age65to7-------- _ ------ 7 13 1 17 -------- 12'. 20 Age75to~.84------- . 13 ------ ------ -------- -------- ------ _ _____- 9ounce: U.9i Yeteranastudy lepp. tableA (48)].. The Doll andi Hill study reported their data in. terms of cancer of' the larynx or trachea (see tables 14 and 15) for.relationships with type and amounts of tobacco smoking. The. Canadian study did notprovid'e separate data on~ cancer of the laryns.. No additional information has become available, since the Surgeon General's 1964 Report, relating the several forms of' smok- ing, i.e., cigarettes, cigars,. and/or pipes, to speci5c.laryngeaL cancer sites (intrinsic versus extrinsic larynx). The study previously referred to (69) which analyaedl the develop• ment of second sites of cancer after cure of a primary ora3i cancer„ reports that of' 37 smokers who stopped smoking, none developed cancer of the ]hrynx but that four of' 65' continuing smokers developed cancer of the larynx. Although. small numbers are involved, beneficiali aspects. of smoking cessation are suggested. Ad'ditionaL epidemiological evidence supports the previous con- elusion that cigarette smoking is a~ sigpificant factor in the causation of cancer of the Paryna. Ci.ANCER OF THE ESOPHAGUS The. Surgeon General's 1964 Reportconcluded:: "The evidence on the tobaceo-esophageal cancer relationship supports the belief that an association esists."' However, the. Committee at that time noted ~~ that there1cas not adequatedata.on which to basea.decision.as to. whether the relationship was causal., The National Cent'er for Health Statistics (94) reports that from 149 Sl 9L

In another setting (27), in which the.oral area. of mice was painted with.cigarett'e'.smoke condensat'e.for 15months;.no lesions were noted in the oral cavity.. However, a significant increase in lbng tumors, lrymphosarcoma, ll'ukemia;, and rebiculosarcomma was observed. REBIINSE The Surgeon GeneralPs 1964 Report established the causall relation- suspected. as causative agents,, when available,, couldl assist in such a. iudgment. Knowledge of the interaction of smoking and other facto'rs known or ; g the general category of cancers of the buccal-pharyngeal. area but ~` =~ present information remains inadequate for a judgment of causality. tlrens the association between the.various forms,ofl smoking and = stsen of other sites in the oral cavity and pharynx. Current information ship of pipe smoking with lip cancer„but did not find sufficient evidence W for a causal relationship of specific forms of smoking, with cancere 14; evidence leads to the judgment.that cigarette smoking is a si'gnifieantt The Surgeon General's 1964 Report concluded: "Evaiuation of'the~ CANCER OF THE'. LARYNX factor in the c.aasati'onof laryngeal cancer in themal'e'" The' National Center for Health Statistics reports' (94) that 2,494 d'eathsattriHuted s to cancer of thee larynx occurred in 1964, '. as. com- paredl with 1,852 deaths in 1950, . a 34 percent increase. Almost all these The Hommond study (40) reports the following information for > llaryngcallcancer deaths of males with a history o'f regular cigarette' ~ smoking; in terms of'mortalitg ratios and death rates: 2a• N deatlis'occurrecl in the male populat'ion,, with a male-to-femal'e ratio of ` about. 8 t'a1.. The' totall dcath~ rate in 1964 was1L3 deaths per 100100& populo.tiony which represented only a slight increase over the death rate of 11.2' tmtedd in 1950.. The mortality impact of tlhisdisease occurs'. primaril,y after middlc age„there being a five-fold increase in the death. rate for males oven i 5' years as compared to' males under 55'5 years of „~ age 'i. TAnLE. 16..-Laryngealcancer mortality ratios and deathh rateafor male :~7- cegarett'eamokers, bysyecified.agegrouys .~ 1W[orta)Ity'ratfov---_-.--------- -----------------.. Deatn rates_____________.---_-.---------__-----__ cigarette smakers. Age 45-64 B.o9' (1): 4 I YumhersIn pazenthesea.ihdib.te death ratm a('pennnme^ho had never smotled cigarettes~ regularly. 9oua[e: Hammond,. E C. (table 2/ (.(0)]. 148 `

TABLE 3.-Lung cancer (women). Number of deatlis,age4standardized death rates, and'raortUlity ratios, by type of smokiytg (lifetime h¢story), current number of cigarettes smoked per day; degree of inhalation, and age began smokizeg, by age at start'of study l Type nt ®oking QlfeHme hietory) Age40~34, Number of deaths Deattl rate AgelS74 Number of deaths Death rate Neser smoked negat9rlY_._._ 25 4 12 102 HlstoryoCcigarettesmokiug_-- --- 48 11 33 YS g1 Current regular cigarette smoking Curre.nt number of cigaretteta d&y: I to 19__...___..._._.__...__.___-- 15 5 7 20 20PIus. __....._____._._.. I 28 IS 22 59 Be Degree of Inhelation: Naneor sll®pL___---- ----- . 16 13 g 13 25 IN oderateno deeP_ 27 11. IB a u Age begansmoking: 7 6 19 21 23 Less tham25 35 14 11 !3 43 Lung cencer mortality ratios (ivomen) Never smoked regulariy HlstaryaPeigaretUe smoking---- ._.._. 1,00 2.82 1.00 1.93 Current regular cigarette emoking Curnent aumber of cl9arettes aday: 1 ta 49_ ..._-------- __.._..._ 2:08 0.62 29PIUS...._-. .__... 1' 6Y 4.91 Degree ofinhalatlon: ____ None or ellg¢t._ 3:33 1112 ..__ Moderate ordeeP____________ 2:9U 4:a Age began smoking: 25urolder---- ------- ..__...._. 1.55 1.76 Less than 25_._ .. -------- ... _ _ 3.'ab 160 `...__. rMortality rstios aretiasedon dtath ratexcarrled outto Smare signl9omnt figure than~ahown: 9ttugaerHammond, E. C.(table23 (40)). Ua, t to 5 to 1101 Clv No, T. Cu 0 Et M

11ToxrArrr DskTa Faoar THE LAxon Pxosrrcrm, STQDrFS Aff 1 '1'. s TASLE 12.-Buccal cavity and' phary7tgeal: cancer rnortality ratios and ~~ M d.eath rates for male smokers, by type and specified age groups Lf ~. . Hammond (40) has reported datafor males having,cancer of the buccal cavity or pharynx;as the underlying cause.of death, by mor tality, ratio and age-standardized death rates (table 12). Cigarettes t I Numbers in parenthese5lndlcatedbth rates of persons who:heid never smoked'd cigarettes re9ularlY.. &onnca: . nammond. E:. C. Oi0). The Dolsl study (49) also has provided infamnation with relation to <a amount and type of smoking'on males dying from: cancer of the buccal _; cavityandpllaryns ('tab1d13)a ~ TABLE 13.. Bueead' caLn:ty and pharyyegeal cancer mortality ratios and d'eath raEes for U.3`. veterarts, &y age, type, and amount of smoking ~,~ Cunena,smakersofel9mettCSonly~ d~ C - ~ PIpa Clema PI9~ . ". Numlierafalgsrettesperday and/or only onlp elBars' I a t-9 1o-2a 21-39: 40+ - - - - -' ~- - -- - ., Succal Cavity: ~ ,i M'ortality ratlo__________________ UaOi 0.86 2.93 7.3( 5,73 3.89 5.11. 8.1°. Deathrates:. ~~ A®ed5to.5f_-------- _____ __---- . -------- . -------- -------- . -------- 28 -------- 97 A"55tb:64 . I^ 3 . 6 1R 9. 5 3 2 AgeB5toY8 ------- -_ __ 1 f. _ l0 19 9' IS IB 11 ~ A8eR6Alip.____ __---- ____ -------- _ __....._.. -------- _ ._..---- _ -------- 12 33 .. h1. PHarynr: s Mbrtnlltymtlo___---------- _----- . LaD 7:11 12.91 . 14.59 19.34 3.9& ------- L1I8 Death mt®: A8e.55 to 61_------------- ____ ________ 9. 8 8' ..____.. 2 ~.____.__ ..,.___., k Ags65tu9f___ ___.__.._.__ _ . 1 ~ 12 21 10: 39 4 1---__. 4 ~ TTTPPP. BoUncp: U.S. voterens study lspp- tatll9 A(49)]_ TheCaluldian pensionevs:study (8) has not reported separately on deaths from cancernf the buccal cavity and pharynx. ported on cancer of the mouth and pharynx, including cancer of the The Doll and Hill studies (9,8; 29) of Btitish~ physicians have re-' nose (table 14):. 146~

REsum-i The additional epidemiological, elinical, andl experimentall data strengthen the. association between cigarette smoking and cancer of the urinaryy bladder, but.are sti1P insufficient to infer that the relation- ship is causal- CANCER OF THE STOMACH I The S'urgeon General's 1961 Report statedl that no relationship has been established between tabacco use and stomach cancer. No new evidence refutes this stat,ementl.Epidemiologieal evidence,does not. show a significant relationship between smoking and stornachl cancer. The overall mortality ratios, although greater than f'or nonsmokers, are smaller4han for any other disease related to smoking. There is also no gradient with tlhe amount of Bobaccoo smoked. TABLE 28.-Made morlaltitiy ratios and death rates for ca,ncer of stomacli 6y specifted age groups Dlbrtality ratius_._______________________________ Death rates_.______________.___._____________-__-_ Age 45fi4 1..42 (li1) 16' Age 85-79 ~ 11. 26. (57) 72 I Numbera in parentheses Indicatedeath ratesotperruns who had never.smoked eigarette regnlerlg.. 6ouacs: Hammondl E. Q. (table 24 ({0}(:. TABLE 29.-11lortali'ty rati.os and death rates for cancer of' stomach bv aae. tvve, and amount smoked, tin U.ST.. veterarts fi. Q Clgsrettes/dep Pipe and/or cl@ar Pipa ci®ars 0 1-9 I : 1d20: 21-n I. 4U} btortaiity ratio (total) .____________ Deathh rate:. 1..00 2: 17 1.61 1.35 1.87 1.21 1.20 1.40 Age:45to 54~_._ _ _. 10: 7 _ Agc. 55tio 64 _ _ _ _ 13 27 21 24 53 15 g 21, Age. 655 to 74_ _ _ _ 28' 68 ' 48' 58' 46 40 46 57 Age. 75'5 to 84_ _ _ - 87 1114 212 9buacm:: U.S. Veterans aLudy IaPp. table~A (01. 157'

A, G. e norep [RAE Hedi- L Pal- "age Ican tter- ' Epi- aes. no- (50). KanasaoLZ, Rl A.,,Cneveucs, R. B.,,Rose, J:..C. Changes in cardiopultnonary f4nctions related'' to abstinence from~ smoking. Studies In young cigarette smokers att rest, and eaercise at 3 and 66 weeks of abstlnence. Annals of Internal Mediciae(Pliiladelphia) 62(2).r. 197-207, February 196"a. (51), KavneaoLZ, R: A.,.CHevAr-tea, R. B., Ross, J. C. AA comparison of pulmonary compliancein.young:smokers and nonsmokers. American.Reviewof Res piratory Diseases (Baltimore) 9Z(1). r102=1074 July1965, . 152) L.casoN,.R. K.,.BAaawN;,M. L. T'he.familial occurrenceofc,hronic obstrac, tiue:pulmonary disease. Annals of Internal Medicine (Philadelphia) 63 (6~) .: 1001-1008, December 1955, . 153) LusnMAa', T. Smokiug:in relation to coronary heart disease.and.lung funa tion in.twins, A cotwin control study. Acta Medica Scandinavica (Stock- hoilm):180 (Supplement 455), 75~ pp,,,1966i, /5.q) Masrx, F., MAscyL, M. Frequencies of alveolar cells in concentrated sputum specimens related.tooytologic classes. Acta Cytologica (Balitimore) 10 (5).: 362-367;, September-October 1966: (J5) SICCAnaOLL, JL, C669ELL, E..J., WDLTFla, D. W., MODNTAIN},J. D-,.DLAffiOSD; J:,R., MoonTbrN;.1. Si'- Health and the urban~envitonment~ V. AirpollLL- tion and illness inn a normal urban population. Archives of Environmental Health (Chicago)14(1) : 178-183, January 1907. (i58) Mmane,.J..Mi, SraovLa, BL J. Acute.eSects of'inhalation of'cigarette.smoke om mechanical properties of tnee lungs; American Review of. Respiratory Diseases (Baltimore) 94(5): 721-726, November1966:. (57) Mouzwxrs,. S.. T. Personal communication... Athens, University. of Greece; May 176 1967.. (58) PAxNE, ST.,. K.rELSSeaa,.M: Respiratory symptoms, lung function4 and smak- inghabits in ann adult population. American. Journal of' PnblicHeaLYJS and.the Satiou'sHealth (NewYork) 54(2) : 261-277, February 1964. ~:;8) PsTSas, J: ML,. FEaam, B.G., Ja- Smoking, pulmonaryfunction and respira- tory symptoms in a cot'lege-age group. American Review of Respiratory Diseases (Baltimore). $5(5) : 77.li-782, May1967.. 160) . Pereas, J',. M., Ftmers, R. G., Jm.. Smoking and: morbidity' in a college-age group. American Review of RgospiratoryDiseases. (Baltimore) 95(5)'.: 783-789, May 1967- 161), Perrx, T..L.,.RYAN, S. F., ]frrcum.n, R'.8. Cigarettesmokingandlthe:lungs: R'elationn topostmortem evidence of:emphysema, ohronicmronchitis, and black llong,pigmentation. Archives ofEnalronmeatal Healtli(Ctiicago) 14(1) :.172-177, January 1967. 102)RAnarre; J., GF;n, J. B. II:., Cxosx;. L. Ra: The influenee of'f age and smoking om pulmonatydifusingcapacity in healthy snb7ectB• Medicina Thoracalis (Basel ) 22 H$) : 366-374, 1965. (63) Roasrne;. W..T: Bronchial epitbelium in smokingand.nonsmoking college students. Journal.of'the Ameriean College.Health.Association (Ithaca) 14(4) :.26:r266, Aprili1966: (5; ) Rocxzz,. E'- E., Sern.n,. F.. D... The ill effects . of cigarette smoking inn dogs: Internationall Surgery (Chicago). 46(5) :'.520-530, IDecemlier1966: Ifi.i) SAm, S- I.. Rale of pulmonary surfa¢tentt in health.h andi diseas,e- Medical Clinics.of North. America.. (Philadelphia), 51(2) : 391-402, Bfarch~1967. (;',) SLms-Cnxwna, G. K., WeLa:tms, L.. G., SreneL, H. S. Chronic bronchitis. In miners.and nonminersx An.epidemlolagical.survey of.a conmmunityin the go4d-miningarea in the Transvaal. British Journal oB.Industrial Medicine (London) 24 (1) :1-12,.January 1967- (57) SLVrs-Csne[ea, 6..K., RIALaERs, L. G., Sronxy H. S: Ventllatory function in relation: to miaingexperience and smokingim a random sampleof 115

TdHLE3`L. -MQrtat$ty ratios a1Md' dEdttth rateS for cancer of pancreas by age, type, and'am.ounbsmok'ed, in U.S. veterans 0 ` Cl gerettes/d a9. Plpe nndlor Cigsr Pipe o. ta~ - 1 ro-zo. 2t~.a9 - ~ 4o+ 1-- tg6r9 - I '-- - Nl(IrtaliV ratio (total)------------ 1.00. .87 1.98' 2:18 1.87 1..13 1.52' .74 Death ratie: Age 45 to 54____ ______ ______ 9, 21 ----- 26 ------ _. ______ Age 55ta 64____ 13 15 24 26 21. 19 21 22 Age 65to 74.---- 29 29 500, 56 - - 27 38 58 19 Age75'to 84---- I 109 ______ r---- ------ ______ 32 33 68 Sacacn:. U.S. v¢terans study (epp. tahte A(/&ll.. TAnI.E 33.-Male mortatityratios for cancer of yancreass of' currentt cigarette smokers by amountt smoked Mortality ratiu_._______________ SOVxCn: Canndl2n pensbners stndy (tBble 8.2:(811. )~';ESIIDL}: cigsrettesrdsp. 1n association between cigarette smoking and pancreatic cancer is implied, bnti in the absence of data on other possible catlsal factors,, confounding variables and! interactants, the signi['icance of this as.so• ciation is not clear. 159

1950 to 1964 the mortality from cancer of. the esophagusrose about 8 percent in the male population andi 9 percent im the female popula- tion. In 1964,, males had a death rate for esophageal cancer that was 3.7 times higher than the female. rate. The greatest relative increases were in the age groups under 65 years, especially the age group 35-44 years., ii~ORTtiLITYD'ATA 1''RO)I THE'Iuk110EIk$OfiPECTLVE r.STIIDIEB:The Ham- mond (i4O)~ study reports the fodlowing, death rates and mortality ratios for.males'in theagogroups 45-64 and 65-79 who have a history of smoking regularly: TAS1.E 18.-EsoPhageal cancer mortality rattios: and: death; rates for -mate (cigarette smokers,, by speeifac. agee groups' . A6e 45-6f' Age &f79' Mortality ratfios.__.__________.__._________.______.__ 4. 17 1.74 Death.rates (a) 4 1 (4) 7 TABLE I9.-Esophageal cancer mortdli,ty ratios and deatJu rates for d1.~S^: veterans„by'age; type, and amounGof smoking g I Numbers in perentheses Inditate.deatti rates.uf.persnns who have:never.mmoked.reguiariy. 6ouaae: Hammond. E. C. [table N (40)].. The Dorn study (49) reports the following mortality ratios and `_ death rates in relation to,number of' cigarettes smoked per day' plus ~ other forms of' smokin : Number of dgarettesyer daA Pipe. and CI r ~ . - Piye: 1 l dgar. am y --~ ,~- fo-so 4 21-39 i 40+ ~ -- IMortiality ratios_ __ 1.00 I ~I 1. 76~ I 4. 71 11. 50 7.65 '~ 4.05 . 5,33 ~ 1.99 DeatHh rates: Age 55 to 64___ li 2 5 14! 9I 5 8!. Age65to.74___ 3 16 25 10' 20. 23 '. SB Age 75 to84___ 45 ~._____ ~___.___ ________ ______ 41 ______ from causes other than esophageal cancer. The smoking histories were recorded' but not known to the person examining the slides. The fimd- ings were stbikingly simillar to the abnormalities generally accepted as 12,598 sections of esophageal autopsy tissue from 1,268 men, who died '.-~.3')`. been' performed by Auerbach (3)',. A microscopic study was made of ~ Autopsy studies of' smokers as compared witli~ nonsmokers„ sper cifically observing the pathological changes in esophageal tissue, have p gg cancer., 6uusoa: UIe. Vateransstudy I@pD• tabis A(/9)], . . The Canadian veterans study did not give separate information A~ about deaths from eso ha al "' 150 rel ep: far "at chi pr( mc crc lbo Ai in ill T.

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; habi eptums, !a.. New 4,.1963 clation in In imore Ielium ,ew of 11966 s and aailed 743- I fitors; -paii•s lealth pozy 346'.- 6 and Bmgo- entali runc- tt-74„ ,; I I (19) Caavai.n~, RL. B.,. %RVSCnoua; R. A.,, R'oss; J. C. Reaction of nonsmokers to carbon monoxide iuhalbtion.. Cardipulmonary responses at rest and during eaeroise.. Journal of the American bieddcal.Association (Chicago) 198(10) : 1061-1064,. Dec.. 5,.1966. (20) CoArss, E. OL, Js:,.Bowm, G:.C., 1CFSnsra:x, N. Chronic respiraY,nrydlsease in postal employees.. Epidemiolagic survey of a groupp employed. In one building. Journall of the. Americam Medical Assoeiatiun. (Chicago) 191 (3) : 161-166: Jan. 18, 1965. (21) Coox, W. A.,. Wms; W. R. Surfactant. In chronic ®mokers. The. Annalsof Thoraeic Surgery(Bnston)2(i3)l: 327-33, May1ii66~: (22) Cness, H. R., Spocic, A~, HeexerstNUrox, D:.C. Tbe localiaation.of succinic dehydtogenase, eytoehromee osidase: andd adenosine triphosphatase In eiliated, respiratory epithelum. Journall of Histochemistry,and, Cyto- chemistry (iBaltimore)13'(8) :. 677-6833,. November-December 1966. 1'3p D~rrwarN, T. Studies on trachealciBai+y activity. Speciall reference to the effect.of cigarette.smoke in living animals..American Review of Respira- tory Diseases (Baltimore) 89(6): 870-877, June 1964. (2i)~ Dea:HAM.~; T. Effect of. cigarette smokee on ciliaryactivity.. American Reviewaf Resplratory Diseases (Baltimore) 93(3).: 108-114, March 1966. (I45) DAmawaexy T:, LdueasT®T, BI CBi'ostatic effect of phenoll and resorcinol. Archizesof Otolaryngology (Cliicago) 84(3):: 325-328,. September196fi. (?6). DAr.aaxN, T:,.RruvnEa; R'- Ciliastatie action of smoke from filter-tipped and non.tlpped cigarettes. Nature (~Landon) 201(4917) :.401-1112, Jan. 35, 25, . 1964.. 127) : D~au.a, T., Rxi.esnE$ R'..Clliastatic action of cigarettesmoke. Varying exposure tihies;. Archives.of Otolaryngology (Chicago) 81(4) ; 379 382, April 1965. '(28). DsexE, M., Gocusxvra,.J. R:, TuntA,.DL Respiratoryconditions.in outside warkers.. Report on outside plant telephone workers ih San Francisco and Los.Angeles. Archives of Environmental Health (Chicago): 10l 323-31„ FeBruary 196"a: (29) DoLS, R.,,Hizr{ A, B. llortal'ityia relatiomGo smoking: 10~years' observa- tions of British doctors(pt.. 1).. British 3fedical Journal. (London) 1( 539"0) . : 1399-141Q 31ay 1064. 00) Dou.; R.,, Hn.r., A.B. Mortality in relation to smoking: 10 years' observa- tions of'British doctors (concl!uded.):. British~bledical Journal, (London) 1l 1460.1467,June. 1864.. (31). Exraanisx, P. E. The effects of occupation, on chronic respiratory disease. Archives of Environmentai Health. (Chicago..)14(1) : 189,200, January 1967. (32I)FEaxls, B. G., Ja:, Busaess,. W. A., Woaeta7ea, J. P'revalance.oflchronic respiratory disease fnn a pullp mill and a papermilll in the United States. British Journal of Industrial Medicine ( London ) 24(1 p:. 2637, January 1967. (33), Feasts, & G.,. Ja.,. Wa¢rrasacaoas, J. L. Effectaof community air pollution on prevalance of respiratory disease: NewEngland Jonrnall-of Medicine (B'oston) 275(25) : 1413-1419, Dec..22; 1966. (•i¢) Fr.c'ronna, C.. M. Bonsows„Jt B'., NmaN, A,. H. American emphysema and Btitlshbronchitis. A standardized comparativee study. Amerdcam Review of'Respivatory Disease (Baltimore).90(1) : 1-13, July 1964. 03) . Gasss, G. M:,,CAnouNl.D. The depressant effect of cigarette smokeon the in vitroantibacterialo activity of alveolar macrophages: New Eagland dburnall of'~ Medicine(Boston) 276'.(8) : 421-427, Feb. 23L 1967. 113

coronarlvheart disease. American Jonrnall of. Public Health~ and theNation'S Health (T4ew Fork). 56(6) :.962-971, June'.1966: gill. YAr=eeRnea, R. S:,, Ja., Wrtr.rexs, J:.L. Mortality from stroke in former rotlege stndents.. Framingham, Mass. U.S: Public HeaRh, Service'„ Na- tional Heart Institute;. Field E~tidemlological. Research Section., n.dl2a pp. 81.1^_. PEVwcosT, B.,.SBrLmsasoso; J. The acute effects.of.emoking,on myocardial perfbrmance in patientswitL corronary arteriall disease.. British Hleart. .Iournal. (Londom); 26 :.422-129,1964. 5113. PnuuN, 11. J.,, ffaoTj L. H., Baosar STEw',teT,. B. Smoking and food prefer-ances. British bledteall Journal ( London) 1: 3d37.388; Feb..11, 1961. . et] k. Pich, R. The present state of knowledge about the prevention andl therapy uf' atherosclerosis. Medicall Clinics of Narth America (Philadelphia)', 51 (1) ; : 97-16f, January 1967.. FIL-, _R:taa, IV:.The neurogenic metabolic factor in ischemic heart disease. 1':dhogenesis and prevention.. Diseases of. the Chest. (Chucago) 46(2) : 1:~157, Augast1961. 8111L RA.w; W:. Origin, prediction andpreventiomd of ischemieheart disease. Japanese Circulation Journal (Kyoto) 29c 113-22,, February 1965'L S1.1I. Rena; W., IsnziwAnES, H. J:. Cardiovascularsympatlietic tone and stressreslwnse related to.personality patterns and.exercisefiabits. A potential mrdiac'c risk andd screeningg test.. American Journal of Cardiology (New ] ork) 16 (1) :.42-:i3,. July 1965. 8111\ RE[D: I9. D... HULLASD,. W., W'., HUMEHrELT, S., RU6E, ('iM1, A aardioCascnlar' survey of British.postal workers. L.ancet. (Lnndon) 1: 614-G18,. Sfar. 19;, 19% . F7II9. itOitr,. 0., BEasr„ A., Wor.ar, G. D: Long range otiservationstn 53 young'g patients.tvith.myocardiaL infarction. The American Journal'of Cardiology i New I'ork) 19: 331-338, March 1967. SLP. XxcsEirr, Dl L.,. WiNSr.ESrerrr, W.,, Ja. The relationshipbetween.cigarette usage and aortie atherscLerosis. [Unpublished.] 5.tcaxxcu;. J. S.. Cerebral symptoms due to cigarette smoking. Journall of the. Louisiana State yledical. Society (~NewOrleans); 117(7) :'. 227-229, July 1965. '- SCniErEZBErs, ]kS. Effects.of nicotine and. other alkaloids on storage andl release of'biogenic amines. In: Thirdl World Tobacco Scientl8c Cbn• gress Praceediags:. Heldd at, the'. University Collegeof Rbodesia and Nyasaland, Salisbury;. Southern. Rhodesla, Febrnary' 18-26, 1963. Pp. 625-fr13. a12 , yG3xxacarr.nx, W:,.NEEa, C. Raucligecsobnheiten.und.Hereihfarkt. Muachener3ledizinisehe Wochenschrift (Munchen) 108: ~: 963-9151, 1966. 81_4, Scawaxxz;. D., Lsr.wcca, J., ANOUESA, G., BeeuaorvT, , J. L.,, LENECaE,. J. ToUacco and.other factors in.the etiology of ischemic heart diseasein man..: Results.of a.retrospective survey:.Journal.of Chronic Diseases (St. Louis) 19(1): 35-55, January 1966. `!725 . Sn:tpmo, S„ WErxncerr, E., FRANK, C. W:,. SeaEn„ R. V.71he HLILP. study,of'.incidence and.prognosis of coronary heart d'.sease'. Prelimihary flndings on incidence of myocardial infaretibn.and angina~ Journal of' Chronic Diseases (St. Loui6). 1fl(6) : 527-558, June 1'965. 81:.r,. tiuwcm.o, S., WErsnLear,. E., Phceex,. C.. W.. SAGER, R. E:, D®sszx, P,:. hf. The:H.L:B..sthdy ofincldence'and'prognosis of coronary heart.disease: methodology:.Journal of Chronic Diseases, (St. Louis) 16'~: 1281-1292,. Deeember.1963~: 83

8184. Wgrnss, E. L., TAaUCSt,. K., BdDEN, Y., HoerMenN„ I). a+l.studyof tobacco carcinogenesis:, IX. The eBQetl of passive inhalatioa of cigarette smoke on the respiratorptract of.mice:Sloan-KetteriugInstitute for Cancer Re- search„ NemYork, N.Y. Supported by Grant'~ No. 231 from the American Cancer Societyandi in part by Grant No. Ca08747 from the National Cancer Institute:. September 1966. [Unpublished.] 22Ipp: 5183:. ZAvom, Yh R.. Crop chemica]e and lung cancer (letter). Lancet (London) 2':1072, Nov. 2% 1965.. 5186: Zn.eEa, I. 11.,, PosTNisove„ Z. 9.Indoctlon of's leukemogenioagent by a chemical.carcinogen.ln Inbred mice., Bethesda, Nattonal. Cancer Institute htonograph.No. 22, September 196& Pp. 397-N73. 177 s C a

TA>3DE 21. Atypical nuclei in basal cells of epititelium of esopllagus of malesr by amount of smoking and'd age .r; Current ei8srette.amokets...- .. Never emnkedd regularly Celis with atypical nuclei <1:Paek. 1-2PacYs 2iF P6<5a Num- II Pet- Num- Per. Num• Per. Nilm pg li¢r I CBnt'~ iMr eent b9r eent,t bR Cent A. Aa esw'-------------------------- 91 -------- 179 -------- 03 -------- M --- Totelsectlonsl___.._______._..___ 787 100.0. 1,6fi1 1daJ0 8,629. 10W0. 1,579 Nostypicalnuciei'-------- .------ 733 93.1. 89 &8 39. 1.1. 39 2 6 8omebut<dOpetcentetypical_ 52 &6. 1,341 8bJ8 2;957. BV.51 1,091 69.1 dOpementm.mareiatypltel___ _- 2 0.3: 1I8 T.4_ 83T 17:4 449 ~.4 H. Men undee s8e 50: ' Numbermen_._.._..______.______ Tataliseetlons'_._.------------ -- 26 22 ----- 100.0. 40 433 100:0 __ 132 1,ibA . 1ao:0: 55 657 ------- laao No.atypicalinuciet._______-_.- 190 85.2 48 11.1 21. I T.B' 2 0.4 aomebut<fi0pement'.atypicai:- 33 14.8 38$' 88:2 1;089 , 93J2 392 9opeccentor, more:atypical ------ ' ..- _ 3. a7 b9 bld. 73 160 ' C: Men seed 59-W: Numlrermen_. .__ 44 ---- --02' ,. ..__---- 240 ___-._ 113 . . TotalsecttonsI _ $/9 100.0 ' 789' 100:0 2,11d 100:0 948 1 0 Noatyplcai'nuolel_._._._.._-__ 373 98.4 ~ 80 a8 18 0.9. 35 ' SeomebutGbOpercentetypleal__ 4 1.1 . O91. B'!:9 1,8d] 76:9 814 Wpernent,or.moieatypical_____ 2 0.5' 64. 8:3 49t 2a2~ 299 Dl Men aeed 70 or old'er. - Numbermen._________________ 21 ______ 38 __..__ _ 41 __..._. 19 ___ Tutel:seetlonsl._..___________ 185 I00.d. 322 100.0 . 041.. 10a0 174 l0a a Naatypicsiuuciei..___.____. 1]0 91.9 I 11. 8.4 _____ -------- 2 111 ieal m lb 8.1. 2~ 52a 1 ibl T5:9 95 54b - - ',reatypice/ BO peruent or mo - - _ - I 83. 2i1 Tf 1 Sections with sume epitheLLum present. ebnsen:Auerbach, O., etaL (table 3(J)): E%PEEr1YrENTAL r.5'TIIDI'E SES Because of the association noted between esophageal cancer and' ~ aleohol consumption reported in the Surgeon General's 1984. Report, .~. a study (58) was undertaken to consider the possibility Uhat the car- •- cinogens known to be present in toliacco smoke could penetrate esopha- ~: geall tissue more readily, if dissolved in aqueous solutions of ethanol. .~+ 11Qice were' esposedl to several compounds by intraesophageal tubatlon ~ Tissues were then hen removed and studied by fluorescence microscopy. ,.- Deeper penetration and a different distribution were found when benzo (a)pyrene was di'ssolved in aqueous solution of ethanol as com- ° pared to benzo (a)pyrene dissolved in olive oil. It was also found that benz(a)anthraceme and flhorantlhene dissolved in ethanol solution or aqueous cafl"einesolution, could penetratethe' epithelfiumof the esophagus: RYsL ME' The present evidence strengthens the conclusion that a four-fold to fi've-fold increased risk of dying from, esophageal cancer is associated 152 witt ares of A dem othe ethx ing but tior nee 7 get thc the in sm TA B TV, P d 1

CHAPTER 4 Other Conditions and, Areas of Research CONTEN1fS' PaRe Smoking and PepticUlcer-------------------------------- --_ 181 Smoking.and Disturbances of Vision----------------------- 183 Smoking and Cirrhosis of the Liver------------------------ 184 Effects of Smoking During Pregnancy---------------------- 185 Smoking and Accidents---------------------------------- 187 Psychosocial Aspects of Smoking-------------------------- 188 References--------------------------------------------- 193 0 179 ~

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TABLE 30~.-Death h rates for eavtcer~ of stam,aeh by t'ypee and~ amourd~.;~:. I TAI smoked,. in Bratl.sh physiceiane Non• All Cigerette Amount ot tubecm dagy (;,) . t eivenup ' J. Plpe a smokers emokers smukers smvking M1ced etger 1-14 1'3-1A RS{~ Au 'I amounts . ., 27 25 30. I 28. 28. 28' 28 18 14 30 e 1 g~=L' Cige(ette per deY=SS Us. tGbaaca p4r wfi6k. SOURCE: 6tudy of'. British physkisnsItablea 14 and' 15 (LBJ[. RESmmg Although cigarette smokers:appear to have slightly higher de" rates from. cancer of the stomach, the differences are small and db not bear anv consistent relotionship with amount smoked. CANCER OF THE PANCREAS t The Surgeon General's 1964 Report did not report on cancer of the pancreas.. The more recent epidemiolbgic evidence shouss an increase in the .- ' death rates and mortalit ~ ratios for pancreatic cancer among male cigarette' smokers (/r.0;, J~.9}~.. Comparably elevated ratios are noted for w females but not to the estent, noted for males (40) (see tables 22', 31, f 32, 33):. Both.the LT.S. veteransstud}r (49) and the Canadian pensioner= " study. (8) reveal a gradient of mortalfity risk increasing with the,' amount of cigarett'es smoked. I)ata, are insuthcient to draw any con= clusions for plpe and/or cigar smokers. Tv.Br,E 31'_ Mortality' ratios and' deat'h ratea for cancer of Partcreas by.sex and'c speatifac age grouPsin cigarette sm.okers -` Age IS6s. Femete IISortality ratio_ ID.eath rate-------_-"-------'- Male AgegS:'1B Female, 6fkle ~~Camputedifrom epp. toble 19i. t~ I~umAers inipar®[hesesindimte dealh rates of persons who hsdlnever smoked vigarettes.tegulerly 9ooxce: Hammnnd'l E. C. [tables 24,26, snd app, teblelg{{0yy, 158 T. M c

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10 8 ~ C U5 N ~ 4 2 0 F[oUask.-Percentagedistribution bgbirth weight'of infantsof mothers who did not smoke dhring pregnancy and of thoaee wboo smoked.d one pack or more per day. 9ourcerblacDfahon,.B., et al. [tig.1 (19).][. Steele (.?9) suggests that smoking is associated with suddem unex- pected deaths in infancy. The relationship of smoking in mothers to increased fetal morbidity, either perinatally or after long-term follow- upy hasnot been adequately probed and is a, major area for future researchL . Some studies show a, relatiotvship between smoking and decreased gestationall age (6;.8; 32) ; others donotl(7,. W).. Gestational age probably is a better indicator of fetal prematurity than birth weight. Therefore, it rmay better reflect perinatal risk. Yet even in thestudiesshowinga.correlation.to smoking, this.relationship is less marked than that to birth weight. (6;. 8, 24, 32'), This may be due to the relative ditficulty in d'etermini'ng the last menstruai period accurately and t'hereforethetrue.gestutional age. Themechanisms by which smokingaffects pregnancy have not been elucidated. Events influencing decreased fetal birth weight have been attributed to several factors: 1- Placental vasoconstriction due to nicotine. No direct' evidence of' this exists at the present.time: The effects of smoking on uterine blood flow are being conducted in animal experimentation (R)_, 1 Birth weight (scale in pounds.;; intervals of 44 oze.) 186 ( (

has advantlages which were discussed at the 1967 behavior research conference (8). The.use of such laboratory methods and controls has been shown to be particularly useful in communicalcionsresearch, inc]uding the study of factorsthat.affect a person's acceptance and use of health information. More systematic efforts are neededl which will relate the content of'the message, the.form of the message, the kind of medium used; and the characteristics of the co®mnnicator to changes in smoking behavior which are also related~ to the psychosociall nature of the target audience. In particular,,emotion.provoking communica- tions need to be studied in relation to. various . factors. that are known to maintain actions, such as. public commitment andl conformity to group norms. As in the case with epidemiological investigations, however, itis probable that more prospective research studies. combining, social- psychological, sociological, and anthropological concepts must be car- ried outbefore a better understanding of smoking behavior initiation (or non-initiation), continuation, or change can be a,chieved., 192

death rate from this cause was' 5.8' deaths per 100,000 populationy and the female'.death rate was 2.6 deathsper400,000 populktionL -t~y The mortality data fcomthe.large prospective studies are presented below..The Hammondstudy'reports the following mortality ratios and death rates for cancer of the bladder and other urinary tract sites, for males, by' history of regular smoking; TABLE 23'.-Bladder cancer mortatity' ratios and'age-standardized ' death rates for m.a:le cigarette smokers, by speoiifoed age groups Itlort'ality'.ratios________________________________ Deathrates_________________________._______ Clgazatte smoters. Age SS-6/ 2.00 t (4)7 Age 95-79 1e: 2.9& ;: (17)50: I Numtiersln parenthases iadicate death ratesior.persons:wDo have never smaked'regalarlyd eovaczi Hsmmnad', B. C'...[table R4:(40)], . The: Canadian Pensioners studly (8) included bladder cancer in the general category of genitourinary cancer. TABLE 24(s'enit6urina,ry cancer mortality ratios jor Canadian veterans by age and'amou.nt smoked' IHortulity.rstios. All ages--------------------------'---- - Age 70---------------------'------'----- N amber ol <i gazetbes sm oked pen d oy Ptpe I sndpr Cigars Plpe - I dg9rs 0 1'-9 , 10-20 2439 Wk ~ I t- Mortalityy ratioe.- 1. 00~ I I.:10. 1.93 3.20 2.52 I 1.09 0194'~ I 1.20 Death rates: .: Age 45'54___ _______ _______ 13! 18 ------- ~_____ _._____ __ Age 55-64'..__ 8I 2~ 12' 14 20. 14 18 '. 14 Age65-74,__ 22I 25: 28. 90 45, 20 9, 28 Age 7Fr84,-_ 89. _______ _______ _______ _______ ______ ______ ____1 1. 4'3 2,43 E Sovxca: Canadian pensbners sthde Iteble 82(8)1. 4r The Dorn study of U.S'., veterans (49) reports the following mor- V, 1. tality ratios and death rates for males by quantity of cigarettrs ,gI smoked per day andd by pipe and/or cigar smoking: ;~ TABLE 25,-Bladd'er and other urinary tract cancer mortality ratios and "~ death rates for U.S. veterans, 8yy age, type and' amount sm.oked ,~ 8mmcs: L.B, veterunastady lepp. tableA.(48)1.. 154I fal TA 8 T a

r.- AII'IIOrsY' STCmLEs There have been no reported. studies analy.zing changes in the bladder tissue of' smokers compared with nonsmokers. Studies of this type would be helpful to determine if smoking is associated with pathologic changes commonly thoug)It to be. premalignant in other types of'tissue. E7irERrMENTAL C.YacINOGENESIS. ~,. Cigarette smoke condensate as welli as several tobacco smoke con ~- st.itiuents were implanted with cholesterol directly into the bladder of mice (16). Only hydroquinonc produced a. significant number of ': bladder tumors. lt`fETAnOLIC STI'D[FS OF ENnOGENOII&CiARCINGGENIC SCB&ThNOEB IN 1KA while the normal end metabolite decreased an. average of 34 percent ,~ weeks, with a concomitant decrease in the excretion of N'-methyllnico- tinamide,.a normal end product of tryptophan metabolism. After hav ing stopped smoking for.5 weeks, the tliree.smokers showed decreased urinary excretion of these same intermediate metabolites and an in« crease in Ni'-methylnicotinamide excretion., The carcinogenic metabolites increasedan averagee of 50 percent had substantially increased urinary excretion values of 3-hydroxyan- thranilio acid and 3-hydroxykynurenine, after having smoked for 5, smokersand three nonsmokers: He found that the three nonsmokers Kerr, et al. (51, 52), performed metabolic studies on six men, three ,,'i Certain ortho-aminophenols and aryl hydroxylamines are known to be carcinogenic (1'5).. Three normal intermediate metabolites of tryptophan are ortho-aminophenols (3-hydroxyanthranilie acid, 3- hydroxy-2-amino-acetophenone,3-hydroxykynurenine) andlareknown to induce.cancer when placed i¢I the bladder of mice (15). arinary tract, sho+.red'that 29 of 201 bladder cancer patients had both kynurenine and 3-hyd'roxykynurenine;:in wntrast.to eightof 167 pa- tients with other urinary traot diseases„neoplastic, and'.d nonneoplastic. Elocvever„ more renal.cancerpati'entshad 3-hydroxyantbranilieaci'd thanbladder cancer patients. Thisstudys did not include data concern- ing current smoking habits of'the patients studied. , stopped smoking:,These studies suggest that cigarette smoking changes ~ v t'he normal metabolic pattern of tryptophan, leading to the accumula- ~ tion of careinogenic metabolites in the urine. Further studies are ,~ needed to confirm thesefindings: Another study,designed to.d'etect abnormalities of tryptophan (6) ' in patients witllvarious neoplastie ornonneoplastie conditions:of the Q u. .c~Iiv::ac ~av.. ~iguaci,.~c o.u~n...~., z.crc.a..u .vua n~racu.ua~..ca ~no iucu 156 str th( shi bi e• b- a d 0 7

829. DAax„ J.,. PeMUSaroN, M., OrCoxxoa, M:, Russ.ua, M. M . Relighting of cigarettes andlung cancer. Briltish Medieall.Journal (London). 2(5366) :: 1164-1166, Nov. 9, 1963. 530. DeAY„ G.. Lung, cancer among white South Africans. BritishMedical Journal(London). 2: 120-1i21~July 14, 19621.. S3L Dexs;, G: Lungi cancer In the Channel Islandia. Britf9h Journali of Cancer (1london ) 19,:: 661.G86 1985. 532. DEAn,. G., Lung, cancer and bronchitis In NorthernIreland,.1960-82. British. Medical Journall (London), 1: 1506'-1514, June 1966. 533: DeueavE; N. C. Reconsideration of somesigni8cant aspects:of the cigarette smoking-lung cancer controversg.. Canadian Medical Association Journal (Toronto) 89: 1277-1283;: Dec.. 21, 1963: $34. De Stesrsm-Gnmv~taa, J., DR MAavea,. E. EHect of carcinogenic and non-carcinogenicc hydrocarbons om interferon synthesis andl virus plaquedevelopmentl. Journal of the National CancerInstitute. (Washington) 34(2): 26:r272;, February 1665. 835. DrPdow;. J. A.,. gann, P. Teeatogenesis-oncogenesis:: A study of possible relationshipx Archivess of Pathology ( Chicago), 81:: 3-28, January' 1966. S361. DoLr„R. Interpretationsof epidemiologic data. C'ancerReseareh(Chicago): 23(10):: 1613-1623; November 1963. S37, Dauu„ R, EpLdemiologicaf observationss on susceptibility to: cancer in.n man. with special reference to age. Aeta;,Unio-.Imternationaliscontra Cancruna (Louvain) 20: 747-752, 1964. 538. DOLL, R.. Cancer: Thee poss[bilities. British Medical Journal (London), 1(i5433) : 471-473;, Feb. 20',. 1965. 539: Douc, It.. Cancer bronchique et tabae Bronehes (Paris) 16(5l: 313-324: September-October 1966., S-f0.. DoNxENwn.r.,. W. EapeoimentelleUhtersuchungen. zar Genese des Lungen. carcinoma Arznetmittel-Forachung(Aulendorf) 14'::,774-780; July 1964.. 541. Dosr>:v}vrLL,. W., Raoszea„ G., STAnma,. L. IInhalationseaperimente im Zigarettenrauch:. Beitr$ge.zurTabakforschung (Hamburg), 3:438 145; 1966. 842: DROCENarax,. A. Cl Smakingand.lungcancer. Triangle; Sandoz Journal of Medical Science (Basel) 7: 166~-169; 19661 843. DvvN, J. E.,. Jn., WEIa, J. ML Cancer experience off several oeeupational groups followed prospectively. . American Journal of Public. Health and the Nation's Health (.NewYork)~ 55(9) : 1367-1375a.September 1965. 544: Duses-Rtrswns, F. Stludiess on the combined e8ectsof fowl pox virus and metAylcholanthrene Lnchickens.. Annals of the New York Academy oC Sciences 54: 977r991,.1954. 5451, ELMExaoasT,. H., REcxzen;. G, Aromatische RohienwasserstoHe.im Tabak- rauch..Beitrage zur Tabakforachung (Hamburg) 2(5),: 180~204, May 1964. 846'. The endocrineandgenetie factorsin cancer of thelwng: Growth. (Phiia, delphia) 28(1)':: 1-15,.March 1964. 547. ErsrErv;. S. S. Twosensitive testgforcareinogenx imtLa aJtr. Journal of the Air Pollution Control Association (Pittsburgh).16'(10) r,545--.561,.October 1966. 548. Easrzts, S. S.,,Joen:, S., ANaaeA,.J., MaxTsn.; Nl, SAwresr„ E., Szwrccev,.T., TAaon, E.. Ci. Carcinogenicity of organicpartdeulate pollutants im urban air after administrationn of trace quantities to neonatal mice. Nature (London )212 ( 5068).: 1305-1307; Dec..17;1066: 169

The Surgeon General's 1'964Report points out the association be- tween heavy smoking and exeessiive alcohol intake: In view of the fact that"The increased death rate fiom cirrhosis among, smokers may reflect the consuamption of alcohol and associated nutritional deficiencies rather than the effect ofi cigarette smoking" (5);, further research is needed to elucidate the association between smoking andl cirrhosis of the liver. EFFECTS OF S1ISOKII; G DURING PREGGNAIv CY The current neavliterat'ure on.pregnancy and smoking supportstheSurgeon. General's findings that there are a greater number of "low birth weight" babies and premature babies as defined by weight alone (,2,500 g.) in those women who, smoke during their pregnancy (6y 9, . 187 QQ,, 21!„ w4-26, 28, 30-32, 36):. Furthermore, this decreased weight has been shown to be consistent in each trimester ($8, 31', 3£;.34, 36)) and is proportionall to the amount.smoked during pregnancy (5, 2¢- 2G',30-32,34, 36)., There are many factors which affect the outcome of' preegnancy: These include constitutional, pathobiological and psychological fac- tors. Multiple-regression analyses of these various factors have shown smokingto be a: significant negative independent variable with respect to birth weight (1;5, $7):. Smoking has been linked to ~ increased incidence of. abortions and/or stillbirths (6, , 25; 26„ 28, 30, 36), prematuree rupture of inembnances. (30-32) and decreased male/fernale~ birth ratios (,11;.25, 26) ;',however;, other studies do not support these findings (7, 9; 2'4,. 3D-32)'.., The significance of low birth weight and premathrity in regard t'o increased fetal and infant mortality, has.not been clearly demon- stratedL Most studies show no ii creased mortality (9, 31, 32). How- ever; Xerushalmy (34) and Underwood (32), point out that although the overall mortality isthe same between infants oL smoking versus nonsmoking mothers„premature.baliies (asdefined by birth weight of less than. 2,500 g.) of smoking mothers have decreased mortality. Other studies show a slight but signifi:cant increase in fetal mortality for mothers who smoke (.6, 8):.. blacltiiahon. (19) shows. that rather thann increasing the proportion of lbwbirth weightt babies, smoking, actually causes a. shift to the left in the entire weightl distribution (fig. 1). Jansson (15) in.liis studly states :: "Thus, in 2he absence of other com- plications, smoki'ng mothers seem to makee a proportionallygreatsr contribution to infants in the weight group jjust below 2;500: g. wrhere the prognosis is betrter:" 185

2.. Increased carbon monoxide in cord'blood (l$). 3.. Decreased carbonic anhydrase activity due to increase in cord carbonmonoxid'e (%0). 4'.. A postulated direct effect on the fetus of some toxic agent'in cigarette stmoke: 5'. Decreased caloric intake due to decrease in. appetite.of smokers (1P). Several studies have shown that there is no difference in. weight gain during pregnancy between smokers and nonsmokers (28, .7D, 36). Since smoking in general, does decrease appetite, it mightbe.weTl to consider adifference in the type and/or distribution of caloriointake bet'ween smokers and nonsmokers. Sumar (17), hasshown an inerease in human uterine activity after smoking, both in frequency and magnitude of contractions: However, these findings weru not observable in every patient.. There was no significant effect of nicotine on myometrial st!rips in vitro from preg- nant human uteri. King and Becker (h,,1B) have done experimentall work with nico- tine.one pregnant rats. High concentrations of nicotine had.greater toxic effects on: pregnant rats.than controls. The offspring were light'er in weight and survived less well tham controls. REscd Clearly, more research is needed to el'ucidate the significance of the relationship~ of smoking, in pregnancy and lt w birth weight. Addi- tional long-range morbidity studlies are needed, as well as studies on the effect of smoking on uterine activity and placental blood flow. Smoking does have an effect. on the outcome of pregnancy.. How- ever, it is not known whether this effect is deleterious or not. IIntil such evidence is presentedl so as to clearly define the role of smoking in pregnancy, it is more prudentlt at this time to adlvise pregnant women: to stop or decrease their cigarette-smoking practi.ces.. SMOKING AND ACCIDENTS The most'.obvious cont'ribution of smoking to accidents is as a cause of fires. Estimates of the proportion of'fire loss due to "smoking and matches" (includes fires attributed to careless smoking and the care- less use of matches and lighters by smokersy does not incllude misuse of'f matches by children) vary from 19 percent to, 25 percent. The. 187 e` 46 am

representing premalignant tissue changes in the respiratory traet epithelium. Dsophageal epithelial. cells'with atypical nuclei were found far more frequently in cigarette smokers than in nonsmokers. The term "atypical nuclei" describes nucleii with an irregµliar distribution of chromatin.,Other abnormal changes includrllg giant nuclei may also be present. Basal cell hyperplasia and hyperactive glands also were found more frequently im cigarette smokers than in nonsmokers. An in- crease in frequency with amount of cigarette smoking was noted for both epithelial cells with atypical nuclei and basal cell hyperplasis. Atypical nucleil in epithelial cells were also more frequently found in ea-cigarette smokersas cvmpared'.to nonsmokers. Tables 20 and 21 illuistrate the frequency of these findings: TA:aLE ~ 20. Atypi.cal~ nuelei~i in liasal'.cells.l of eptitieel'iu7mm of esophagus~ of nta.lea,, by, smoking Aabl.ts ¢nd age Nev er Curr ent ama kedl dear ette , E:-cig grette Pipe, Ggar Oth er A4yp{calnucleL re8trl arlk I ~- - . Num- Per- Nirm- Per- Num- Pen 'Num. Per- Num- Per- ber cent ber cent ber cent ber cent't ber <aut A. ALLYEN Nirmber.men.._------------- _ 01 ------- T]9 __.._._.. 181. ------ 89 -______ ---- __ Totalsectionsl . 78T 100:a 6,762 I100.0 1,586 100.0 768. 100:0 522 100.0 NostypicalnucleiL___ ]33' 93:1 167 ' 2.5 , 770 48.5 53 69 T95 37.4. 9ome but <60 percellt atyp{cai------ ------------ _. 62 6;6 5;389 79.8 765' I 48.3 6N 89:8 317 60.7 60peleentormoreatyplcaL. 2 0:3'. 1,196 17.7 61, ' 3.2 i 2'J 3.3 10 1.9 e. MEN UNDERAOR60 I NumberIDan__ .. _ 26 ___. 236 ______ 25 9 ._ 7 __... Totalsectionsl_.__-_.____._ 224 ID0.0 2,059 300.0 - 58'. c0:0. TJ 100..0 63 100.0 No etyp{calnucle{.______.._ i 190 . 2 .2 85 71 3.4 5E 21.'Y 1 1.3 4 i 7.6 8eme but'<60 percent. atypical_______.__._..____ 33'. l48 1i863 i 90.9 195 7S6 74. 964 46 80.8 OOpercentormomatypical__ _.__-_ _-_.._. 135 0.6I 7. 2:7 2 2J8 3 6.7 C. ItEN AOED So-6R Numbecmen__...______-..__ 44 _..__._ 415 __.___._ 109 _.__._ 86 ._____ 31 ._.___ Tothlseetiansl--..--._--_-_ 379. 100.0 3ie63 100.0'. 953 100:ai 3I0 109.0 256 100.0 Noatypicalnuclei______.___ 373 98:4 83 2.2. 461 48.4 37 1119 74 28.9 9ome but.<60 parcenG atypicrel._.__.______.. 4 ' 111 I2;915 5 76.6. 4521 47:4. 4 21 281. 84.2 9 3 ~I 178 4 69.5 6 1 60parcentormorestyplcalL__ 2 0.5 85 SE.2 40 .: 12 . . U. W ENAOEr1.90 O6: OLDER I NumbermeR _ ~-' -- 0 98 44 13 . 29. - Totalseetions 136'. l:O 840 - - 375. l00.0 399 100:0 213'.. IU0.0 Noetyplcalnudel_ -_ 17a 9L9 13 , 253 6T1 15 4.0 ' 117 . 9 .9 64 3ome but, <BOipercent e p LS 8+1 7410 Il I 3 353 ~ B3 41 cent'.o re atypical -. W pe r . I-..__ ._.___ ~ 4.5.. 2 + L1 2,9 ' ./ ] 9ectlons with some epithellum present. BoonCe: Anerbactli,O.,ntal.[table2(J)1. 271-]3< Q-.67 - lD 151

venting duplication and wasted effort, developing better measuring instruments, and providing assistance in conceptua'liaing, new theo- retical models or further developing approaches already proposed. Much prior research, in the psychosocial aspects related to smoking, while yielding valuable data and suggestive theory, has been concerned largely with discrete variables or at't'ributes and has looked for gross differenees between smakers and'. nonsmokers. Since it is unlikely that such research will discover that either group possesses an attribute that is, unique to it other than the behavior of'smoking, the ability of any single attribute to differentiate between tliese.two populations is; bound to be limited. It is because of this that a number of investi- gators have turned toward trying to distinguish subgroups of smokers, as. well as toward developing more unifying concepts. Tihese efforts are part of'the attempt to obtain greater insight into the dynamics of' smoking and develop more powerful predictive instruments.. One area that. shows conceptual and methodological maturation is that of.the.study of smoking and personality. Much prior research studiedd snnokingin relb<tion tosucho conceptss as exttoversion,., intro- version,neuroticism, emotional stability,. orality,, femininity, mascu- linityy, hypochondriasis;, psychosomatic symptoms, risk taking and'~ chance orientation, psychopathic tendencies, achievement needis, social approval, relationships to authority, independence, aggression, and the like. At the 1066'behavior research conference,,it was pointed out that a better understanding of the to&vl personality stbucture must be achieved in order to increase understanding of some of.the psycho- logical correlates of' smoking. F'actor and hierarchical models have much to contribute to this approach (1). At.the1967conferencethist and other points pertinent to personality research.related to smoking were discussed„ andd a reminder of' thee utility off multivariate tech- niques was repeated (f'l1).11oward this end these investigators are.now studying university students, seekingg factors in the realm of person- ality tintegcation such as experience of. control,. scope of' awareness,. reality contact,,self'-insight,, temporal perspective, independence, anxi- et'y,, and the like. After these factors have been identifiedl they can be used as independentt varisbles inn testingg hypotheses suggested by otherdevelopmemts, such as the recently developed typology of smokers, illustratling the potential yield from a cross-fertilization of unifying concepts. Theories which emphasize the role of anxiety in the development of. personality andinthe understanding of personality dyinamics (7) pro- vide a unifying frame of reference which, when combined with an understanding of the gratiflcat.iions derived from smoking„may lead to useful explanations and investigations into smoking behavior. They may also provide some cohesiveness to research. on suchi concepts as 189 li ,.

SMOKING AND CIRRHOSIS OF THE LIVER' Increased mortality of smokers from cirrhosis.of the liver is found imthe prospective studies. This has generallgbeen thoughtto be largely secondary to an association between smoking and heavy alcohol aon- sumption.. Published dlataa are inadNuate to test this interpretation. The three prospective studies (1; $, 3, 4) all show increased d'eath rates and mortality ratios from cirrhosis of the liver in cigarette smokers. TABLE 1.: MortaliCy ratios and death rates for liver eirrhosis by sex and speeifec age groups Mortality ratio._.--_. __ __.-.----- Deathrate__.__________________ Female NSaIE Female Male 2.16 2.06 1 1.40 --_ 1.97 1(5)i0 i'(19)19 (10)14 (16)31 r.Calculated fmm app: table 19(f) r'Numbers irt parentheses lndicate death rates for persons who have neeer smoked regulariy. Sou®cc: Hsmmond..E. C. /tables 9A, 29;.and app table lP (.1)/.. TABLE 2.-llfale mortality, rattios and death rates for liver cirrhosis by age and amount smoked; tin. U.S; vetera-as C Wrent smokers of eigarettes oul y 0 1-9 Io- 20 21-3g 40+ Mortality ratio:(total)_______.-.- 1.00 . 2.72 3 .15 316 1 5. 50: Death. rate: Age 45 to 54 - 91 - 7 7 162' Age 55 to 64. --. __ 15 12 35 4 4 46 Age65.to74. . __ __ 16 74 57 5 7 87 Age 75'.to 84. . _-.-. --- 53 ----- Sunace: U.S. veterans study (app. table A. (i)]. Do111 and Hill present their data .rith respect to cirrhosis of the liver and alcoholism combined. See table 3. TnntE: 3.-Male death rates for liver av.rrhosiss by. type and amount smoked, in. British pluysiciares Nnu- All Ciga- NumtierofGgamttes ~ divev I Mfxad' I Plpa I smnken smokers xett¢, _ I i ~ psmok- Ismotera on smokere 1-14 1y-24 2G} _ I A ll bmouvtv _ I 1ng. . ~ -- ',. I ~- Cirrhosis of Ilcer and I ~ aicoholism___...._. I 0 11. 12 S g I 4a 1S. 3 11. 1 Souaca: Study of.BYltLVh phYsieiaus,, i[ablsa 21 and.22 (1)]. 1&4 7 twe fac ma def res, eii- - Sl hi (. lf h: T t S t,

(68): MAasDES,. E. Some aspects~ of the relationship of radioactivity to: lung cancer. NewZealand. Medical Journal ( Wellingtbn) 64: 367-376, July 19, 1965. 169)MOORe, C: Smoking and cancer ofthef mouth, pharynx, and larynx. Journal of.the American Medical Association (Chicago): 191(4) : 107-116, Jan. 2Ci, 1965:. (70). Mosx, K.. Enhaneement.of experimental lung cancer ii2 mice byinhalation off cigarette: amoke: Gann;; the. Japanese Journal of Cancer Researeh (Tokyo) 57::537~`41„ October 1966,. (71) , NEURATH, G.,. DUROER„ M., GEEVE, J.,, LUTTICI[, W, WICHEa.Y„ H. Unter- s.uchung der fliichtigen Basendes.Tatiakrauches. Beitrage.zurTabak- forsebung. (Hamburg) 3'':563.-369, 1966:. (72). NmuaAT$ GL,. PffiMA,YN; B:,. LtiTrICH;. W.,. WICHEBS, H.. Zur Frage der N-Nitroso-Verbindungen.im Tabakrauch II. BeitrHgeTabakforscbung (Hamburg.). 3:.251-262, 1965.. (73) NEURATH, G., PIRMANN, B.,. WrcHEaN, H. Zur. Frage der N-Nitraso-Ver- bindungenn in Tabakrauch.. Be3trhge Tabakforschung 2: 311-310, 1964. (74) NoAxxe,.D:.N. The carainogenicity oflinsecticide-sprayed.tobacco in mice. Food and Cosmetics.TosicologP (Oxford) 3':305-310, August 1965. ( 75): NoaMAx, V., KEImH„ C.. H. Nitrogen oxides in tobacco smoke.NakuiR (Z.ondon): 200'(4974) : 915-916;. Feb. 27„ 1965:. (76.). RADFOan, E. P.,. Je., HUCaT, V. ft. FoIonium-216: aa volat3leradioelement in cigarettes. Science (Washingtann) 143: 247-249, Jau. 17, 1964: (77) R'AOeaaD4 E:P.,. Ja,. HUNT, V:, R.. Cigarettesi and polonium210. Science (Washington) 144: 366-367;. Apr:, 24, 1964. (78) ILEEVEN;. A.. L.,, DEITOH, DL, VORWALD, A. J.. Beryllum, earcinogeIlesVI. Inhalationn exposure of. ratsto beryllium sulfate aerosoL Cancer Re- search (Baltimore) 27(3') : 439:--445,. Sfarch, 1967. (79) Roexnr, E. E. Evalution of cigarette smoking technics iIIr dogs. Eater natianal Surgery-(Chicago). 46(5): 409-413, November 1966: (80) ReexEx; E.. E.,, SPEER, F: D. The ill effects off cigarette smoking in dogs.. Iaternationali Surgery (Chicago) 46(6')I: 520-530; December 1966. (a4l) SSFFIbSI, U., SfoYTE8AN0, RI, SELLAKCMAR, . A. R., BORG, S: A. Expert-mental cancerr of the lung. Inbibition.n by vitamin A of the induction of~ tracheobronchial squamousmetaplasia.and squamouscell tumors. Can- cer(Pbiladelpilla,): 20(Fi.):.857-864, May 1967:. (82) StaxwaL,. D. Verglelch derI)npfindlichkeit zwicchen Ratte und Slaus gegen die carcinogeneWirkungvon Tabakrauch~ Kondensaten. Arznei- mittel-P'orschung(Audendorf) 17: 405, 1967. (83) ticHMxixL, D., THOMAS,.C:. Vergleicheue Priifungvon Tabakraucbkonden, saten bei subeutaner and mvaler Appllkation auf carcinogene airkung beI Rattlen. Zeitsehrift £Or. Ktebsforsebung, (Berlin) . 66:291-296„ 1964. (84) SEELxore,. C.,.1Llcxss:u, W:, iDiloM,. G. Lrntersucltungeriiber die: kreb.ser-zeugenden Eigenschaften des Zigarettenbeeres:. Zeitschri£It fur Krebs- forschung (Berlin) 65::241-249, 1963. (fi5) SELIKOFF,. I. J., HAMmeNn, E. C.,, CHuno, J:. Asbestos exposure, smoking andi neopiasia.. Presented att the: Sections on Diseases of the Chest and. Preventive Medicibe of the American hledical Association:and:theAmer-ican College of Chest Physicians, Atlantic City, N.J. June. 19, 1967. [U'nl'mblished.] (86)SERFaxTxmt, W. J.,. HUazeR, P. -\*itrusamihes asenvironmentals carT:iuo- gens: II. Evidencefon the presence of nitrosamines in tobacco smokecondensate. Cancer Research~ (Chicago) 26 (pt. I) : 57fr579,.Apri119661 166 !i' f I N

guilt, self-punishment, need to fail, and ri'sk-taking behavior as they relate to the initiat4on, continuation, or inability to diseontinue smnk- ing; Concepts from~ depth psychology, and ego psychology in par- ticular may additionallly illuminate the source and function of'so¢ne of the apparent inconsistencies among,attitudes, beliefs, and behavior noted by various investigators beyond that provided bydissonance theory (2). tknother area showing some growth is represent,edi by attemptt.o dis- tinguish between the diffecent levels of dosage to which smokers expose themselves beyond that indicated by the average number of'cigarettes smokedi daily. Mlore sophi'stieated'dosage measurements (18)' obviously have:applicatlion in epidemiological research. They mayalso prove use- ful in psychosocial research. There is t.'he possibility that an interplay exists between the degree and kind of exposure, . physiological and psychologicall processes„ and thedynamics, mechanisms, or degree of difficulty involved in. achieving Iong-term, cessation of'smoking. Another conceptual developmen6 was contained in the proposal, re- ported at the firsh of the national behavioral conferences (16) and.later refined (15), ofl a new way to. define smokers-in terms of the smoker's use. of cigarettes to help manage affect, i.e., emotions. Ftrom the types of smoking identified (habitual smoking„smoking to increase positive affect, to reduce negative affect, andy psychologically addictive smok- ing) and from a theoretical discussion of the: dynamics involved in their formation,, possibilities esisU for the development, testing, and application of theories and t'echniques for producing cessation either in a clinic or a natural setting.. PSy identifying differences between smokers in the psychological use of cigarettes, the.typology makesi't possible, to develop theories and techniques to reinforce behavior change and toexpand knowledge of the dynamics of smoking behavior. These concepts are undergoit g empirical identification and verifica- tion at both the national level and in a varietyof clinical settings studyingbehavior change., In one study (73)i, for example, which compared'tMree methods of aid to people whoo were trying to give up smoking, efforts were made to assess the subjects' progress, the nature of't.he change process, and the social-psychological factbrs which influence the ability t'o give up smoking and resist resuming. The investigators are analyzing their data from the conceptual base of smoking types as well as'feorm~other points of view in an examination of cessation processes. The smoking typologyi s also.o being applied in.ank anallysis of a.survey of adlults' and adnlescents''smoking habits and attitudes in the L?nited Kingtlom. (10). . At the recent 1967behavioral7 conference resul tsweree presentedi showing the relation between these smoker types and nervous irritation and relaxation smoking,scaSes; wishing and trying to give up smoking, and adHiction indicators for both adolescents and adults.

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SMOKING AND DIISTURBA\CES OF VISION 1 I TOBACCO AAfBLYOPn1 Recent evidence points to the tobacco and/or alcohol amblyopias as being manifestations of nutritional amblyopial (4; 7, 8~ 17;. 25, 26)'... Various deficiencies in factors of the vitamin B complex have been implicated (4;,6,7;.10;17,$'5,$6). A new theory that chronic low vitamin B,e, levels potentiate the toxic effects of cyanide in tobacco has recently been expounded (8;10;$2;Q.4). The anatomical lesion in amblyopiaseems to be, a demyelinization of' the optic pathways, particularly in the papillomaculkr bundl'e (1CJ,17, ~?5). In view of the fact that cyanide is neurotoxic, more research is needed in this area t'o further elucidate its.association wi!th.this disease entity. OTHER DISE.tiSES Several studies have hypothesized that Leber's:optic atrophy, which also isattributeds to a.demy,elinization process in optic pathways,,may' be associated with a defect in cyanide d'etoxification; which is aggra- vated by the cy nnide in tobacco smoke (1, 27):. VISII'AL t10IIITY The Surgeon C.eneral's. 1964 Report, and. otihers; cite evidence of increasedRevels of carboxyhemogiobin in smokers (20, 24'), due to tliee carboni monoxide content in. tobacco smoke. It has been suggested that a decrease in.nighttime visual discrimination in smokers is related to this increasein: carboxyhemoglobinn levels (9; 15,.16, 19).., It may.' also possibly be due to the relative anoxia.produeed by the'carbon monoxide inhalation: from tobacco: smoke: A valueof only 5.percent carboxy hemo- globirt saturation, not uncommon in smokers, creates a physiological state of anoxia equivalent to being,atan elevationof 8,000 feet, with an arterial O,, saturation.of only 91 . percent (15,,16)i. RESIIEIE, It is suggested that tobacco amblyopia is but a manifestation of nutritional amblyopia,, which is aggravated by tobacco smoking. hloreresearch is needed on the toxicity of tobacco, smoke,, with special con- cern for the cyanide component. Experiments have shown a visual discriminatiom deficit, possibly related to the carbon monoxide content of tobacco smoke. Further work is needed in tlhis area.in~order to, ascertlain anyelinical consequences.. Ztl-38, Q, sv - L] 183 0 )

There were other kinds of'analyses described in this research which provide the. stimulus for further development and testing, of theory.. In this country, a parallel set of'surveys has been going on which utilized.many questions from the above-mentioned survey just as that survey also borrowed from it. Ccoss-cultural comparisons are thus possibie:. The national surveys of adult smoking behavior, beliefs,, and at- titudes in this country stimulated, and were also based upon, an organizing framework which. discussed some dimensions of a model for behavior change (Fi). This.framework incorporated the coneept'ss related to the typology of smokers previously mentioned and also leanedlheaa•ily on a behavior model developed originall'y to provide a,theoreti!cal base underlying participation in a mass X-ray screening program (3, k,12).. Four dimensions of the framework.are discussedi and postulated asbeing essential in considering whether smoking be- havior change will or will' not take place. They are: The motivations for change (e:g.,.t'he exemplarr.olk; economics, estheticsi,mastery,,and others beside ttle health4}Lreat) ; the percept'ion of the threat (e.g,,the awareness of the threat, the acaept'ance of the importanae of the threat', the personal relevance of the threat, and.beliefs about the susceptibility of the threat to intervention)~; the reasons for smoking inn terms of affect management.,,andi the potential development and use of'alterna- tive psychologicall mechanisms; and factors supporting or inhibiting continuing reinforcement (e.g.,, the role of social forces, interpersonal influences; the mass mediay the behavior and attitudes of' certain key groups, and the general.level of acceptability of t'he behavior). Baeked by the longitudinal data. at. the national level and subject to. multivariate analysis, this conceptual framework can~ potentially be developed to the point whereby the'parts may be related quan- titatively.andy qualitatively to each other and thus afford a more'dy,iamic interpretation of the behavior change under consideration. The possibility a1Lo exists for the developm,ent.of an instrument for the prediction of change, as wells as an opportunity for thwverification of some prospective findings reported earlier (14). These constructs have also since.lbeen extended to considerations of the process of either taking up smoking or remaining a nonsmoker (5). IIn another area: of investigation, one project (19) is.concerned not soo mnch.with individhal d6fferences but with cultural differences in val- ues, at.titudes, and behavior related to smoking among various ethnic groups in. the Southwest and has as its main assumption the probable existence of a common:core.of psychosocial factors operatingtopro.duce different motivation patterns among young people'socialized'e inn a~ particular culturall environment. Another kind of research-thatof' the controlled experiment manipulatingone.variiable at a time with a number of'small samples-- y] I-SBf O - Hli- 1~ 191 O W ~.~ Vh'f 1M 'o /~ ~. W , . . . . .. . _..~ . . . 1 . .~ . . . t.... . . ~ . .k• ~ 51v„T3a1~~E$'.1~~1~6Alt~. ~ f.

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869, . Hoaexsxx,.IDL, RAxnxAVx,.G., AND Wzicue& E. L.Comparison.of theyields of severall selectedeomponent8 in the: smoke from different tobacco prodncts.. Journal of'f theNationat Cancer Institute (Washington) 31: 627-637, September 1963L. - S7o:. HoeFvsNNl. D.,, Rumv, J. Chemicall. studies un tobacco smoke: I. The quantitative determination of indbl'esin cigarette smoke, Beltritgesur Tabakforschung. (Hamburg)3: 409-414, 1966. S71t HoeencxsN;.D., WYNDKI, E;.L. Selective filtration of pbenols ftomefgarette amoke: Journal of the National Cancer Instibute: (Washington~): 30: 67- 84, January 1963. 572: Hor.tANn, R. H~,. Acnvs.oo, , A., R. Current. ststus off arsenic in American cigarettes. Cancer' (Philadeiphia:) 19: 1248-1250, September 1966.. 573. HnL[sxp, R. H.,. WILSan, R..H., Acevnoo,A..R.,.McCzrx, ffi'. S., Ctaae, D~ .A.,. LAna; H1 C.. 7rhee cigarettesmoke-arsenicrcancer oftlhe lung problem. Aeta; LFnio Interaationalls contra Cancrum (Lousain). 15:.608-611,. 1959:, 574. HsnE„ L. Cigarette smoking and cancer of the lung. Iiss thene really any ettologic relationsbip2' California Medicine (San Francisco)I 98(8) : 313-317, J'une.1983. 575. JeLLZNCk, P:. H.,. IawsN, L.Eifect of earcinogenic polynuclearhydrocarbons on the metabolism ofestrogens. Nature (London) 190(4'S82).:.787-788, May25;.196[t 576. Kaexs, dL. Thesmoking.e enigma Canadian7ou!rnat of Public. Health (Toronto) 56(3) : 10.r1D8,1Vfarch,1905,. S77. Keti.ca; A 2 Tsnms bf The association.of alcohol and tobaccowithean-o can- cer of the mouthandi pharynx. American Journal of~ Public Healthandl the Nation's Health (New York.) 55(10) : 157845®5„Oetober 1985.. 578.Keus, bL G.,, vEwroN, W. L.,, O'Gdae,. Il. W. Susceptibility off newborn germ-free mice to tumor. tnduction, by s:methylcholanthrene. Cancer Research (Chicago) 23(7)' : 978-982', August 1963. 579. KENsusm, C. J.,,BArnsrA„S. P.. Components of cigarette smoke with oillary- depressant activitq. New England Journal of Medicine. (Boston) 269:( 22 ):: 1161-1168, Nov: 28, 1®(13-. 580: KtLavxs;,K. HI, Saizeao,.J. El, editors- Symposium on structure, function and. measurementt of respiratory cilia. American Reviewof Respitratory IDiseases. J3:(No. 3, pt. 2'),:. 184„ March 19(i6. S81S Kxsses, D: SL Thee significance of personality in llungg cancer in men. Annalss of the New York. Academy of Sctences 125::. 820.-826;, 1966;. 882;. Korx:r, P:,. FAme, Ei. L.AtmospherGc factors. in pathogenesis of lung cancer. Adk'ances in Cancer Research. (NewYork.) 7: 475-514'„1963'.. 983. Kar¢s, P.,, \Yisef.az;, D:. V: Production.of lung cancer in mice by Inhalation exposure to influenza virus and! aerosols of hydrocarbons. Progress in. Experimental Tumor ReseareL, (Basel). 3': 186-215, 1963. 884. Kovracsax, IL, Hnsrsan, J:.I. Pathologie comparEe du cancer bronchopul4 monaire ctiee 1'homme et.cilezla souriscancr:Yis6e.par Ie goudron.de lafumee de cigarette. Bulletin de 1'AcademiieNat9onale de Medicine (Paris) 148: 34~)Oy,1984. $87. . Kocrmc.sxx, R.,.IlAreeax,.J:.L.. Camparaisonm.murphoIogique„radiologiqueet biologiqueentre le cancer pulmonaite provoque.chez 1s souris.parle goudron de bum@e de cigprettes.et le cancer bronchopulmonaire spontan~ chez 1'homme. Journal Francais de.Medicineet Ctiirurgie.Thoraciques (Paris) 19: 467-478; May-June 196G. 171 ji ; p

National Fire Protection Association gives"smoking and nnatches"'as "~ v a reported cause of fire in various buildings for 1965 as follows (3) : i Percent - r ~ Apartments _________ ____ ___________________________________________. 26 ._ Boarding,andlrooming..houses----------------------------------------- Dormitories, ete _________________________________________ Dwellings (1~ and 2-family)~------------------------------------------ 30 24 19 c. Hospitals.------------------------------------------------------------ 21 .?7~. Hotels, seasonal------------------------------------------------------ 24 ., ~ Hotels, year round___________________________________________________ 35 ~ MoteIs--------------------------------------------------------------- . 20 1`Iursiug.------------------------------------------------------------- 25 . In 1965 theree were163y900' fires linked to smoking or the matches used in smoking lcith, a,concomitant property.~ lossof. $80,400,000-in 1964, there were 159,4W fires and a property loss of $79,500,000 (5). The statistics on the number ofl deaths attributed to those fires are not avaiilable{ but it is.estilmated that 1,800 people per yeear willldie due to fires caused by smoking and matches (7). Smoking has been shown to cause decreased visual discrimination especially under conditions of low illumination (4). This could have s serious implications with respect tonight-time driving. Several studies (1, ~?, 6)h:oveindicated an association between smokingnnd traffic and industrial accidents, but the evidence is insuffi- cient at. this~ time to draw any significant conclusions, J4ore research is needed in. this area~ PSYCHOSOCI Afi, ASPECTS OF SMOKING There. has. been. a sharp increase in the attention devoted to behav- ioradl research si'nce the Surgeon General'§1964 Report. A.number of new concepts have beenn develbpedl andd more sophisticated multi- variate approaches are being used. However, because of the recency of these studies, veryr little in the way of findfings has been published on.mh'cch firm c,onchisions mav be based. One of the byproducts of tlhe Surgeon General's 1964 Report has been its stimulation.of more research in all areas of smoking, includ- ing the psychosocial. bTuch research will soom be completed but has nofiyet been reported in the literature. Threee behaviorall science conferences have been heldd since the Sur- geon General's 1964'Ifeport. The content of'these conferences are either in print. (9) or will: shortly be published (11',.Q1),.These conferences dealt withh many differentt studies andd research findings, theories, methodological criticisms, and discussions on a number of important issues. Among the primary purposess was thedevelopmente and speed- ing, up of communications among those doing work in the field, pre- Q) ~ , QD , yf~ ~

SMOKING AND PEPTIC ULCER Since the publication of the Surgeon G'eneral's1984.Report, three of the continuingprospective mortallity" studies ($, 3; 6,7) have provided additional information which eonfhcros the association between ciga- rette smoking,and mortality from peptic ulcer, especially gastric ulcer.. The mortality ratios increase with increases in amounts smoked.. The tables presented below illustrate the relationships involved. Although Hammond's (6) studycontained a large number of females, insufficient deaths from. peptic ulcer have occurred in cigarette smoking females to provide statistically reliable data,.A trend is observable among cigar and/or pipe smokers with regard to increased mortality from gastric ulcer, but the number of deaths is too small fbr significant conclusions to be drawn. TnHr.E1. Death rates and mortality ratios for gastric and duodenal' ulcers by specific age groups of male cigarette smokers slte GastTlertl)cer_ ,_ Duodenal tilcer Age MS-0f Death tsts t(2)'7 (3): 7 Mortality rstiae 2.95 186 Age 65-7Y , Death m/o, (7) 26' (21) 31 4.00 1. 50 I Numher in psrenthcres SndiPSt es death nuee for pereuns who neverr smoked regularly, 8ouact Hmnmond,.E. C. Itsbl e24,{B)]. TABLE 2. Male deathh ratesaatd m.ortality ratios for gastric and dttoderutd' ulcers by: sgeei,fu age groups for current. and ex-smokers of cigarettes only. Current'elgotette smokers.only S:.cign.atte smokeremnly.. &te Deathrate~. Mortalitp'rstlo Mortality rstio: 8'r74 75-ef (tute) . (tots) . Gastric ulcer___________ t (2)'. 7 (5) 17' (',-)26 4,13 2.74 Duodenal ulcer__________ (4): 8 (10)' 29 (37)'~ 122'~ 2.98 2.13 I Numtierl In psrentheses indiestesdeath rstetore persons who have,nevsr smoked. 6ouncl: U.9, vetersns study [epp, table A('J)]. ' All death retesi throuehoutths:eliapta are pa100;epg popttiatinn„vnles otherwise Ihdiea[ed. 181 Mortaaty ratias 3i

TABLE 3. PePtn:a ud'cer death rates 8y type mnd amount smoked; in males t cigarethesmakera. 6lven~up Mlzed Plps or Nonsmokers Allhmokers __ I cigar rie emaYera lgar e . All ... 1-19 RS} IS2F amoking am~ 01 13 . 13 2 18. 19 12 12 10 I IhNudea gastdc and/ur duodenal ulcers. 8006C8: Study of Hraisd, physicians Qta6les Td and'TA (2)]. A recent survey (13),..based.on.a national sample of.421000.house- hold interviews, shows that the prevalence of peptiouleer is almost 100 percent greater in male cigarette smokers and aver 50 percent.higher in females who smoke cigRrettes as compared tothose males and femal'es who had never smoked. PIammond's data (:5) shows twice the number of cigarette smokers reporting the occurrence of peptic ull'er over.a 2-year follow-up period as contrasted to nonsmokers., This also in- creases with i'ncreases in the amount smoked. Severalsnall retrospectivee clinical studies (4,8, 12) havee shown significantly more smokers and less nonsmokers in their peptic ulcer patients as compared to control groups. Doll (P) reviewed various pro- spective stugllies on gastric ulcer therapy regimes, such as : diet-bland, normal,.high and low fat;, milk drips with alkali; drugs; and advice to stop smoking. The best results;were obtained in patients who stop- ped or cut down on their smoking habits. The Surgeon General's 1564 Report (14) points out the conflicting literature concerning the effects of smoking, on gastric secretion and motility. Lee (10),, in a small series of peptic ulcerpatients and controls;, showed that.after smoking, 74 percent of patients andi 58'percent.of controls had a significant rise in free gastric acidity.. Those subjects with initially normall or hyper- acidity had the great,estt response;, whereas;, of . those with iniAiall hy po- acidity only 28 percent had an increasein gastric acidity. Five of nine controls, smoking,a non-nicotine ci'garettepreparation„also had a rise in gastric acidity, perhaps due to, factors in. smoke other than nicotine or to oral stimulation- R}sIIME Ciga~rett egarette smoking isshbwn to be associatedl with peptic ulcer. ''his.rellationship is greater for gastric than duodenal ulcer and is proportional to the amount smoked. 7fhe etiology of tPoe peptic ulcer diat.hesis is still unknown.. Smoking isa definite risk factor im peptic ulcer mortality:. It tnay also be a. factor ire the delay in healing of a gastric lilcer: More research is needed on the physiological effect of smoking omthe gastrointsstinali tract. 1'82 be Vin tc (1 0 ( in

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