the health consequences of smoking · 1965 report on the health consequences of smoking. these...

The Health Consequences

of SMOKING 1968 SUPPLEMENT TO THE 1967 Public Health Service Review

U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE Public Health Service

1968 Supplement to

Public Health Service Publication No. 1696

Library of Congress Catalog No. 68-60025

For sale by the Supexintendent of Documents. U.S. Govanmrnt Printing Office Wadingcon. D.C. 20402 - Price 55 cents

Foreword Section 5 (d) (1) of Public JAW 80-02, the Federal Cigarette Label-

ing and Advertising Xct, requires the Secretary of Health, Educa- t.ion, and Welfare to submit an annual report to the Congress “concerning (A) current information on the health consequences of smoking and ( 1%) such ~e~onlnlentlntiolls for legislation as he nlxy deem npproprintc.” This 1068 Supplement to the 1067 Public Health Service review, “The Health Consequenws of Slnoking”, was prepill+ed for the Secretary pursuant to this section. The Secretary’s report was delivered to the Congress ou July 1, 1068. It is printed below.

The information presented in the accompanying report, “The Health Con-

sequences of Smoking, 1968 Supplement,” confirms or strengthens the conclusions of two previous studies published by this Department-the 1964 Report of the Surgeon General’s Adrisory Committee on Smoking and Health, and the 1965 Report on the Health Consequences of Smoking.

These conclusions are that smoking is a serious health hazard in this country, one which is bringing about much unnecessary disease and death within our population. In the words of the 1964 Report, adequate remedial action is required. In my opinion, the remedial action taken until now has not been adequate.

I therefore recommend : 1. The warning statement required by the Federal Cigarette Labeling

and Adrertising Act should be strengthened. This Department would support the wording recommended last year by the Federal Trade Commission, or a suitable paraphrase of the wording.*

2. This warning should be required to be placed not only on the cigarette package but on cigarette rending machines and in all advertisements.

3. Levels of “tar” and nicot.ine in cigarette smoke should be published on cigarette packages, on rigarette vending marhines, and in all advertisements. Authorization is also needed to make it possible to add other harmful agents to this listing.

4. Appropriations should be made to the Federal Trade Commission to permit the Commission to test all cigarette brands on a quarterly basis for “tar” and nicotine and other harmful agents in cigarette smoke.

Secretary.

l The wording recommended by the Federal Trade Commission (Report to Congress, June 36, 1967) was “Warning: Cigarette Smoking is Dangerous to Health and May Cause Death from Cancer and Other Diseases.”

iii

Preface The following pages provide a review of current information on the

hea.lth conseqwnces of smoking. as will be seen, the evidence attesting to the harmful effect of smoking on health has continued to mount during t.he past. year, with new research findings confirming the clini- WI, eI;l)ermlenka~, and epidemiological relationships I)etween tobacco smoking and many forms of illness related to it. The convergence of research findings continues without. substantial negat.i\-e scie.ntific evidence. Sew considerations are presented concerning some bio- mechanism in\-ol\-et1 in the pnthogenesis of cardiovascular and bron- cl~opulnionnry diseases.

This 1968 Supplemcnt;tl Report reviews the recent research literature on cardiovascular disease, chronic broncllopulmonary disease and cancer that has become a.vailablc since TAe Henlt?~ Conxeprtewcs of Xm.oking, A Public Health Sercice Recieza: 1967 was published. This publication in turn was a review of the research literature which had al)l)enrecl in the 31/s years since the Surgeon General’s Advisory Corn- mittee issuecl its monumental report in 19&L The current research findings should be consi’dered in the perspeotire of the resea.rch evidence previously presented in t.he 1964 and 1967 reports.

Problems created by oigarette smoking hare made t,his a difficult health issue. Effective preventive programs must be created if we are to meet smoking’s grave challenge to human health successfully and reduce t:he burden of suffering and economic loss involved.

Swgeon General.

Acknowledgments The National Clearinghouse for Smoking and Health, Daniel Horn,

Ph. D., Director, was responsible for the preparation of this report; Albert C. Rolbye, Jr., KD., M.P.H., LLX, n-as senior editor and David 0. Wember, M.D., was st,aff director.

The professional staff of t.he National Clearinghouse for Smoking and Health owes a debt of gratitude to the many expe&s in the scien- t,ific and technical fields, both in and outside of the government who have provided much advice and assistance. Their contributions are gratefully acknowledged.

Special thanks are due the following:

AUERBACH, OSCAR, M.D.-Senior medical investigator, Veterans Administration Howital, East Orange, N. J.

ATRES, STEPIIEN RI., M.D.-Director, Cardiopulmonary Laboratory, Saint Vin- cent’s Hospital and Medical Center of New York, Sew York, N.Y.

BELLET, SAXLXL, M.D.-Director, Division of Cardiology, Philadelphia General Hospital, Philadelphia, Pa.

BINQ, RICHARD J., M.D.-Professor and chairman, Department of Medicine, Wayne State University, Detroit, Mich.

BOCK, FRED G., Ph. D.-Director, Orchard Park Laboratories, Roswell Park JIeruorial Institute, Orchard Park, N. Y.

BOERTK, ROBERT, Ph. D., XD.-National Heart Institute, Sational Institutes of Health, Bethesda, Md.

BORES, HOLLIS, M.D.-Clinical investigator, Veterans Administration Hospital, Denver, Cola.

BRAUR’WALD, EUGENE, M.D.-Department of Medicine, University of Oalifornia at San Diego, San Diego, Calif.

BIK-GNFIPTI, IDA L.-Health educator, Adult Heart-Preventive Programs Sec- tion, Heart Disease and Stroke Control Program, Sational Center for Chronic Disease Control, U.S.P.H.S., Arlington, Va.

C~XADWICK, DOXALD R., JI.D.-Director, Sational Center for Chronic Disease Control, U.S.P.H.S., Arlington, Va.

CHANCE, BXITTON, Ph. D., SC. D.-Director, Johnson Research Foundation, Chair- man, Department of Biophysics and Physical Biochemistry, School of Illedi- tine, University of Pennsylvania, Philadelphia, Pa.

COOPER. THEODORE, M.D.--Director, Sational Heart Institute, National Institutes of Health, Bethesda, Nd.

DOYLE, JOSEPH T., U.D.-Professor of medicine, Albany Medical College, Albany, N.Y.

EUERER, FaEn-Statistician, Biometric Research Branch, Sational Heart Insti- tute, Sation8.1 Institumtes of Health, Bethesda, Jfd.

ELIOT, ROBERT S., M.D.-Assc&ate professor of medicine, Department of Jledi- tine, Division of Cardiology, College of afedicine, University of Florida, Gainesville, Fla.

Vi

EXDICOTT, KESSETH ;\I., M.D.-Director, Sational Cancer Institute, Sational Institutes of Health, Bethesda, Nd.

EPSTEIS, FREDERICK H., l\l.D.-Professor of epidemiology. Department of Epidemiology, University of Michigan, School of Public Health, Ann Arbor, Mich.

FALK, HANK L., Ph. D.-Associate scientific director for carcinogenesis etiology, National Cancer Institute, National Institutes of Health, Bethesda Md.

FARIIEIL, EJIMAXUEL, M.D., Ph. D.-Profesrjor and chairman, Department of Pathology, University of Pittsburgh. Pittsburgh, Pa.

FERRIS, BENJAMIN G., Jr., M.D.-Professor, Del)artment of Physiology, Harvard School of Public Health, Harvard University, Boston. Mass.

Fox, SAXUEL M., III, M.D.-Chief, Heart Disease and Stroke Control Program, Sational Center for Chronic Disease Control, U.S.P.H.S., Arlington, \‘a.

E'ICEDERICKSOS, DOXALD S., JI.D.--Chief, Laboratory of Jlolewlar rJi.sease, Na- ational Heart Institute, Sational Institutes of Health, Bethesda, Jld.

FROL~, ARTHUR H., M.D.-Heart Disease and Stroke Control Program, Sational Center for C?hronic Disease Control, U.S.P.H.S., Applied Physiology Labora- tory, Georgetown rniversity, Washington, D.C.

GELLER. Hawlx--Chief. Operational Studies Section, Canwr Control Program. National Center for Chronic Disease Control, U.S.P.H.S., Arlington, Va.

GITTLESOHN, ALLAS, Ph. D.-Johns Hopkins University, School of Public Health, Baltimore, Md.

G~DnJARx.4SOS, SIG>%UNDUR, Ph. D.-Department of l\ledicine, \\T'aylle State University, Detroit, Xch.

HA>~JIOND, E. CWLER, SC. D.-Vice president, epidemiology and statistical research, American Cancer Society, Sew York, S.Y.

HESS, CATHERINE B., M.D.-Assistant to the chief, Oancer Control Program, Sational @enter for Chronic Disease Control, U.S.P.H.S., Arlington, Va.

HIGGISS, I.T.T., XD., JI.R.C.P.-Professor, Department of Epidemiology, rni- rersity of Michigan, School of Public Health, Ann Arbor, Nich.

HOFFJ~AXX, DIETRICH, Ph. D.-Associate member, Environmental Carcinogene- sis, Sloan-Kettering Institute for Cancer Research, New York, S.Y.

IMBODEN, CLARENCE A., Jr., M.D.-Division of Regional hIedica1 Programs, Sa- tional Institutes of Health, Bethesda, Md.

ISHII, KAREO, M.D.-Chief, Serology Division, National Cancer Center, Research Institute, Tokyo, Japan.

KANSEL, WILLIAX B., M.D.-Medical director, Heart Disease Epidemlolo~ Study, National Heart Institute, National Institutes of Health, Framingham, Mass.

KELLER, ANDREW Z., D.M.D., M.P.H.-Chief, Research in Geographic Epidemi- ology Research Service, Veterans Administration Central Office, Department of Medicine and Surgery, Washington, D.C.

KESNER, HARRIS N., XL).--Jledical consultant, Heart Disease and Stroke Con- trol Program, Sational Ceutrr for Chronic Disease Control, TI.S.P.H.S., Arling- ton, Va.

KERSHBUA~K, ALFRED, M.D.-Assistant chief, Division of Cardiology, Philadelphia General Hospital, Philadelphia, Pa.

KOTIN, PAUL, M.D.-Director, Division of Environmental Health Sciences, U.S. P.H.S., Research Triangle Park, S.C.

KRLXHOLZ, RICHARD A., M.D.-Director, Medical Chest Department and Pul- monary Function Laboratory, Charles F. Kettering Jlrmorial Hospital, Ketter- ing, Ohio.

LILIENFELD, ABRAHAII, M.D.-Professor and chairman, Department of Chronic Diseases, Johns Hopkins School of Hygiene and Public Health, Baltimore, ;\Id.

vii

MCLEAN, Ross, M.D.--Professor of medicine (pnlmonar~ disease), Emory Uni- versity, School of Medicine, Atlanta, Ga.

MCXILLAN, GARUSER C., JI.D.--Sational Heart Institute, Sational Institutes of Health, Bethesda, Md.

MEPER, JOHN S., M.D.-Professor and Chairman, Department of Il’eurology, College of Medicine, \Va~ne State l:niversity, Detroit, Jlich.

MOOBE, GEORGE E., M.D.-Director, Rosaell Park Memorial Institute, Buffalo, N.Y.

MOUKT, FRAXK W., M.D.-Acting chief, Chronic Respiratory Disease Control Program, Sational Center for Chronic Disease Control, U.Y.P.H.S., Arlington, \‘a.

XURPHY, ED~IOND A., M.D., SC. D.-Associate professor, University of Colorado Medical Center, Medicine and Biostatistics, Denver, Colo.

~‘ADEL, JAY A.. JI.D.-Carclioras~nlar Research Institute, University of California JIedical Center, San Francisco, Calif.

PAYSE. GERALI) H., M.D.--Chief, Adult Heart-Preventive Programs Section, Heart Disease and Stroke Control Program, Kational Center for Chronic Disease C’ont rol, T.S.l’.H.S., Arlington, \‘a.

PETERSON, WILLIAM F., AID-Chief, Obstetrics and Gyneco1og.v Service. USAF Hospital, Andrews Air Force Base, Washington, D.C.

PETTY, THOMAS L., M.D.-Assistant professor of medicine, University of Colorado Medical Center, Denver, Colo.

PTRI, PRITPBL S., M.D.-Department of Medicine, Wayne State University Medical School, Detroit, Mich.

QIIISLAS, CARROL B., M.D.-Deputy chief, Heart Disease and Stroke Control Pro- gram, Sationnl Center for Chronic Disease Control, U.P.P.H.S., Arlington, Va.

ROBIXS, MoRTos-chief, Program Statistics and Analysis Section, Heart Disease and Stroke Control Program, Sational Center for Chronic Disease Control, U.S.P.H.S., Arlington, Va.

Ross, WILLIAX L., JI.D.-Chief. Cancer Control Program, Sational Center for Chronic Disease Control, U.S.P.H.S.. Arlington, Ya.

SCHACHTER, JOSEPH-Statistician, Adnlt Heart Activities, Heart Disease nud Stroke Control Program, Sational Center for Chronic Disease Control, U.S. P.H.S., Arlington, Ta.

SVHL?~~AS, LEOSARD JI., JI.D.-Professor of epidemiology, l’nirewity of Minne- sota, School of Public Health, Minneapolis, Minn.

STAJILER, JEREYIAII. JI.D.--(‘hiwgo Board of Health. Health Research Founda- tion, Chicago, Ill.

THOX, T~osras .J.--St;ltirtic,iatl, Program Stntistirs and Analysis Section, Heart Disease and Stroke Control Program, Sntional Center for Chronic Disease Control, lV.S.I’.H.S.. Arlington, Tn.

\YEsT~-RA. Enwrs E., M.D.-Heart Disease and Stroke Control Program, Sational Center for (‘hronie Disease Control, l~.S.l’.H.S., Chief, .$lrplied I’h~siolog~ Laboratory. Georgetown Vnirrrsitr, Washingtou, D.C.

IVYSUER. ERSEST I,., Jl.D.-Asweiate member, Sloan-Kettering Institute for Cancer Research. Sew York. S.T.

%T~(EI.. WII.I.IAN a., M.D.--1seist:int Director for Collahorntive Stndies. Sational Heart Institute, Sational Institutes of Health, Bethesda, Md. The following professional staff of the Sational Clearinpl~ouse for

Smoking ant1 IIenlth contributed to the preparation of this report: Selwp 31. Wniqyon-, Dorothy E. Green, Ph. D., Robert S. Hutchings, Ric.hnrd 11’. White, Emil (‘orwin, and Robert F. Clarke, Ph. D. Special thanks are due Jennie 31. ,Jennings and Donald R. Sllopland.

. . . VIII

Foreword_-----______________________---_--------------- Preface-------__-___-----_-________-------------------- Acknowledgments _________ -_- ____________ ---_--__----_-_ Part I. Current Information on the Health Consequences of

Smoking__----_-_-_-___--------------_------- Highlights of the Report- -__--___-- __________ Smoking and Overall Mortality- - _ _ _ - _ _ _ _ _ - - _ -

Part II. Technical Reports on the Relationship of Smoking to Specific Disease Categories ___________ -------_--_

Chapter 1. Smoking and Cardiovascular Diseases- Chapter 2. Smoking and Chronic Bronchopul-

monary Diseases (Non-neoplastic) _ _ Chapter 3. Smoking and Cancer- __ - - - _ _ _ _ _ _ _ _ _

Page . . . 111

V

vi

1 3 5

11 13

63 87

ix

PART I

Current Information on the

Health Consequences of

Smoking

Highlights of The Report

LIdtlitioi~nl physiological and epiclen~iologiral evidence confirms the previous findings that cigarette smoking is the most important cause of chronic non-neoplnstic hroncliopulmoiinryv disease in the United States.

Cigarette smoking can adversely affect pulmonary function and disturb cxrdioplllnlollarv ~~h~siolog~. It is suggested that tllis can lead to cardiopuln~on:~rg disease, notably pulnlon:lry ]lypertension xnd car pulmonale in those intlividuals who 1Mve se\-ere chronic obstructive bronchitis.

3

SmoA-ing and Cancer

Additional rvidcnce substantiates the prcrious finclings that cigarette smoking is the main cause of lung cancer in men. Cigarette smoking is causnll\- related to lung cancer in n-omen but accounts for a smaller proportion of cases than in men. Smoking is a significant factor in the causation of cancer of tile larynx and in the development of cancer of the oral cavity. Further ep*idemiological data strengthen the association of cigarette smoking with cancer of the bladder and cancer of the pancreas.

Smoking and Overall Mortality

The 1964 Advisory Committee’s Report (3) clearly and em- phatically outlined the dangers of cigarette smoking to health. The conclusions of the Committee, as outlined in the 1067 Report (2)) were as follows!

CIGYYRETTE smoking is associated wit11 n ‘i&percent increase in the age-specific death rates of n~;~lcs. and to a lew’r extent with increased death rate of females. The total number of excess deaths causally related to cigarette smoking in the l’.S. population cannot be accurately estimated. Tn view of the continuing and mounting evidence from many sources, it. is the judgment of the Committee that cigarette smoking contribnte9 sul)stantinllv to mortality from certain specific diseases and to the overall tleath’rate.

In general, the greater the. number of cigarettes smoked daily, the higher the, death rate. For men who smoke fewer than 10 cigarettes a day, according to the seven prospectiT-e studies, the death rate from all causes is about 40 ljercent higher than for nonsmokers. For those who smoke from IO to 19 cigarettes a day, it is about 70 percent higher than for nonsmokers: for those who smoke 20 to 39 n clay, 00 percent higher, and for those x-ho smoke 40 or more, it is 120 percent higher.

Cigarette smokers who stopped smoking before enrolling in the seven studies hare a death rate about 40 percent higher than nonsmokers? as against 70 percent higher for current cigarette smokers. Men who brpn smoking before age 90 hare a substnntiallr higher death rate than those who bepn after age 9~. Compared rlth nonsmokers, the mortality risk of cprette smokers. after adjustments for differences in age. Increases w-lth duration of smoking (number of years), and is higller in those who stopped after age 55 than for those who stopped at an earlier age.

In two stirdies which recorded the degree of inhalation, the mor- tnlitv ratio for :I 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-N) represented in these studies, and declines with increasing age.

Possible relationships of death rates to other forms of tobacco use were also investigated * * *. Th e death rates for men smoking less than -5 cigars n day are ahont the same as for nonsmokers. For men smoking more than 5 cigars daily, death rates are slightly higher. There is some indication that these higher death rates occur primarily

5

ward trend is reported in lung cancer death rates for the cntjre pcmp (smokers, es-smokers, and those ~110 never snroketl. co111l)ined) along wit11 n very sharp rctluc-tiou in cipwttc siiioking II\- the ph~sic~in11, is the Ibest n\ailnble PSilll l~)lC of :I controlled wssatloll ~spriiiif~nt with retlurtioii of risks re511lt i11p fro111 rctliictioii of ~111oI;iuy. Tlie fintlii~gs of tliis report snpport the \.ic\v that cl)icleiliiolo~ic:il tl:\t:i sl~owll1g lower dent11 lY1tt5 :1111011g fol~lllel ~mokcrs tIl:lu amoiig cwitinaing smokcr5 cannot Iw tlisilriswl ai tliic to ~clwti\-e I)i:i~ niid that tlie lwne- fits of gi\-ing 111) ~111oliing haye l3rol~nl~ly IWCI~ iindci5t:ltctl.

5. Clgnrctte smokc~i~-: li:il-e lii~lirr ixtes of tliG;ll)ilit\- tll:ln n~~i~~ii~ok- PI’S, \~Ilt?tllt~~ llli?ilSlll~t~tl by tl;l\S lO?t fro111 \YOl’Ii :llllO;lf tll? Pllll)lO~Pd Iwpi~lntioii. 1)~ tlnys q&t ill’in Iwtl. 01’ 11~ tile ino5t ,pnrixl i~i~wiire

--dnp of “re.-;trictetl :Icti\-it?-” tliic to illncc~ 01’ ilrjrir\-. T)at:l froiii the Sntionnl ITealtI1 Siir\-ey l)ro\~itlc :I I);ts(~ for e.+ti,rl:rti~y tliat in 1 yeal’ iii tllr I’iiitctl StiltC’S aI1 :icl~litiorl;ll 77 1riilliol1 1Jr:ll~-tl:lj~i \\‘el’t’ loqt flY)llI u-ark, an :~cltlition;il 8s nlillion 111:111-~l:i~.i \vert’ 5lw11t ill i1r lwtl, alld ai1 :~dditinn:~l XX iirillioii i11;1n-t1;1~-~ of 1wti~ic~tcvl :1c‘t ix-it F \wre cspe1+ e11cwl bccnn5c c*ig:1Wtte s;11lOkt’1.5 llil\.C’ liigIlI(~r (lixllbilit,y 1’:ltW tll:lll IlOll-

smokers. For 11~11 :ye 4.i to (;4. 28 lwuw~t of tlrc tllwl,ility (lay- (IS- 1)erienced represent the excess associated with cignrctte duoking.

In the 1067 Report tl1c follow in, m qliwt ion9 \wrv r~111I~li:1~izctl : 1. How much mortnlity and PSWSS diwl~ility :IW ;l+ociated with

smoking 1 2. How nrwh of this earl- ljlort:xlit,y ant1 esce~~ tlisahility nollld

not, linvc occ~n12ml if Iwople 11ntl Ilot t ;IliCll nl’ ciprrt te :irroki1i,~? 3. ITOK mnch of tliis early nloi?:llity ant1 exws5 (li-:\I)ilit y ccailtl be

nrertetl I)!- the crssntion or reduction of cipnrettc .SJllolii11~? 1. What are tlic l~ioi~ir~~linuisiiis R-herthy these eflwts take place

and what arc tire crit icnl factors iii these niecl~nnisnis? The problem of ho\\- Iwst to me:1~11rc the relation-Ilip betn-een amok-

ing and inortnlitv was presented by three menningfiil measiires of romparisoii :

1. Mortality Ratios: Obtained by cliriding the death rate for a clns- sification of smokers by tl1e death rate of a comparable group of nm-

smokers * * * A nlortnlitv ratio has been considered to reflect the degree to wliictll :1 cIasxificGtioi1 \-:iri:\l)Ic itltwtifir-: or 111:iv acwmiit l’ol varintion~ in tlwtli rates. -1s s\ic*li. it is ;I Itiwqiiy of i.rl:iti’\-e risk v-liich indicates the importance of that, variable relative to uncontrolled vnri- ables-an iiicliwtor of jmf~~fifr/ /~;0/0~ji~ul .~;~q/1;fiuinw.

2. I)iffei~eiicw ii1 Jlort:llit\- IZntcs : Ol+t:\illctl I)\- 5liI)t rncting froiii the death r:ite for wroker5, the death rate of a c~~n~Ix113hle gronI) of nonsmokers * * *. Thi? measllre rcdlwts the atl~lwl l~rnl~xl~ilit~ of death in :I !-year Iwriotl for the ~111okcr c)\xar that for tile 11ow111oker. *Is such it is a 11iea~ilre of p1~1w~~~~7 7~~07th s+pi~~o7~~~i~. :I I~I~:II~S for the intli\~itln:1l to rStiil1atc tlie ntltlctl ri<k to \vllicli 1~ is esIw5ed.

3. I’:scws 1)c:itIis: ()ld:~inctI 1)~ biil,tr;lc+iiig fro111 t11c~ i~uir~l)c~r of tlenths occ111*ring iii a gr01ip of Ginkcr5, tile 1l1lnllwr of clcatlls which wonld 11nkr OCT~~IT~ if that gro11I) of .~n~oI;~rs had crperienwd tile same mortality rate5 as il co111I~araI~Ie gror1p of nonw1ol~e1~~. Tn the esamI~le whicll f0110\\-5 this Iins been reportetl :15 i1 Iwrccllt;ige of all

315-131 O-68-2 7

TABLE 1 .--Comparison o-f mortality rates -for smokers and nonsmokers by age and sex: Based on data from U.S. Veterans Study and Ham.mond Study

- I

Study popnlntim, sex, and *nedsure of mortality

-_.

45-54 years

I_ 5wM years

6674 yeus

366

264 728

2. 76

464

43

13, 840 17, 550 1,932

1,056 2,411 6,214 1, 819 4,032 8,471

1. 72 1. 67 1. 36

763 1, 621 2, 257

21 17 8

5,297 8,427 8, 12.5 3, 968

406 925

2. 2s

1,202 2,202

1. 83

1,000

25

I 1

3, 168 7, 863 4, 788 5, 674

1. 51 1. 23

51s

3s

1, 620

U.S. I-ETERANS: XEN i

Total number of deaths- _ _ - _ _ 383 Death rates per 100,000:

Never smoked reg\darlg- - - - - - _ 127 Current cigarette smokers- _ _ - -. 232

hlortalityratiol----- ____ --.--_-_. 1.83 Difference in death rates per

1oo,ooo~--.----~-.--~--.-~~...~ 105 Excess deaths as percentage of

total3 ______ -----.-_-_--~-~.-~~_ 33

HhMUOND P\IEN 1

Total number of deaths- _ - _ _ 631 Death rates per 100,000:

Ne\-w smoked reglllarly_ - ~. - . . 210 Current cigarette smokers. _ - - . 397

Mortality ratio 1-_-v--~--.- _._.. 1. 89 Difference in death rates per

1oo,ooo*----~..-.~-~--.---~--~ 187 Excess deaths as percentage of I

total3 ____._ -~..-~_----~-_-_----/ 33

Total number of deaths-.. _.: 727 2, 82f 4. 18%

3, 514 5, 846

99

3,915

16r5 304 6% 186 354 SDS

1. 13 1. 26 1. 20

Deaths rates per 100,000: Never smoked regulnrl~_ - - - - Current cigarcttr smokcra- - _ _ -’

Mortalit\ ratio I- - _. . ~.~. - - -. _ Difference in death rntw per

100,000~-~--~-~-.~---~~~.~....~ Excess deaths as percrntage of

tota13._-_..~.~-~..~..-~-----.~.

1,913 2, 229

1. 17

21 SO 104 316 68

8

cleaths in the appropriate age group * * *. It should be noted that, this measure not 01~1~ depends on the differences in death rates between the smokers and the nonsmokers, but also on the proljortion of smokers in the gmnp. Thus? even with a large difference in rates between smokers and nonsmokers, a population with very few smokers would ha\-P very few excess deaths. This ~nens~~re is therefore an indicator of the g)uh7ic hen7th xiyni$rc/nce of the differmces found since it, measures the number of’ people affected and therefore the magnitude of the problem for society as a whole.

-1s seen in table 1, from the 1%; report, thr n~agnitntlc of tllc problem is reflected in the statement :

Rcvie\Cng both study Frnnps it appears that for mm hetn-rcw the ages of X.5 and 60 nppros1ni:rtely one-third of all deaths that occnr are ~‘scess deaths in the sell+ that illrv n-nlild not have occurred as earlv as they did if cigarette smokers hhd the MIIIC tlrntll mtes as the IIOI;- smoking group. For worm, the percentage is nr~lch lowr. reaching a peak of !I percent of all deaths in age gronp 15-51.

,Inother valuable measure of comparison was recently calculated by IIammond(l), from his study of over 1 million men and women. T,ife expectancy of men with respect to cigarette smokers and nonsmokers is shoxn in tables 2 ant1 3. The life expectancy for a two-pack a day, or more, smoker at age 25 is 8.3 years less than that for the corresponding nonsmoker. Fen nt age :%? nnd over, whn smoke two or more Ijacks of cigarettes per da-y, have between 20 and 25 per cent less life expectancy than their corresponding nonsmoking counter- parts. Even “liqht:’ smokers, those who smoke less than 10 cigarettes per day, have from 2.8 to 4.6 fewer years of life expectancy than COP responding nonsmokers.

TABLE 2.-Estimated years of life expectancy at various ages for males in the United States, by daily cigarette consumption

Age Never

:moked regularly

Number of cigarettes smoked per day

l-9 10-19

48. 6 44. 0 43. 1 43. 9 39. 3 38. 4 39. 2 34. 7 33. 8 34. 5 30. 2 29. 3 30. 0 25. 9 25. 0 25. 6 21. 8 21. 0 21. 4 17. 9 17. 4 17. 6 14. 5 14. 1 14. 1 11. 3 11. 2

-

:

_~

-

to-39

42. 4 37. 8 33. 2 28. 7 24. 4 20. 5 17. 0 13. 7 11. 0

-

4

.j-

-

---

LO and over

40. 3 3.5. 8 31. 3 26. 9 23. 0 19. 3 16. 0 13. 2 10. 7

9

Sonmx: Hammond, E. C. (1).

TABLE S.-LOSS in life eqecta.ney at various ages for cigarette smokers compared with nonsmokers

Age

.‘- I 25 years~~----------

30 years~~---------- 35 yc!ars_-----m---m- 40 years---_--mmm-.. 4.5 years--_.m.mmme.. 50 years------------ 55 ycai--------~~~. 60 years--------....

4. 6 4.6 /

9. 5 10.5

4.5 / 11.5 4. 3 12. -5 4. 1 13. 7 3. 8 14. 8 3. 5 16. 4 3. 1 17. 6

5. 5 11. 3 5. 5 12. 5 5. 4 13. 8 5. 2 15. 1 5. 0 16. 7 4. 6 18. 0 4. 0 18. 7 3. 5 19. 9 I

65 years----------~.’ 2. 8 19. 9 I I

2. 9 ~ 20. 6 /

l-

Number of cigarettes smoked per day

l-9

Years / Percent lost

-___

K-19

Years 1 Percent lost

-I-

-

I-

.-

z-39

Years I Percent lost /

__- / /

6.2 ~ 12.8 6. 1 13. 9 6.0 15.3 5. 8 16. 8 5.6 Il8.7 5. 1 19. 9 4.4 20.6 3. 9 22. 2 3. 1 , 22. 0

40 and over -

YeKS 1 lost

8. 3 8. 1 7. 9 7. 6 7. 0 6. 3 5. 4 4. 4 3. 4

?ercent

17. 1 18. 5 20. 2 22. 0 23. 3 24. 6 25. 2 25. 0 24. 1

Source Flammond, E. C. (1).

REFERESCES (1) HAMMOXD, E. C. Life expectancy of Americnn men in relation to their

smoking habits. Presented at the World Conference on Smoking and Health, Sew York City, September 11-13. 1965. 23 pp.

(2) U.S. PUJJLIC HULTII SERVICE. The Health Consequences of Smoking. A Pnblic Health Service Rericv: 1967. Washington, U.S. Department of Health, Education, and Welf:lrc, Public Health Service Publication So. 1696,1967.227 pp.

(3) U.S. PLTILIC HEALTII SERVICE. Smoking and Health. Report of the .%drisory Cl)rnrnittw to the S~uewn (:r~npr:~l of thr I’nhlic IIralth Srrvive. IY;~shinp- ton, F.S. Department of Henlth, Education, and Welfare, Public Health Service Publication So. 1103,196-I. 387 pp.

10

PART II

Technical Reports on the Relationship of Smoking

to Specific Disease Categories

CHAPTER 1

Smoking and Cardiovascular Diseases

Contents Tntroduction________------------------------~-------~-.-

Conclusions of the 1964 Report_---_~-----~__--------- Highlights of the 1967 Report--_-----~---------------

Smoking and Coronary Heart Disease-_--_-~-~-----~-----~- Coronary Heart Disease Mortality- - _ - - - - - - - _ - - _ _ _ _ _ _ _ C’orouary Heart Disease llorbidity- _ - _ _ _ - _ - - - _ - - - - _ _ _ Relationships of Cigarette Smoking to Other Risk Fnctors-

Age___________-_-~----------------------------- High Blood Pressure _____ -_---_---__ __-_ --- ______ High Serum Cholesterol and Related Diet- _ _ _ - - - - _ _ Physical Inactivity-------------- ______________-- Sociological, Psychological and Personality Variables- Multiple RiskFactors------------- _-__ ---- _-___- Genetic and Constitutional Studies- - - - _ _ - - - - _ _ _ - _ _

Influence of Smoking and Nicotine on Blood Lipids---- -- Epidemiological Studies- _ _ _ _ _ _ _ _ _ _ _ _ - - _ _ _ _ - - - _ - _ _ Experimental Studies-Animal-- - _ - _ - - _ _ _ - - - _ - _ _ _ _ Studies in Humans __________________ ---___----_-

Studies on Thrombus Formation _ _ _ _ _ _ _ _ _ _ _ _ - _ _ _ _ _ - - - - Catecholamines----- ____ -_--__---- ____ --- _.___-_ Blood Lipids ____ ---- ____ -----__-----_----- _____-

Cardiovascular Response to Stnoking and/or Nicot.ine-- _ - Experimental Studies ____.________ --_--__-----_-- Studies in Humans-- ________ -_-----__----__- ____ Human Jlyocardial Tissue Function in Relation to

Anoxia and to Carbon ~Llonoxide__-----_-------- Glucose Jletabolism and Possible Cardiovascular

Effects.________________-_--------------------~~-- Additional Considerations Regarding Coronary Blood

Flo~~~_____________________--~--------~---~---~-~--- Summary, Concept and Conclusion- - - _ _ _ _ _ _ - _ _ _ _ - _ _ - - _

Page

15 15 15 16 16 17 21 21 21 22 23 24 28 28 30 30 30 31 32 32 32 34 34 36

38

40

41 42

13

Page

Smoking and Cerebrovascular Diseases--- _ - _ _ _ - - - _ - _ _ _ _ _ _ - _ 44 Cited References----_---_---__- ____ -_-_-_-_---___-__---_ 45 Supplemental Cardiovascular References------------------- 54

14

ISTRODUCTIOK

Male cigarette xnokers liner n liifhtr death rate from coronary artery disease than nonsmoking malw;, but it is not clear that the association has causal significance.

HIGIILIGIITS OF TIIE l%i REPORT (I@)

1. ,\clditional evidence not onlr confrms the fact that cigarette 9~lolwri h:~\-e inrrf3srtl tlwt 11 r.;ltG fr0nl c0ronnry heart disease. but also su~ggc~ts how these deatlls nrny lw cnus~l 1);~ cigarette smoking. There IS an increasing c&~erpncc of many types of e\-iclencr concerning ciprette 9nioking ant1 corollary llr3rt tlisrasc which stl.Ollgly suggests that cigarette smoking can cause death from coronary heart disease.

2. Cigarette smoking males have n higher coronary heart disease death rate than nonwloking males. This death rate may, on the average. be 70 lwrcent gre:iter, anti, in some. even 200 percent greater or more in the presence of other known “risk factors” for coronary lieart tliS1~ilsc. Felll;llr cigarette Slllokrrs :IlS h:l\-e it liigllcr coronary he:Irt diseace tlc:ltll rxte thall do ll0ll.~lllOliill~ fenl:Iles, nltllOllgll 1lOt as high as that for males. In pieral. the dc:lth rntrs from this disease i l l~~IY:lSc with :~mount ~mokctl. (‘rwtt ion*’ of c*ifawttc~ ?I~~c~liillc~ is followed by n reduction in the ri.qk of tlving frown coronnry heart disease n-hen fTJltlpred wit 11 the risk incurred by those who continue to smoke.

3. A grenter frequency of :idwncerl ~orona~ry arteriosclerosis is noted in male cigarette ,wolters? eq~ecially 111 those who smoke heavily.

15

SJIOKISG AND COROSllRY HEART DISEASE CORONARY HEART DISEASE MORTALITY

,2s in the past two decades, coronary heart disease in the T_Tnited Stiltes continues 11s the lending cause of death? being responsible in 1967 for 56i,‘il0 deaths or 31.0 percent of the total of l&33,900 deaths.

Since a<gc specific data are not yet available for 1967, table 1 shows the number of deaths due to coronary heart disease and the death rates per 100,000 persons by age for 1966.

TABLE I.-Coronaq heart rlisease deaths and death rates per 100,000 population, by age: hited States, 1966

[Disease ‘ategory 42~ in the ICD Munual, 19571

Age Death rates

573, 191 292.7 250 0. 3

1,469 6. 6 12, 522 52. 0 45, 997 206.3 99,647 577.3

162, 55.5 1, 405. 2 171,737 2, 979. 5

75,8i4 7, 015. 5 160 (Xl

X-Not applicable. SOURCE: %mthly Vital Statistics, 3ational renter for IIdth Statistics (147).

Tllcsc tl:lt,a illll.~tratc tile tlr:~~>~iltic increace in death rates as age advances, with the incrtf~e being particularly- marked after age 45. The cleat 11 mtrs for coronary- lleart disease for n~en and u-omen continue to shoed il cwiisl)iruon tlitrernice. In 1966 it was Xl.6 for males ancl 22K:i for feirmle-; per lOO,OOO population.

While seven~l studiw of wriow ns;pec.ts of the association between cnronar~ hc:lrt tlisense nlortality and viparette smoking have been rrportetl dilring tllr l,:tct year. tile. most significant studies of this association are cont:~inrvl ill the 1067 report.

Tht se\-rral ne\v .stlltlici of variom aspects of the association between coro~ul:\- hr:rrt tlistme Inortality and cigarette making follow.

Friedman ($6) reportetl a strong positive correlation betm-een per ml)ita c*igawttc sales ant1 ~wro~~:~~~ 1leilr-t disease death rates by states. The correlation is 0.76 when d:lta only from tllosc states with relatively acmratc information of cigarette consnnlption are. analyzed. Related factors sw11 :\s urb:\nization or softness of the local mxter supply do not explain this degree of association.

16

Other studies tleal with the excess deaths associated with smoking. Strobe13 et al. ( I.#) reported that among 3,479 Sviss physicians, over 30 percent of tlic exce.ss deaths occurring over a g-year period among siuokers n-as due to coronary heart disease.

In contrast to the study above and c1nt.a from the T-nit& States in whirh nl~proximatelr one-half of the excess deaths associated with sinokiug are attrilmted to cardiovascular causes (I.$!?), preliminary data from Hirayama (6;;) show that the excess deaths in Japan associated with s1ii0kiii.g were priniarily cxpl~ained 1)y cancer of various site,s. Only Ii! percent of tlie excess dentlis were associated with cardiovascular causes. This prospective study of %.5,118 adults over the age of 40 encompassed ;I followup period of 15 months. -1dditional followup by TJirayanla slwuld yield useful tlnta with respect to smoking and excess mortality from cardiovascnlar diseases in this ,Japnnese population group, p:vtticularly with regard to the younger adults in the study.

Hyams, et al. (67)) on the other hand, speculate that the apparent increase in the occurrence of coronary heart di+ase among +Japa~wse males, especially rmder tlie age of fifty, may be tlnc to a t,rend toward Westernization in both diet and smoking habits among younger Japanese men.

Hammond (,54), in his prospective study of over 1 million men and women, showed a positive relationship between the duration of the smoking habit and coronary heart disease mortality. In the Framing- ham Heart Study (71)) no association wa.s found between the. duration of the smoking habit and the incidence of mortality from heart &tacks among men who were “heavy smokers” (more than one package of oigarettes per day).

These diswepancies between t,he relationship of smoking to the incidence of t&al coronary heart disease and mortality from acute ooronary heart disease may be accounted for, in part, by the differences in population ,q~~~ps studied and by the possibility that duration of smoking may have a greater association with t,he fatal forms of coronary heart disease..

Knmrel, et al. (70)) in more recent. data from the Framingham study, indiwte that the fatal and more severe forms of coronary disease are more st,rongly associated with c.igarette smoking that the less sel-ere forms (figure 1).

Coronary Heart Disease Morbidity *

Rlnc.1~ of the morbidity da,ta reported during this past year resulted from retroqwti\-e studies of patients or cross-sectional studies (106, 107, 127, 134, 151). In these studies the findings revealed that there

l Also may include mortality data in this presentation.

17

2.50 -

*ing,na Pectorlr

Myocardial Fatal Infarction CHO

S”ddW Death

2.20

.g 1.50-

E

e 2 e

s LOO-

NOW kleavv Non- NW- Heavv NOW Smoker Smoker Smoker Smok;‘ Smoker Smoker Smoker S&k&

OES. = number obsewed EXP. = number expected Heavy smoking indicates more than 1 pack per day

FIGLYRE I-Morbidity ratios for .qxvified manifrstntions of coronary heart disease. nruonfi men aged X&SD years at entry into Frnminghnm Heart Stuclr, classified by smoking habit : 12 years’ experience.

~OCRCE : Iiannel, et al. (70).

were reht i\,ely more smokers among the groups with coronary heart tliSfXW, tll;\ll :~llIOllg tilt? ~Olllp\l’iSOll, 01’ COlltrOl pOllpS.

In n retrospective stitlltly of myocardial infarction patients in *Japan, I-Iy”ms, et :\I. (67) reported siinilnr findings, particularly among the mm untler age 50. DitFrrences measured 1)~ an exposure index com- bining intensity and duration of smoking showed the same trend, t.liougl1 the tl:lt:i were not statistically significant.

Dorkcu (.M. .I/) reported on t\vo retrospective studies in Hamburg, Gerni:liiy : one: a study of female patients; the other, a study of male patients. IIe. cwnc-ludctl tllnt there is a strong association between w~oking :tu~l nivoc;lrdinl infarction in both males and females under the age of 45.

In Dublin. JIulrnh~, et al. (106, 108, 109) studied groups of male and fem;lle coronary heart tlisense patients under age GO. He. found that a much greater portion of the patients, in comparison with a sample of the general population, smoked cigarettes. Also, the intensity (amount, multiplied by tlurntion) of smoking was RS much as 234 times gre.nter among the male patients and 3 times great,er among the

fe.mnle coronary heart disease patients as contrasted with the males and females in the general population.

In a study of 6’75 aviators, smoking histories taken in 1963 did not sllow a positive association in the prevalence of coronary heart disease with either amount, duration, or intensity of smoking. These findings are based on 38 cases (5.7 percent) of coronary heart disease of all forms among a very select population and are therefore subject to large sampling variations (9G). Moreover, since smokers may have an escwsi\-e mortality tllwing an acute nlyocartlial infarction. as mcn- tioned before, prel--alence rates are not as good a measure of the association between snloking and coronary heart disease as are incidence r&es.

Epstein (,?9), although finding no prevalence differences between smokers and nonsmokers in his Tecumseh Study, found an increased incidence in cigarette smokers of both fatal and nonfatal coronary heart disease.

In a short prospecti\-e study of 14,000 Kern-egian men (12,000 with smoking histories), ?;atvig (113) did find an increased risk of incidence of first myocardial infarction or angina pwtoris among those men 50-59 years of age who smoked.

Since the 1967 Report, t,he continuing prospective epidemiologic studies have comewhat clarified the differential relationship between smoking and each of the manifestation categories of coronary heart disease : angina, nonfatal myocardinl infarction, fatal myocardial infarction and sudden death.

Data from the Framingham Heart Study (G9) revealed that “heavy“ cigarette smoking, more than 20 cigarettes per day, is positively associated with uncomplicated angina in males but not in females (figure 2).

Similar findings were report,ed by Weinblatt (155) in a study of male subjects in the Health Insurance Plan with t,he associations more pronounced among those men who smoked two or more packages of cigarettes per day. As can be seen, in table 2, the arithmetic differences in rates between smokers and nonsmokers are greater for myocardial infarction than for angina; however, t.he risk ratios are similar.

In a ret,rospective study, Heyden-Stucki et al. (61) found no association of smoking with angina or other chest complaints.

The inconsistencies in data on the association bet.ween smoking and the development of angina may be due in part to differences in methods used to diagnose and classify angina and to record smoking habits in these epidemiologic studies. Further standardization in this area may help to determine more accurately the relationship of smoking to angina.

19

2.00 -

1.61

l.!iO-

; > : l.OO- d L

NCl”- Smoker

OES. = “umber Observed EXP. = number expected

NOW l-20 >20 Smoker CigaretteSmokers

FIGURE 2-Angina pectoris morbidity ratios among persons aged 3&59 years at eotry into Framingham Heart Study, classified by sex and number of cigarettes smoked : 12 years’ experience. SOURCE : Kannel, et al. (69).

TABLE a.-Age-adjusted incidence rates per 1,000 males aged 35-64, and morbidity ratios, for speci$ed manifestations of coronary heart disease, by smoking category: Health. Insurance Plan Study

13 year observation data]

Smoking catrgory Myocardial infarction Angina

Incidence Morbidity Incidence , Morbidity rate ratio rate ratio

I- --+----

Current nonsmokers ____ --~~---~ . .._.._ - 3. 27 1. 0 1. 37 1. 0 Current cigarette smokers_-_- - - ~. _ - ~. 7. 01 2. 1 2. 62 1. 9

Less than 2 packs_~~.--~~~-----~-~- 5. 05 1. 5 2. 08 1. 5 2 or more packs--~---_----_.- __._. 20. 80 6. 4 6. 64 4. 8

Source: Feinblatt, E. (f56).

20

In the Western Collaborative Study, Rosenman et al. reported !iipher rates of silent mvocardial infarct ions in ~~outlger men, 311d liigher rates of recurrent myocnrclial infarctions at all ages among those who smoked nwre than 25 cigarettes per day (13.3. 124).

Friedemann, et al. (44) reported reinfarctions occurred more fre-

Dorkeii (27) found in a series of 330 men of all ages, in Hamburg, who surriyed at least R and up to 6 years after their first. nlgocardial illfarction, that 172 (5” percent) had stopped smoking completely after the first, infarction. In contrast, of 8~ sul)jects who had died from a second myocardial infarction or sudden coronary death after learing the hospital, oi11y I&S (Z.9 ljercent ) had given up smoking completely (P<O.OOl).

REI,.\TIOSSIITPS OF CIGIKETTE SJIOKISG TO OTHER RISK FACTORS

The ongning prospective and other epidemiologic studies have yielded fintliirgs which permit analysis of tire interrelatioirxhips among cigarette smoking and other factors considered to increase the risk of coronary heart disease.

Age Generally, the tmtlings show that the incidence rate of coronary

heart disease increases with age, both among smokers ancl nonsmokers. The morbidity ratio of coronary heart disease in ~1l~Oli~l~S versus nonsmokers decreases with age though the absolute number of excess deaths among smokers increases with age.

High B7ood Pressure Recent reports on the relationship bet\reen smoking and blood

pressure appear t,o support the findings in the 1967 report:

,ilthougl~ the inhalation of cigarette SlllOlit? is frequently aCCQlll- pniiiecl by acute trill>Sit elevations in blood l)ressitre, ln~l)itunl smokers teiid to 1ral-e lower blood pressures thall do 110111;11~01it?1’S. Hut, gi\-en the ljresence of high blootl pressure in an indi\-itliwl, smoking acts as an additional risk factor for the developnlent of coronary heart disease.

Heyden-Stucki et al. (61) report that, among 500 workers in Slvitzer- land, smokers, particularly heavy smokers, have lower blood pressure as a group than do nonsmokers. Smokers also were found to have normal or subnormal weights in contrast to nonsmokers who had a greater mean weight ; thus, confounding the relationship between snroking and blood pressure level. Tibblin (144) in a cohort study of Scandinavian men born in 1913, found a lower mean blood pressure among smokers than among nonsmokers. As the population was classified according to levels of blood pressure, a step-wise decrease in the prevalence of smoking was noted as the level of blood pressure in-

21

TABLE 3.-Mean age and man systolic and diastolic blood pressure, by sjnoL+irLy category: Los Angeles Heart Study, 1962

Current cigarette smoking status Blood pressure (mm. of Hg.)

Number of, Years of Systolic Diastolic subjects age

-1 -,-,- I

Smokers.~~~~~~.~~-------~~~---------- 407 54 133. 6 82. 5 Nonsmokers--.~~-------~~.------~-~~~- 728 57 ~ 137. 0 83. 9

I

SOURCE: Clark, V. A. (2s).

creased. A similar trend for both systolic and diastolic pressures was also reported by Clark, et al. (23) as shown in table 3.

In the study of 675 arintors (96) smoking intensity, although not found to be associated significantly with systolic or diastolic blood pressures, was positively associated with pulse pressure. Reid, et al. (122) in a comparative study of workers in Great Britain and the United States noted lower diastolic blood pressures among smokers than among nonsmokers in both groups; adjustment for Tveight variations reduced this difference appreciably.

Rfulcnhp (207)) in a retrospective study of 100 women coronary heart disease patients under 60 years of age, reported that ,50 to 60 percent had diastolic. hypertension (>nO mm. HF.). Hypertension and cigarette smoking, together or separately, were present in over 80 percent of these patients.

In the major prospective studies, when both smoking and hypertension were present, an interactive increase in the risk of developing coronary heart disease \yas noted. When to these two risk factors elevated cholesterol levels were added, the risk of developing coronary heart disease was further increased (figures 3 and 4).

High A‘Temm~ Cholesterol ad Relcrted Diet Certain of the retrospective and cross-sectional studies (6’9, 151)

have, in general, demonstrated higher cholesterol levels in smokers than in nonsmokers. Pincherlc, et al. (119) and T,ane. et al. (9G) report similar finding?. Ai stud7 by Heyden-Stucki (GI) of ,500 Swiss workers found a similar trend but the differences between smokers and nonsmokers with respect to cholesterol levels and other lipids were not statistically significant.

A recent report (A’/;) describes some of the variability of interrelationships among smoking, blood pressure and cholesterol levels in different population groups througllout the world. It concludes that though nonsmokers tend to be heavier and have higher blood pressure levels than cigarette smokers, heavy smokers tend to be in the top

22

150-

positive weight W.C.H. cd” any 2 any2 any 2 any 3 any 3 OnI" only On," only or all ""I" O"lY OnI" or

3cml" all 4 CHD 46 1 0 2 8 4 6 12 17 23

N 1,329 94 161 227 260 159 204 484 222 264 6 42

Relataonship between status with respect to four coronary risk factors thyper- cholesterolemia, hypeRen~hm. overweight. and cigareffe smokingt as evaluated on original examination and incidence of cltn~al coronary heart disease in men or,ginally age 40-59. free of definite CHD. and followed subsequently wtfhout systematic interventgon. Peoples Gas Light and Coke Company study. 1958-1962. W is overweight, le. a ratio of observed weight to desirable weight of 1.15 or greater, C is hypercholesterolemla. ie, Swum cholesferol level of 250 mg/lOO ml or greater. H is hypertensmn. ie. a diastolic blood pressure of 90 mm. Hg or greater: S is smokmg of ten or more cigarettes per day.’

FIGURE 3-1ncic:enre of coronary heart disease among men aged 40-59 years at entry iuto I’ctiol~les Gas Light and Coke Company Study. classified as to presence of specified risk factors: l!Xbl962.

SOURCE: Stamler, et al. (1%).

cleciles for blood pressure nnd rrlntiye x-eight. Cholesterol-smoking relationships described in these studies do not show a consistent pattern.

Tn a controlled dietary intervention study of postjnfarction patients Leren (W) fount1 that smokiiq Ilabits did not iilflilence the serum cl~olesterol level or tllr cwronary llci1rt clisease relapse rate in the colltrol

group. i~lllollg the stlltl) gronl) of clictcrs there was il suggestion, :~lthough not statid ically >igl~ilicxlit at tile 0.05 level. that smokers had a higher coronary heart disease relapse rate than nonsmokers.

Physicd rnnctic4y The independent and combined effects of cigarette smoking and

physical :ic.tiCty, as dr~~ribetl in the 1!)67 rrlwrt. vontillne to be demonstrated :IS more data are :Ic~,,l~llllllntetl. Tile apparent l)rotcctire effect of plrysical :ic*tiritJ appears to be more pronoiinwd with regard to myocarclial infarvtioll tlian :lllgiu:l [t;Ible 4, (255)]. Differences in methods of assessment of liistoq, of l~ll~sical acti\-ity ill cape versus

315-1310-66-3 23

6.00 -

1 .w -

0.00 Any one Any two Any three

OBS = number observed EXP = number ex~ecfed

Number of abnormalities

FIGIXE 4-MFocardial infarction morbidity ratios among men aged 30-59 years at entry into Framingham Heart Study, classified according to presence of selected riak factors : 12 gears experience (Risk factors are: cholesterol lerei over 250 m&100 ml., systolic blood pressure over 160 mm. Hg., smoking over 1 pack of cigarettes per day).

SOURCE: Kannel, et al. (70)

control groups may account for some differences in the incidence rates noted.

Hlackl~urn, et al. (10) folmd no relationship of smoking to the prev- ale,nce of postexercise KCG c.hanges in a study of 10,260 men age 10 to 59 years. TTo\vever. there were only .51!1 (.i.l percent) subjects with a, “positi\7” TSCG response.

Sociologirn?. Pqvh~olqicn7 and Pwsonalify Variables Tn-o studies ($5. R/t) demonstrated an inverse relationship between

t,he frequency of coronary heart disease and the educational level of the subjects. In the Bell Telephone System (Cd), those men without a college education had higher coronary heart disease rates than those with a college education. Also, those not at.tending college tended to smoke more.

In a study of factors related to coronary heart disease among Cleve- land attorneys ($5)) the quality of the law schools attended by the sub-

24

3. 27 1. 0

6. 33 1. 9 2. 14 1. 6 3. 07 0. 9 1. 67 1. 2 3. 01 0. 9 1. 32 1. 0

7. 61 ‘2. 3 4. 71 1. 4 3. S.i 1. 2

11.27 3. 3 24. 09 i. 4

2. 0.i 1. .j 2. 37 1. 7 1. 9.5 1. 4

4.97 3. 6 5. 09 3. 7

12. “0 3. 9

jec.t were ranked independently by a law school professor. I,a\~-~ers attending s~~l~ools in tile “lliglrest law ~:cllc:~ol quality growl)” Ilad lower rates of coronary heart disease than those attending schools in the **lower law school qlwlity group.” *use, t11ow ill tile 1attrr group had started snloking at an earlier age. Since additional differences were noted for other risk factors, smoking alone may not be responsible for tllr total differences in these rates. In both stnclies, it uxs liyl)othe- sized that with respect to susceptibility to derelopmellt of coronary heart disease, behavior patterns and attitucles estal~lishetl l)rior to professional traillillg and prior to stresses rcsnlting from job mobility and job tension, were nlore significant than the later stresses x-hich resulted from their present jobs.

Rec,ent clata from the Western Collaboratire Group Stll(ly (IX) appear to show that among met1 X-49 Jears of age. cigarette smoking ~-as associated with several coronary heart, disease risk factors (table 5). Though these findings may be statistically significant, the differences between smokers ancl nonsmokers I\-ere small.

25

TABLE 5.-Age-adjusted means for selected coronary heart disease risk -factors and personal chSaracteristics, by smoking category: U’estern -Collaborative-Grolrp Study, males 39-49 years of age

[4)< years overage observ.dion data]

I Smoking category

-

Variable NWX

smoked

I- Serum cholesterol- _ _ _. _ _. - _ _ _ _. - _ -___ Beta/alpha ratio _____ --_--_--__- __.__ Lipalbumin~~~~--~~-~-~~~-~--~.-~--~- Systolic blood pressure--_. - _ _ ___- _ - -_ Diastolic blood pressure--. - __ _ - _- _ - -_ Ponderal index _____ -----.---- ._____._ Physical activity on job..-- - - - -_ _ _ ____ _ Amount of exercise-_-_--_--_-_-----~- Income__-__-_-__-__________________

217.2 1. 9

21. 1 1‘26. 3

82. 0 12. 6

1. 95 2. 18 2. 75

T

_-

Sources Rosenman, R. H. (fZ5).

Smoked 26 cigarettes or more

per day

231.8 2. 1

19. 4 129. 9

81. 3 12. 7

1. 95 2. 05 2. 75

--

I -

Percent diBerenw

+6. 7 +10.5

-8. 1 $2. 9 -0. 9 +o. 8

0 -6. 0

0

TABLE 6.-Pewent df.vftlibution by behtlz*ior type of smokrrs and non- swokers: IVe.stem Collnborntire Group #t&y? mnles 39-p yews of ac7e

14% yews average observation data]

Behavior type

I I Smoking category

Tota1 ‘--Never 1 Former Current 1-15 16-25 smoked smokers pipe or

26 cig- cigar&k5 cigarettes aretteS

cigar only per day per day or more per day

,-~~-~ -___

Total ___._ -__-_- 100.0

I 1

100. 0 100.0 100.0 100. 0 100.0 100.0 -_________________-

;:;:;::::::::I ii:; 1 ii:; j :y :;:; ;;:; 1 Q;:; :!g

Test of difference of distributions: Xz=24.;0; df=3; p=.@X. SOURCE: Rosenman, R. H. (125).

Behavioral pattern type A is characterized by an enhanced com- petitiveness, drive, aggressiveness and hostility, and an excessive sense of time urgency as contrasted to type B. There was a difference in the distribution of personality types A and B among smokers and nonsmokers (table 6).

The foregoing data refer to concurrent observations gathered in 1960-1961 on 3,182 men who were then free of manifestations of coronary heart disease. A follow-up of this population during the

26

nest 41/i Fears disclosed that cigarette smokers experienced substantially higher rates of coronary heart disease tllnn those who had never smokd This finding is based 011 clata for men 39-49 vx~rs of age, whic~li hair been adjusted for the c*onfouncling influences of related risk factors, such a’: age, cllolesterol, etc. (table 7).

TaRLE ?.-InCit/enCP ?f new coronary heart diseaw by WIoking CatPgory: Western Collaboratioe Group Studyl: males 30-49 years qf age

[4x ~mrs arernge observation data]

Rate per 10,KKl population

?;ever smoked---------~---~-~~.~.~ ._...... 540 36 29 Former cignrcttc smokers- __ _ _. _. . . . . . . . . 241 67 92 Pipe and cigar only ___._..._...__.... ._... ~. 406 27 16 1-15cigarettes-----.-~-~~~~.~.~ . . . .._. .__. 212 51 52 16-25 cigarettes__------------------------.~ 436 89 92 26 cigarettes and over--~-_-~-_-~-.-_-.- ._.. 425 95 104

SOCRCE: Rosenman, R. H. (115).

The coronary heart disease rate for those men smoking 26 or more cigarettes a day is seen to be about three times greater than for those who never smoked. The rate for former smokers is still rather high, even after adjustment for concomitant variables. The largest impact, of the adjustment procedure is noted among this group, and suggests that those who quit may have done so because they were already a relatively high-risk group for reasons other than smoking. The relatively low raie among men smoking only pipes and cigars is noted in this as in ot,her prospecti\-e studies.

The nature of the association of smoking and coronary heart disease incidence among type ,I and type B personality groups is not easy to characterize or interpret. Among the type 11 group, the pipe and cigar smokers and the light cigarette smokers had the lowest rates of incidence of new coronary heart disease, while the highest rates were found among those smoking 26 or more cigarettes a day. For the type B group, the lolvest rates occurred among those who had never smoked, and the highest among the light cigarette smokers. The age- adjusted rates of new incidence of coronary heart disease per 10,000 men 3949 years of age are shown in table 8.

Additional data t.o permit concomitant analysis of these variables and those in table 7 are needed.

27

T.\BLE 8.--lncLfence of new coronary heart disease by smoking category and beh,aaior type: Tl’estern Collaborative Group Study, males 39-Q years of age

[4:/z years average observation data] -

Rate per 10,000 population

Smoking category Behavior

type B

Total~~~~~------------~----------~~.-~-~-~~~~~~~-. Ncversmoked~~~~.~~....~...~~-~---~~---------~---~ Former smokers-_.- . . . .._....._._ --.._------------- Pipeandcignrsonly ___...... -.-.-~-..-------------- Cigarettes:

1-15~~--~-----------~------------~-~-~-~-~-~-~ 16-25------~-----------~-~-~~~-~~.~~~~...~~~~. 26 and over-------~-~-~--~.-~-.- ____.___._.__._

91 53

107 18

18 135 149

SOURCE: Rosenman. R. H. (l&5).

33 13 36 36

60 33 51

Lane, et al. (96) found significant relationships of smoking intensity and duration with personality factors-impulsiveness, emotional insta- bility and belligerence scales.

Thomas (I&‘) after reviewing rarious studies of psychological variables related to coronary heart disease, concludes that smoking may have different etrects on different personality types and at different anxiety levels.

ill tdfiph? Risk Factors The acceptance of a multiple factor causation hypothesis for coro-

nary heart disease emphasizes the. need for more sophisticated statistical analyses of appropriate data. Our understanding of the relative importance of rarions risk factors from the limited number of such special analyses has not been altered significantly from that obtained l)y more conventional statistical analyses (38).

Clarification of the apparent independence of several of the major risk factors has resulted.

Trurtt? et al. (245) emphasize that the major risk factors are noted to have a tlifferrnt ortler of importance by age and ses. Cigarette smoking is particularly important among younger males as noted in table 9.

Genetic nnd Connfitutiona7 Studies Baer (5) found that heavy smokers among college males were taller

than light, smokers and nonsmokers. Lane, et al. (%) also found significant associations between body size measurements, including ponderal index (though not with height or weight individually), and amount of smoking in the study of over 675 aviators.

28

TABLE 9.-Linear dkcriminant function coeficients (in standard units) for various risk factors in coronary heart d;sease, by sex and age: 12 Year Framingham St&y

Age ___. . . . ~. - -, Cholesterol.. _ - ’ Systolic blood

pressure~.......~ Relative weight. _ Hemoglobin- - - - -~. Cigarettes smoked- _ ECG abnormality. _,

SOURCE: Truett, J. (146.)

Cederlof (18) has emphasize,d the value of studies of twins for investi,rratinp aspects of coronnr~ heart disease and prewnts certain suggested modifications in methoclolo,~. The 1967 Report (.I@) discussed the studies by Cedcrlof on Swedish t\yin pairs (In. 30). His data on American twin pairs was recently prcscnted and showed results similar to those of the SITedish twins (18).

The problems with interpretation of thew studies nre sever:il. The small numbers of cases and the combinin,rr of dntu for both sexes in various subcategories make rates and ratios subject to significant ~linncc wriations. In addition, use of n questionnaire for nngin;TI, with only modest levels of reliability and vnlidity requires :I larger study population before definit ire conclnsions c:~n be nlnde. The lack of information on the distribution of risk factors other than smoking in subsamples of discordant twin pairs and the total group of twin pairs makes the compnrison of ratios for prevnlence of symptoms difficult to e.rnlu:~te. The inclusion in the “smoking.” group of those who had stopped smokinp np to 3 venrs pre’ions to the study, would also te,ntl to diminish the differences betn-een smokers and nonsmokers. Ijefinitions of discordant snmking habits must conform to those differences identified ns significant in the large-scale population studies.

TIM fact’ that discordance for smoking does occur ;unong monozygotic twins certainly indicates that the snlokinp habit cannot be determined by genetic factors alone. Txl-in studies with further bophi&cation of design, larger number of cases, better definitions of disease, and more significant identification of tliword;~nt exposures have the potential of contributing substantially to nur ~u~tlerstnnding of the interactive factors in coronary heart disease.

29

Tn an artic*le rel-ien-ing wme of the epidcmiolo~ical evidence in the 31/, years subsrqnent to tile 1964 report, Seltzer (1.29) concluded that - . there was no snbs~antinl evidence to indicate a flirther association of

cigarette smoking with coronary heart disease Iw~ond that stated in the lY64 report.

Seltzer nlludcd to \\-hat 1~ called “inconsistencies” in the recent literature relating to duration, aimunt, age, inhalation and mode of tolxwco smoking \vith coronary heart disease.

The addition trf many more person years of esperirnce, from the new and continuing s:tltdies. provides data since the 1064 Report that wn be anal~ztcl age-spwific~ally. When this is done most of these “inconsistencies” disappear.

Seltzer’s cwi~cliisioi~ is v0ntixi.y to that of nlost cI)itlr~niiologists n-ho are familiar lvith the current research. Furt~hermore, he has not con- qidered the inll)ortant relevance of the esl~erinicn~aI, lxitI~ologicnl, and clinivnl data that have I)een r’q~ortecl since 1964 concerning cigarette .wioking nncl cardiorasciilnr diseases.

Epidemiologicnl Rfzrdies

The results of epidemiological studies on the relationship of smoking to serum lipid levels haT-e not been consistent. Several studies reported no significant difference in serum cholesterol (Z’6: 40. (il. 1:X)) and triglyceride Icwls (40. 61) between Pmokers and nonsmokers. In their study of twins, I{Iomstrancl. et al. (11) state that pro- longed smoking had an insignificant effect on all Fernm lipid levels in their monozygotic twins and only elevated phospholipids in their dizygntic group. However, they quote a personal con~munic:~tion from Carlson, et al. who fonnd elevated trigylceride levels in smokers in a prospective study of 6,000 persons.

In a wry ~otiil)i,cliensire Stllily of 6;if former naval aviation cadets over n period of *3:\ years, Harlan, et al. (.X) investigated the rclnt.inn- ship of \-arious constitutionnl and cnvironn~entnl fwtors to serum lipid and lipoprotein levels. They fount1 that serum Sf O-12 (hcta) lipoproteins and cholesterol levels were related to cigarette smoking ~1x1 that the duration of smoking also had a significant correlation. The autllors felt that the relationship of smoking to these lipids was l~res~nna~ly dircrt, l~c~cau~~ cigare.tte smoking did not correlate with other fxtors related to lipicls.

Experimenta Studies-Animal, Studies in dogs of the immecliate effects of tobacco smoke inhalation

and nicotine :~dministrntion showed an increase in serum triglycerides but not cholesterol, in addition to a rise in free fatty acids (76). There

30

were no differences in cigarette, ci.gar or pipe smoke effects when the depth of inhalation was kept constant. Chronic administration of nicotine in dogs resulted in a 50 percent rise in serum chole~tcrol levels but did not affe.ct triglycerides (82). Kershbaum, et, al. (83’) have also shoFn that pronethalol (a beta-receptor blocker) inhibits the serum- free fatty acid and triglyceride rise. induced by nicotine in dogs.

In studies of the lipid and atherogenic effects of chronic nicotine administration in cholesterol-fed rabbits, one report found no effect in serum lipid levels but a significantly higher incidence of aortic fibrosis (51). Other investigators found that nicotine, increased the amount. of cholesterol in the blood ancl the intensity of lesions in the aorta (28). In cholesterol-fed rabbits administered vitamin D, Has.?, et, al. (59) found that, nicotine induced severe calcific athero-artcrio- sclerosis and occlusive thromboarteritis, especially conspicuous in cardiac? smooth and skeletal muscle.

Astrup (2) has sho,Tn that in rabbits on a high cholesterol diet, chronic carbon monoxide exposure had a marked atherogenic effect.

Gudbjarnason (52) has shown that chronic nicotine administration in dogs leads to a diminution in the rate of cholesterol turnover.

Studies in Humans It. has previously been reported (78) that c’ip?wtte ~lllOliillp nlobil-

izes free fatty acids, resulting in increased plasma concentrations. It was also found that this effect of smoking was the result of increased synpathetic and adrenal activity initiated by the absorbed nicotine (84)) the latter having no direct lipolytic action in adipose tissue (85). This response to smoking has now been confirmed by other inwsti- gators (41,9U,1ZU).

Studies in man, on the immediate effect of cigarette smoking, hare shown no effect on serum concentrations of lipoproteins and lipoprotein lipids (cholesterol, phospholipids, triglycerides) (78, 92, 115). In a recent study, however, an increase in serum beta-lipoproteins was observed 10 minutes after smoking (72).

In a study of the comparative effects of cigarette, cigar and pipe smoking on free fatty acid mobilization and cntecholamine excretion, cigarette smoking was found to hare a much greater effect (81). Less nicotine. absorption in cigar and pipe smoking, clue to the absence of inhaling, was considered to be the explanation for the milder biochemical effects with these two forms of smoking (80). Kershbaum, et al. also compared the effects of various types of cigarettes on these parameters (79). They found no difference in free fatty acid and catecholamine response or nicotine absorption with several brands of filter and non-filter cigarettes. Cigarettes containing shredded lettuce leaf had no effect.

31

In other lipid studies it was observed that smoking might increase the tendency of human blood serurn to crystallize cholesterol (87).

Kershbaum has also sho\yn that cigarette smoking increases the blood steroid levels in humans (86).

STLYJIIES ON THROMBUS FORMATION

The 1067 Report reviewed the effects of smoking on in z&o thrombus formation, varying platelet characteristics and other serum factors associated with blood coagulation. It is not in the scope of this report to go into a detailed analysis of blood coagulation and/or thrombosis. However, the role of smoking and blood lipids on thrombogenesis mill be briefly discussed, as they relate to thrombosis and c.ardiovascular disease.

The role of cntecholamines (especially epinephrine) in thrombo- cwlesis must, 1~ stressed (111). The nic~otillr-illtlrlced catccholamine Lelense, lvhich plays a major role in cardiovascular dynamics might also be. the mediating factor in the. relation between cigarette smoking and thrombosis. Ardlie (I) has shown that catecholamines enhance --1TP or -1DP induced platelet a,, ~~regation. -1DP and noradrenaline in 10~ concentration (up to 0.M pg,/ml.) were found to increase platelet mobility (.G). The reverse was true in higher concentration. Rowsell (1%) has shown increases in both t,hrombus formation in an extracorporeal system and clotting time in silicon-coated tubes with moclerate doses of epincphrine. Large doses gave values closer to the control state. I3estermnn (8) has shown a diurnal variation in “platelet” stickiness which might he associated with diurnal variations in catecholaminc release. Flynn (48) found no difference in platelet ag,rrregation between smokers and nonsmokers.

Shimnmoto (13.7) prolwses that epinephrine has a primary effect on the arterial wall causing the release of a thromhoplastin-like substance which then leads to increased platelet aggregation. An autopsy stutly in I~IIIII;IIIS 1)~ ~~nrrl~ch i.1) showed inweawd fibrous thickening in the ~nlls of arterioles and small arteries of 5 organs, in smokers as conlpared to nonw1okers. This effect might be secondary to platelet c>hnnp~ wllich then calwed damage to the arterial wall. As discussed earlier in the s;tudy by Hass (59), in which rabbits on a high choles- te.rol and \.itnmin T) tliet were given nicotine. at the site of the occurrence of thrombus there was usually an inflammation of the arterial -ivall.

Blood Lipid.9

Conner, et al. (26) and Varner, et, al. (2.53’) have described various experiments in dogs and rabbits, in which infusion of long-chain saturated free fatty acids caused extensive thrombosis and death. In

32

?*;t~o coagulation and platelet, aggregation were also increased. Long- chain unsaturated free fatty acids, ho\\-ever, did not have these effect,s although microscopic platelet. aggregation was observed (CC). Zn vitro studies hare showy that linoleic and linolenic acids might, hare a pro- tective effect against platelet a ggregation induced by long-chain satu- ratecl fatty acids (73,101).

The rise in plasma-free fatty acids which follows cigarette smoking was associated with increased platelet adhesiveness (210). The long- chain fatty acid-induced platelet aggregation 1~~s suggested to be due to :CDP release from platelets (58). Harrison (57) suggests that in vifro platelet adhesiveness tests are influenced by AT)P release from damaged red cells and that the platelet change might really be a reflection of red cell abnormalities.

Bray (I$) found that coronary heart disease patients hare an ex- xpgerated platelet aclhesireness in response to ADP or ATP.

Several studies have sholr-n disturbances in lipid and carbohydrate metabolism in coronary heart disease patients (24, 95, 1%).

Kurien (95) postulates that the increases in free fatty acid levels immediately after eitlier an acute myocardial illfilITtiOl1 or ccrehro- VRSCU~RP accident, result from tissue anosia with a secondary catecholamine release, which then leads to the increases in free fatty acids. Malhrotra (103) studied two population groups in India. There was no difference in the cholesterol, triglyceride, and free or esterified fatty acid levels bet\j-een the two groups. However, the incidence of coronary heart disease was much higher in the population n-hose diet and fat absorption predispose to an abundance of long-chain fatty acids.

A majority of coronary heart. disease patients have an abnormal glucose tolerance test. In most of these patients there is a greater decrease in free fatty acids in response to glucose and a slower return to normal values (24, 136).

Solot?’ and Schwartz (236) hare determined tKo subgroups of these pntients: one ‘*_Y”, in which the free fatty acid response to glucose resenlbled a nornlal curve except for an rsa,,- ~r(~erntrtl rise aftrr 5 hours: another “B”, in which the free fatty acid response to glucose re- sembled that. of diabetics, there being a slower decrease and a subnormal return of free fatty acid levels after 5 hours. The significant effect, however, is that type “B” patients had a relative hyporesponse of stearic acid (long-chain saturated) decline with a relatively decreased rise in linoleic acid (long-chain unsaturated) after 5 hours.

These findings may be related to the effect of saturated and unsaturated fatty acids on blood coagulation and suggest’ further research to delineate the specific fatty acids elicited after smoking and in coronary heart disease patients.

33

This section should be read in conjunction with the findings re- rierred in the 1967 report.

Experimentn? Studies Xadeau, et al. (119) cnnnulated the sinus node artery in an-

esthetized dogs and noted chronotropic c,hanges in response to doses of nicotine ranging from 1.0 to 100 ,.~g./ml. Imranodal atropine abolished bratlyc~artlin and intraliodal l~rol~r:~nolol or llesnnletllonillin abolished tachycardia. Nicotine inllibited the effects of cervical wgus ner\-e stiniiilatinn witliout, modifying the response to intranodall;v injected acetplcholine. Nicotine did not inhibit the effect of stellate ganglion stimulation. These results illustrate the varying effects of nicotine under P’S])~l~illlPlltill contlition:: on tlie c~onil)licatetl netiral and humoral mechanisms affecting heart rate and rhythm.

Sleight (1,35) and Bergel, et al. (7’) have demonstrated carcliovas- cular depressor reflexes in dogs elicitrcl by nicotine stimulation of the surface of the left ventricle. Studies hare been undertaken in dogs to determine the effect of beta sympathetic receptor blockade by propranolol on the carcliac actions of nicotine. Westfall (158)) Edmundowicz (A’), Papacostas, et al. (116)) Shanks (1.32) and Puri (120) have noted that propranolol can prevent the usual positive inotropic effects of nicotine or norepinephrine stimulation on the m\-ocnrdium as well as the indirect beta dilator effects on peripheral vessels. This results proportionately in a greater increase in left ventricular afterload accompanied by a reciprocal decline of the velocity of myocnrtlial fiber shortening (120). It x-as also noted that resulting unopposed alplia receptor nctiriation by nicotine could lead to increased total peripheral resistance with impaired storke volume and cardiac output. This is further eridence that catecholamines, the release of which is induced by smoking. intrrmetliate the cnrtlio~xs- cular response to nicotine.

The effect of nicotine in single and repeated administrations n-as +tlitlietl on tllv tt?l~lllillill \-asc*iil;~I* lml of tile Iwart l)y (‘or~ilii. et al. (2;‘). lie~iilts intlicntrd that in dogs with intact coronary circnlntions. the single intral-enous infusion of nicotine (1%) pg./kg. lmtl~ weight I’ minute) incrcwed both tire left veiitricular capillary blood flow as well as tlie terminal ~ascnlar (‘aparity: the c,hronic intramiisriilni~ ;Itliiiiili~tl.;itiol~ (O..Y irig. kg. Iwtl\- weiplit. piwii .7 tilii(+, (LIT for 2

months). however. had no such effect. In Contrast, in dogs with coil- striction of the c~o~~oii:i~~ arteries, iiivotine ndniinistratioii in either (single 01’ rcprtiti\.c tloscs) fot2li resriltcd in ;I f;lll of (‘~l~)illil~~ 1~100~1 flow lmt ai1 inctrrnse in the tei-iiliilal \xw~il;~r cxl):i(*ity. (‘;i~)illary l~lootl flow as measured in these studies represents a nutrient inflow to the niyovartliuni. Sirotine :itIilliili~ti~atiolt rwiltetl in iill increaw in both

34

the \-elocitx of myocardixl shortening as vie11 as the force of contraction, and these effects: of nicotine are itlentic21 to those of norepinephrine. In addit,ion, there was also an iiicrra5e in thr rate of left ventricular pressure rise (dp/dt) ant1 a decline in left J-entricwlnr end- diastolic pressure (131).

(‘olemun, et al. (2,;) studied isolatctl cat papillary n~nwle~ to deter- niilie the mechanism of the nore~~ii~el~l~ri~~e-i~l~l~~ce~l ~tiililllation Of ni!-ocartlial oxygen cowunil)tion. They follntl tllilt ~lol~cl)iiit~l)lll~i~~e does Iiot illcreilstl tlir iiiy0c;irclial ticdue ox?pll clel~l;llltl 11111t?+ COll-

tractility is increased, otller facstors being held colM;\llt. Sorel)ine- l)llrille i, known to increase m~oc:\r(li:~l contruct ility.

FurtIler studies (49. 1-14) on anesthetized ol)ewchest dogs to determine the relative inflnenc*e~ of cli;tiigi~ in eitllcr tile colltrac.tilc state or in ten,4on dewlopn~ent on m\-owrdinl t irsur 0syp11 wnwmpt ion, intliwte that both are signifiwnt filCtOrS. Has;11 osygeii wqIlirenlents, :lcti\-ation energy, and the cwt of contrnc*tile eleillent ~hortrning :piiis;t ;L loatl :lppe:w to inflnencc i11\-ocartlial I iaue osygelr cyol~s~llllp-

tion to :I lesser degree. (‘hitl*y, et al. (21. ;?2) Stuclied the relation-hii) of llorcl)iilcl)llrili~~

to heart failure and the functional state nf tlie liunl:~n n~yoc2rclium. They reemphasize the role of norepineI)lrrine iii nlterity ilryacardinl fiber length and contractile status as delll0llStl7ltf?d ill l l lu~l~111 left

ventricular papillary muscles removed from patients i\t the time of mitral rxlre replacement.

*lyres (4) has noted products of anaerobic cnrdinc nletabolism in dogs made ischemic by exposure to ~~IIGOI~ monositlc. Tlleie will be presented in a subsequent section of this chapter. Weisslrr. et ;\I. (1.X)) in experiments with isolated perfused rut hearts, have rrl)ortetl on the importance of glucose as a substrate for anaerobic nietal)olism of the heart subjected to anoxia for SO minutes. When glucose was added to the anaerobic perfusnte, the electrical and mechanical performmic~e of the heart improved markedly, as did the recovery of the heart during the subsequent period of reos?yenation. Lactate pro(luc~tion was fivefold greater in the glucose-supl)orted nnosic Iwart th;tll in the nnosic heart without glucose. In similar fashion, niorpllologic cli;lnpes of the mitochondria ancl longitudinal tubules of tile ;lilOxic* lleart noted 1)~ electron microscopy, were averted by the illclll>iotl of plllcwe ill the perfusion fluid. This experiment suggests tllat glnc~w nlight hell) trnil)ornrily to prevent niy)wrtlial infarct ion, cnwetl by relative myocnrdinl anoxia, b3 proriding 8 substrate for ail;ierol)ic* (‘:l~tliilc’

met.&01 ism. The isolated perfused rat heart W:IS also stlltlietl 1)~ Iira~l~frltl, et al.

(I.?) to cleternline the eflects of nicotine on l~so~oii~al, ~~iito~Itoi~~li~i;~l. :llltl supernatant enzpic systenis of tile myoc:~r(linlrt. Tlwy .snggested I tllnt Ilicotine toxicity may be esl)reswd ill ternis of (1;1111ilF(’ to tile

35

1ysoson~a1 membrane and the cell wall. Shibata, et. al. (IZB?) studied the. ;~(Lt ion of nicotine on tile transmembrane potential and contractility of isolated rat ntrin. They suggest that while nicotine may influence nrembrane electrodynamics, there, may also be a direct action on the contractile mechanism of the cardiac muscle cell by changing the duration of the action potential, which implies alterations in potassium fluxes.

Sicotine-induced cahanges, in dogs, in action potentials and conduc- tion depression, with enhancement of Purkinje fibre “automaticity,” may lead to the development of ventricular fibrillation (.50). Post myocnrdial infarction dogs were much more sensitive to the administration of nicotine, as measured by electrocardiographic changes, than were normal dogs, especially in the acute stage of myocardinl infarction (6). Webb, et al. (154) state that changes in fibrillation thresholds after riyxrette smoking noted in dogs, by analogy, “may have relevance to the higher incidence of coronary deaths without increased incidence of angina in cigarette smokers.”

8 fu.iPs in Wumans The 19Ki report noted that sudden death from previously undetected

coronary heart disease appeared to occur frequently among cigarette smokers. Kuller (94) showed in a study of sudden death in Raltimore that arteriosclerotic heart disease was a major cause (61.4 percent) of tleath. Ko smoking histories were recorded. Luke, et al. (99) reviewed 275 consecutive autopsied cases of sudden unexpected death from natural causes? in individuals age 20 to 4,5 years, and noted that asymptomatic. coronary artery disease comprised 28 percent of the causes of snclden death. AgainY no smoking data were taken. Data t)ooletl from 10 studies available to Rurch, et al. (17)) indicated that, ~ardiornscnlar disease accounted for BI percent of 8,151 adult sudden deaths.

Present. clinical evidence. indicates that ventricular asystole or fibrillation may be the mechanism of sudden cardiovascular death in most. cases. It is known that hypoxia, hypercapnia, isrhemia, electrolyte, disturbances, and increased catecholamine activity all can predispose to ventricular fibrillation. From available physiological rvitlence noted elsewhere in this and the bronchopulmonnry clrapter? ~1~1 also in the I!IG’i Report, it would appear that smoking can directly or indirectly contribute to the development of these predisposing conditions. It is well accepted clinically that ventricular, nodal, or atria1 premature contractions can be increased or induced by cigarette smok- inF, as well as by other factors, and ~11 be retlttced by the cessation of caiprettc smoking in both normal and ischemic hearts. These pre- nlature (*ontractions are frequently prec~nrsors of their resl)ec$ivr t:lc,ll?c~:iI.fli:Is. .Ilso, a l)erson with an acute or impending nlyoc~ardial infarction subjected to the sympathondrenal effect of snmliillg cor11d

36

more readily develop a fatal arrhythmia (75). The relationship of smoking to cardiac arrhythmias must be studied further to determine more exactly both the physiolo,q and the mechanisms involved in sudden deaths from cardiovascular disease.

Iierrigan, et al. (74) studied cardiac output in both smokers and nonsmokers vho had no evidence of coronary heart, disease and found rises in cardiac. output in response to exercise and to cigarette smoking separately and then in combination. They note that the total increase in cardiac output appears to be t.he sum of the exercise and the smoking effects, Smoking may create an additional myocardial tissue oxygen demand above and beyond the demand attributable to exercise.

Moses, et al. (105) reported that pretreatment of healthy normals with glucose blocks the increased cardiac output response to cigarette smoking by inhibiting the increases in stroke I-olume but, not heart, rate.

Frankl, et al. (&) noted that after 5 nornlal male chronic smokers were given propranolol, cigarette smoking caused a significant increase in systemic blood pressure and a significant decrease in cardiac output. Thus cigarette smoking after propranolol administration may be especially hazardous. Yanuwnoto noted similar results (160).

Sen Gupta, et al. (130) studied 11 ischemic cardiac patients and 14 healthy controls for abnormal ECG changes after smoking one cigarette and noted specific or nonspecific changes in almost all of the cardiac patients as compared to few changes in the healthy smokers and no abnormalities in the healthy nonsmokers. Pentecost, et al. (117) studied the acute effects of cigarette smoking in patients with angina or post-myocardial infarction as compared with normal controls. Sormal men and those with angina in the absence of infarction beha\-ed similarly with an increase in pulse rate, mean pressure, stroke volume, and cardiac output. The majority of the patients among the post-myocardial infarction group showed a marked fall in stroke volume and cardiac output while smoking. In another study (.&?) to evaluate the interrelationship of smoking and exercise effects on cardiac output, a fall in cardiac output that, occurred in some postinfarction coronary patients as a result of smoking alone was noted. Also noted were decreases in cardiac output after smoking and exer- cising as compared to post-exercise cardiac output in the same patients before they smoked.

Starr (139) suggests that the ballistocardiographic (BCG) findings in cardiac disease and after cigarette smoking may luovide ~alunble information about the rate of accelerat,ion of myocardial contractile velocity that cannot be deternlilled by studying cardiac output or stroke volume alone. h disease,d heart has a slower accbelera- t,ive rate of contraction. BCG abnormalities have frequently been

37

related to cigarette wmking in subjects with or without heart disease, iii(~ludiiig angina 1)rc~toi.i~. The IK’G findings of ~Jackson, et al. (68) indicate that tip:lrette wInking itself may have acute and chronic h:lrnlful effects on nlyocnrtli:tl function, since duration of smoking was also correlated xith certain abnormalities.

Gazes, et al. (47), 13ral~ll\ri~ld, et al. (1.1), and Rlensch, et aI. (91) ha\-e folliA higher plasiri~ iio~el~iiiel~llriile levels in coronary lwtients at. rest aid after sniokiiig 2s compared to normals. I<erslih:um~, et al. (77) lin\.e relxwted that the rise in free fatty wids after cigarette waking is also greater in patients with coronary heart disease, lxob- ably due to iI11 enhanced iioi*rl~iiiel)lirine response.

I3iu~c~li, et ;11. (16) 21~0 stress the importance of tlie action of norep inrl~lii~iiie 011 the vmoiis \-;willar F;vstem. “Greater than YO’i; of the l~lood \-olume is rolltnined within the systemic venous system and a 107c redact ion in venous c’apacity \v-oold result in the sudden shifting of 330 i111. of blood (:wumiug a blood volume of 5 I,.) centrally into the pulnlonnry veins ant1 atria. 111 the presence of a diseased left ven- t,ricle, suc~h a sudden increase in central blood volume may result in acute left ventricular failure” (17). (Additional cardiol,ulmonar) consider:ttions are noted in the 1)ronchopulmonarp disease chapter of this Report ) .

Likoff, et al. (.W) suggest that a11 oxygen-diffusion impairment 01 illnl)l)r(ll):.i;lt~. oxygen Iltiliz;ltioll ;tt the n1yot*:trdial nricro~irc~lll:Itor! or cellular level could be. responsible for the angina1 symptoms and ECG signs of apparent n~~oc~nrdial iscliemia in the presence of adequate arterial x1tilr:ttioli ant1 l):ttriit c~m~~~a~y arteries 1);~ coronary

arte.riopraphy. Alyres (.$) and Eliot (33) suggest that these mecLh:v nisms luay be relatetl to tile carbon monoxide effect and abnormal hemoglobin function.

In ndtlition to a review of the coronary circulation as related to myocardial iwhrmia mcl angina pectoris, Elliott, et al. (3) studied zollal inyoc:lrtli:il i~clicmin (GO) by ECG, coronary aiigiography and regional Iil('tZltt' nletnltolism ii] 31 1XlticlltS with proven coronary heart disensc. Tlley folmd tlli\t tllc E(‘G findings rould be normal w-en when severe (~~ron:~rv tliscase ww present with myocardial production of lxct:\tc. The regional lactate pattern \ws very helpful in determining the lowtioii of nlyoc2rtli:il i%~l~Pll~iil ;llltl signih-ant coroii:\ry :irtt~ry lesions.

In studies of coronary 1)atients exposed to relatively low levels of cnrhon nlonoside, -\yres (4) has reported that myocsrdial lactate and pyruvate extraction decreased or shifted to actual production, suggesting the presence of anaerobic metabolism. These data support his

38

l)re\-ious findings noted in the 1067 report that carboxyhemoglobin can interfere with oxygen delivery to the myocardium to the degree that relative myocardial anoxia can occur. The shift, to anaerobic cardiac metabolism. which is relatively ineffective as a source of energy, indicates the presence of myocardial anosia, and should be regarded as a warning sign. In these same experiments -lyres has noted that tlw m~ocartlial oxygen extract ion is decreased in response to carbon monoxide inhalation, ~1x1 thlls has further demonstrated thr relationships of carbon monoxide with relative myowrdinl anosia and nnaero- hit myocardial metabolism. The sllift to the left of the hemoplobin- oxygen dissociation curve, describing the dcweased ability of l~emoglol~in to release oxygen at the tissue level, is directly related to increased ~arl,ox~liemoglol,in levels.

The animal experiments of Weissler (156)) noted in the previous section, sugfcst that glucose might possibly help to temporarily prr- rent mSocardia1 infarction from relative myocardial anosin, by pro- I-icling a substrate for anaerobic metabolism. Since niyocardial ischemia nlay be vnusrd not only by complete coronary arterial obstruction, but also by increased mJ-ocardial tissue oxygen demand above and lqoncl a\-ailable oxygen supply, it would be important to know whether cigarette smokers haye more proclucts of anaerobic myocardial metabolism than do nonsmokers.

Eliot (3’4) has noted apparent lvxrmgkhiu al)nornlalities in patients with signs of myocardial ischemia or acute necrosis, and in smokers as compared to controls. However, he suggests that there are other hemoglobin abnormalities also present besides the well documented carbos~llemoglobin abnormalities associated with the cnrhn nlonoxide effect of cigarettes. Some reverted to normal hemoglobin status after stopping smoking.

Anomalous hemoglobin-oxygen dissociation was noted in “heavy” cignrette smokers (more than one pack 1)cr tlay) without. knon-11 coro-

nary he,art, disease. In experiments nllere the amount of cigarette smoking was c~ontrolled, there appeared to 1~2 il tlircslioltl etfect : nwic tllan 12 cigarettes per clay caused this anomalous dissociation to occur (53). Rirnstingl (9) reports finding an increased hemoglobin affinity for oxygen in smokers, which does not appear to be explained solely by the increased carboxyhemoglobin levels in smokers.

Research to further study the interrelationships of carbon nlonoxide to the myoglobin of heart muscle should be performed because it is possible t,hat carbon monoxide may replace oxymyoglobin with cnr- boxymyoglobin and disturb the oxygell-dissociation pllenomena of n1yoplobin (XV. IX. I,%). The lilllitntiole of 11100d >111)1)1~. a11t1 the hip11 energy output of heart muscle as compared to skeletal muscle may make the myoglobin impairments by carbon monoxide of possible etiologic importance in cigarette smoking and llwrt disease.

315-131 O-684 39

Hydrogen cyanide appears to be rapidly conve,rted to thiocyanates by the body, but, the absorption by the lung of cyanide from cigarette smoke might. possibly result. in higher serum cyanide levels in the coronary arteries than in the systemic circulation. As noted in the 1964 Report, the cyanide ion is capable of stopping cellular respiration abruptly through inactivation of cytochrome oxidase. In sublethal exposures, the cyanide ion is gradually released from its combination with the ferric ion of cytochrome oxidase, converted to thiocyanate ion and excreted in tire urine. ThiocJnnate blood levels in smokers are three times higher than in nonsmokers and relative differences in urinary excretion are even more pronounced. Cytochrome oxidase is very important in cellular respiration of all body cells. In view of the extremely high myocardial cellular needs for aerobic metabolism? it is possible that the cvnnicle ion inactivation of cytochrome oxidase also can occur in myocardial cells and be of critical importance, especially in light, of other risk factors such as impaired coronary blood flow, the carbon monoxide effect, and the known increases in myocardial tissue oxygen demand caused by the smoking/nicotine-induced catecholamine release. Further research is needed to determine whether or not cyanide ions in concentrations equivalent to those found in cigarette smokers, have a harmful effect on the myocardium, in terms of both acute and chronic exposures.

Glucose Metabolism and Possible Cardiovascular Effects Epstein (37) has reviewed the relationships of hyperglycemia to

coronary heart disease. Although he states that there appeared to be no relationship of cigarette smoking to the hyperglycemia that was associated with the prevalence of coronary heart disease in the Tecumseh population, Higgins (63) reports that the Tecumseh cigarette smokers, both male and female, had approximately a 10 mg. percent elevation in blood glucose as compared to nonsmokers, although the percentage elevations above the median levels were not statistically significant. Since Epstein (39) reported that cigarette smokers in the Tecumseh study population had a higher incidence of coronary heart disease, it would be interesting to see what the interrelationship of the incidence of coronary heart disease is to the cigarette smokers who hare elevated blood glucose levels.

Cohen, et al. (2’4) have reported abnormal glucose tolerance in some postinfarction patients, suggesting the possibility that this group has difficulty utilizing glucose. It is known that smoking induces release of catecholamines which can create an increased demand for glucose by the body. Wahlberg (152) had noted that in patients with atherosctlcrotic dicense but n-ithout clinical diabetes mellitus, the glucose tolerance n-as pathologic in 46 percent as compared with 10 percent of controls, and normal in 33 percent as compared with 71 percent

40

controls. From this he infers that subclinical diabetes mellitus may predispose to vascular disease in the same way as clinical diabetes mellitus.

Kingsbury, et al. (8.9) studied a small group of male patients with peripheral arteriosclerotic disease to determine the serum glucose, non- esterified fatty acids, and immunorenctire insulin responses to sub- cutaneous adrenaline and to smoking. I’nder basal conditions. the fatty acid response was normal. Vhile adrenaline consistently caused a rise in serum glucose. cigarette smokin, w either had no effect or lowered the fasting concentration. In 5 patients smoking caused an elevation in the immunoreactire insulin which could not be explained by blood sugar changes. The implication is thnt these patients were hypersecre- tors of insulin. l?nfortunately? detailed smoking histories are not available for these individuals. Szanto (I@), in a very small study of habitual smokers, noted a ‘.IY-l’erinsulinism?’ response during oral glucose tolerance testing after smoking two cigarettes. This response aas markedly reduced when tile test was repeated after a 14-day absti- nence from smoking. The view that h~perinsulinemia is associated with atheropenesis has been suggested (114. 118, 14.!?! Iti7) and discussed by Mahler (102). If smoking directly or indirectly causes a hyperinsulin response in some individuals, then this may possibly be one mechanism by which cigarette smoking may enhance atherogenesis.

Kershbaum, et al. (8(i) have noted higher plasma ll-hydroxy cor- ticosteriod levels in smokers. Whether the “hyperinsulinism” reported to be present in smokers is related to increased adrenal corticosteriods remains to be determined. Hyperinsulinism could be a response to the frequent catecholamine-induced hyperglycemia caused by cigarette smoking in individuals without. significant clinical or subclinical coronary heart disease; but conceivably the hyperinsulinism response might be more pathological in coronary patients. Also, the potassium and other ion changes caused by glucose shifts in response to shifts in insulin levels may predispose, to cardiac arrhythmias and sudden death.

Addition& Considerations Regarding Coronary Blood Flow

Coronary blood flow, besides being influenced by the size of the inner lumen of the coronary vessel wall and its ability to dilate for the purpose of increasing flow of oxygenated blood when needed by heart. muscle, is also dependent upon the viscosity of the blood (IG). The concepts of fluid mechanics, such as laminar or turbulent flow, are well known. For any given aperture and pumping pressure, fluid flow will depend somewhat upon the physical characteristics of the fluid itself. It has been demonstrated in both cigarette smokers (1%)) and in patients with myocardial infarction that llemoconcentratioll occurs (15,137), sometimes to a relatively small degree, ill terms of absolute changes in hematorrit, but the changes in viscosity are much greater

41

than niight hare been predicted from consideration of hematocrit changes alone. *It this point, other factors related to fluid mechanics also enter in, such as the quality and amount of lipids in the blood. Burch, et-al. (15) hare demonstrated that increased fatty acids increase the force necessary to “shear” the blood, thus contributing to a reduction in the capacity of the blood to flow in laminar fashion through a given aperture. When coronary arteries are impaired by partial obstruction of the inner lumen or by decreased distensibility, there may be a critical interaction with blood viscosity causing marked turbulence of flow and thus reducing further the potential for increasing coronary blood flow.

additional evidence has been presented which tends to confirm and extend the positive findings previously reported in the 1964 and 1967 reports.

1. Epidemiological studies show that “heavy” cigarette smoking is strongly associated with an increased risk of dying from coronary heart disease.

2. New data confirm and help to clarify the relationship between cigarette smoking and other “risk factors” in the development of coronary heart disease suggesting that both independent and inter- acting effects are involved.

3. Evidence indicates that cigarette smoking may accelerate the ~~at~liopl~~siologir:~l (‘11at1ge*s of pre-eXi.Qcllt co~ronary 1lPill.t disease and contribute to sudden cardiovascular death. This relationship helps to explain why stronger epidemiological correlations between cigarette smoking and coronary heart disease tend to be found in incidence studies rather than in prevalence studies where the population is under-represented for those people who hare had fatal outcomes from coronary heart disease.

4. Present evidence continues to support the position that giving up cigarette smoking is beneficial to cardiovascular health.

5. Some progress is being made in the study of the interrelationships of selected 1)syclwlogical factors, smokin g behavior, and the development of coronary heart disease.

Recent data provide a basis for the formulation of a theoretical concept by means of which it is possible to correlate the interaction of w-era1 known co1~o~lilr~ heart tlisende ri.5k factors with the ~~hysiological mechanisms 1)~ which cigarctt(b wlokiiig nl:ly ilffP(‘t tllc

niyocardiuni. The epidemiologic~al studies continue to indicate that “heavy”

cigarette sniokinp is strongly associated with a fatal outcome from coronar;v heart tlisease. This fact may be accounted for by a mechanism

42

whereby, in the presence of impaired coronary circulation due to coronary heart disease, cigarette smoking may “trigger” myocardial oxygen deficits of critical degree. One or more of the following mechanisms may be involved in this process :

1. The increase of myocardial wall tension aud velocity of contraction, largely mediated through norepinel~hrine released in response to cigarette smoking, thereby increasing the myocnrdial demand for oxygen and other nutrients.

2. The relative reduction of nutrient capillary blood flov in the region of the m\-ocartlium distal to and dependent upon blood flow

through a p;lrtiaIIy occluded coronary artery. 3. The impairment of oxygen dissociation from hemoglobin due to

the formation of carbosyhemoglobin from carbon monoxide, thereby diminishing the a\-ailability of oxygen to the myocardium.

4. The reduction of the sul)ply of oxygen available to the myo-

cardium as a consequence of hypoxemia due to severely impaired pulmonary function from chronic obstructive bronchitis.

5. The impairment of coronary blood flow as a result of the increased blood viscosity associated ATit h~perlipemia or hemoconcentration.

6. The increase in platelet adhesiveness which might contribute to thrombus formation or coronary occlusion.

7. The predisposition to acute cardiac arrhythmias as a consequence of harmful neurogenic reflexes or catecholamine release.

8. The possible, although presently speculati\-e, contributions to impairment of myo’ardial cellular respiration by cyanide ion.

Thus, the interaction of the factors which decrease oxygen supply to the myocardium and those which increase the myocardial demand for oxygen may play a major role in precipitating the fatal outcome in some individuals with coronary heart disease. On the other hand, it is possible that the same factors, in less severe clinical circumstances, could precipitate temporary coronary insufficiency or contribute to nonfatal myocardial infarctions or cardiac arrhythmias.

The pathophysiological factors associated with cigarette smoking may further interact with other known epidemiological risk factors associated with coronary heart disease such as high serum rholesterol and high blood pressure. Although not a “risk factor”, unusually high physical stress may also create l~hysiological demands for additional oxygen supply to the myocnrdium.

The finding that those who discontinue vipnrctte smoking ha\-e :I lower risk of dying from coronary Ileart diwnse tlwl those w-110 con tinne to smoke might be accounted for 1,~ the potential reversibility of many of the p~~tl~oph~siolopicnl eflect5 of smoking on the cnrdio- vascular system. It is reasonable to expecbt partial rever+ibility of factors that interfere with oxygen supply, such as the carbon monoxide

43

effecxt? anti the increased platelet adhesiveness, hyperlipemia, and hemoconcentration noted in cigarette smokers. Moreo\yer, the increased myocardiaI oxygen requirements associated with the cigarette smoking- inducetl c~:~techolanline response and neurogenic reflexes could be expected to be eliminated upon cessation of cigarette smoking. In some patients, the cardiopulmonary benefits of stopping smoking may reduce pulmonary hypertension.

An increased ability to predict future cardiovascular events in individual persons will depend upon more precise definition and measurement of the pathophysiologic factors associated with cigarette smoking and their correlation with information about the epi- demiologicxl risk factors.

Because of tlw increasing convergence of epidemiological and physiological fintlings relating cigarette smoking to coronary heart disease, it is concluded that cigarette smoking can contribute to t’lle tlevelopnlent of cardiovascul:~r disease illid particularly to death from coronary heart disease.

ShIOT<TSG .\SD CEREBROVASCUIAR DISEASE8

AIan? of the pathophysiological considerations noted in the above section map also pertain to the relationship of smoking and cerebrovascular disease.

A mortality study in *Japan by Hiragama (6’5) reports findings different from those cited in the 1967 Report (146)) in which smokers nnder age i-5 had n mortality ratio of 1.X)? or more, for stroke.

Hirayama found that deaths due to Yascular lesions of the central nervous system, after age 40: were one-third less frequent among smokers than among nonsmokers. Several factors may account for t,hese different findings, One is that the etiologic spectrum for stroke in ,Japnn includes more hemorrhapic~ strokes than in the United States. ,\nother is tllat the .Japanese study included all stroke deaths over age 40, whereas the studirs in the United States fomd the positive association het~ecn smoking and stroke mortality occurred under age $3 (5i).

In a &utly reported by Kuhn (!A?), ‘30 habitual smokers refrained from smoking for one-half (lay and baseline retrograde brachiocerr- l)rnl angiogram:: were taken : tlleu they snloketl one cigarette, inhaled tlceply. an(l hat1 relwat :1iqiogranls. Only tllo+e over RO years of age fniletl to have sipiiificaant :wc*eler;\tion of flow in cerebral pre~~;~l~illnr~ \-ewls and markedly il~c~ren~etl vessel collnts as in carbon tliositlr ilil~alation experiments.

.\s iI1 (~)l~o~lar~- lw:trt clicw+. it III;I~ IN, tll;lt +il~olii~y 1133 (\ift’tbrcllt rffrc?s tlr]wl~(lillg i1~w~1 the clegree of ~in(lerl\-ing ;il.tr~r,iosclerot,ic disease Ijresent. .1nwng patients wit11 stroke. n~an!. ha\-r :lrteriosclerotic heart disease and a significant number die of myocardial infarcts (10,$).

44

The rate of oxygen uptake in the brain is very high, being approximately 5 cc. oxygen/100 g. brain/min. (104). As discussed in the cardiovascular section, if carbon monoxide causes a shift to the left in the oxygen hemoglobin dissociation curve, it ~vould make less oxygen available to the brain tissue. Those people with an arteriosclerotic cerebrovasculature who cannot inc‘rease their cerebral blood flow in response to smoking may therefore more easily tlerelop a state of relative cerebral hypoxia; ;I situation n-ltich could be il factor in the etiology of stroke.

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61

CHAPTER 2

Smoking and Chronic Bronchopulmonary Diseases (Non-Neoplastic)

Contents

Introduction_______------------------------------------- Conclusionsof the 1964 Report----- ____ --___--___--__ Highlights of the 1967 Report------------.--F---------

General Bronchopulmonary Disease Mortality and Morbidity- Population Studies ________ -- ____ -- ________ --___--__-_--_ Relationships to Pulmonary Infection ____ - _ _ _ _ - - _ _ _ - _ _ _ _ _ - - Smoking and Bronchopulmonary Physiology-- - _ _ _ _ - - - _ _ - - - _

Animal and Experimental Studies- _ _ - _ _ _ _ - - _ _ _ _ _ _ _ _ - - - St’udiesin Humans___--------------------------------

Theories Interrelating Cigarette Smoking and Chronic Ob- structive Bronchopulmonary Disease with Pulmonary Hypertension and Cor Pulmonale-----------------------

Summary and Research Suggestions- _ _ _ _ _ _ _ _ _ _ - _ _ _ _ - _ _ _ _ - - Cited References---------- ____ --_-__-- ____ --___---_---~_ Supplemental Bronchopulmonary References- _ - - _ _ _ - - _ _ - - - _

Page 65 65 65 66 66 70 71 71 73

74 76 76 80

63

INTRODUCTION

The primary l)url)ose of tlie 196ri Supplemental Report is to rerie\T the pertinent literature that 1~s become available subsequent, to the 1967 report. Brief mention of the conclusions of the 1964 rel)ort and the highlights of the 1967 report is made to facilitate an understanding of the significance of the irewer inforniation. Tlie ciirrent research findings sl~oiilrl be considered in the perspecti\-e of the resenrcb e\-i- dence previously reported in the 1964 (59) and 1967 (57) reports.

1. Cigarette snioking is the most important of the causes of bronchitis in tlie I-iiited ,States, aiitl increases tlie risk of dying froiu chronic broncb i t i s.

2. A relationship exist.s between pulmonary emphysema and cigarette smoking but. it has not been established that. the relationship is causal. The smoking of cigarettes is associated wit11 an increased risk of ding froiii pu1i~~onnry eml~hyseina.

3. For the bulk of tlie polml:ition of the lYnited States, tlie inrpor- tance. of cigarette smoking as a cause of chronic l~roiicliol~~il~i~o~~ar~ disease is much greater than that of atmospheric pollution or occupational exposures.

4. Cough, sputum production, or the two combined are consistently more frequent. anion g cigarette smokers than among nonsmokers.

5. Cigarette smoking is associ:rt.ed with a reduction in \-entilatory function. ,\niong males, cigarette smokers have :I greater prevalence of breathlessness tlian nonsmokers.

6. Cigarette smoking does not appear to cause asthma. 7. ~Utlioupli death certification shows that cigarette sniokers have

a moderately increasetl risk of tlenth from influenza and l)neumonia, an association of cigaret.te smoking ant1 infections diseases is not otlier- wise substantiated.

~IIGIKIAGIITS OF THE 1967 REPORT (57)

1. Sew data confirm and to some extent st rrngtlicn the coiicliisions of the Surgeon General’s 196-l Report.

%. Cigarette. smoking is tlie most inil)ortairt of the causes of clironicn Iloll-iieol)l:lstic l~~oiiclro~~i~lliioi~:~~~~ tlisewrs iii tile ITnited St:ltes. It greatly illcreases the risk of (l\.liig not only frolii I)otb clironic boll- c:hitisinit also from l~~~lt~lotl:~i~~~en~pl~~seti1:i.

Z. (‘essation of snlokinp is follonwl 1)~ a rwlcictiotl iti niortalit~ from cluonic l~roiicliol~iilnioi~:~~~y tlisease wlilti\Y to tlw mortti1it.v of those who continue to snioke.

65

GEKERAIT, BROSCHOP~JL3IONARY DISEBSE MORTALITY AND MORBIDITY

The 1967 report (57) pointed out the alarming rate of increase in emphysema and/or chronic bronchitis mortality (table l), There were 25,416 deaths from emphysema and/or chronic bronchitis in 1966 which represent a 25 pe.rcent increase over 1964. The increasing death rates for chronic bronchitis and emphysema since 1950 are shown in figure 1. Death rates for these diseases are increasing more rapidly than are the death rates for lung cancer as illustrated in figure 2.

Last year, payments made by the Social Security Administration to men and women totally disabled because of emphysema amounted to about 90 million dollars; this was ‘7 percent of all disability payments, making chronic lung disease second only to heart disease in this regard.

TABLE 1 .-Mortality from emphysema and/or chronic bronchitis: United States, each year 1950-1964

I ISC codes 501, 502. 527.11

Number of deaths

1950-_-e--.m- 1961-e--_-_-- 13, 302 1962_-sm.m-../ 15, 915

1958~~~--~-~-l 1963-~~-~----i 19,443 1959--------- 1964--m-- 20, 208

SOIJBCE: Vital Statistics of the United States, 1950-1964 (58).

Several papers published in the past year reported the results of surveys of pulmonary function and respiratory symptoms in different populations. All of those which were reviewed and which included a comparison of findings between smokers and nonsmokers reported similar observations. In all instances? smokers had respiratory symptoms such as cough, l)hlegm pmcluc-tion , :lnd clyspnca more often than nonsmokers or ex-smokers of the same age and sex. In surveys which included pulmonary function tests, it was found that smokers did not perform as jvell as nonsmokers or ex-smokers. Substantially, these observations confirm those of earlier years without indicating new associations.

66

I I I I I I I I I 1 1952 1954 1956 1958 1960 1962 1964 1966

Year

B’L~~RE l-Death rates for emphysema and chronic bronchitis. United Statw. 1!)~3)Ll!Mi I .irthritica r;cxlr I. SOTJ~CE : National Center for Chronic Disease Control.

L 40

h 6-

4-

0 I 1950

I I 1952 I 1954 I 1956 I 1958 I

1960 1962 4

1964 1966 Year

Fnwa~ 2-Death rates for emphysema and chronic bronchitis and for lung cancer : United States, 1956-1966 (Logarithmic scale). SOURCE : National Center for Chronic Disease Control.

A few specific surveys might be mentioned. Huhti (27) surveyed 1,028 men and v-omen in a rillage in Finland. Sane of the women smoked. In men the one-second forced espiratory volume. (FEY,.,) and the peak expiratory flow (PEF) were significantly lower among those men who smoked 15 or more cigarettes a day than those ITho smoked less or not at all. So difference in forced rital capacity (FTC) was observed.

Eclelmnn, et al. (2.i) studied 410 men and found lower values of FIXw,, FVC, and maximal rollmtary \-cntilntiow an~ong csllrrent smokers tllan nnlollg nonsn1okers. Tlley also reported an inverse relationship between the nunlber of cigarettes smoked and pulmonary function.

Stanek, et al. (:7-i ) noted a definite assocint ion between chronic cough and phlegm prodnc*tion (chronic bronchitis) and cigarette smoking among :I rantlonl sample of 44.3 men wrl-eyed in Prague. Freour, et al. (.?I) in I<ortlenl~x :lIs;;o rel~orte~l a ni11cI1 greater frequency of s;!-ltiptoms of chronic bronchitis among smokers than nonsmokers in a preliminary report based on 1,055 examinations.

Higgins and his a.ssocintes ($5) reported obwrrations from a nine ye.ar followup study of men in an industrial t,owi in En,rrlnnd. -lmong the 385 men who were age 53-64 at the st,nrt. of the study, nlortality during the nine years was twice as high for smokers as nonsmokers. Ex-smokers had the same mortality experience a~ nonsmokers. ,1mong the survirors of all ages who were teste,cl initially and nine years later, the arerage decline in lung function as measured I)\- the FETTr, was smallest in nonsmokers, slightly greater in ex-smokers, and gren,test in smokers. The findings suggested that smoking was a more important factor than occupation in respiratory disability.

Industrial air pollution studies hare been performed by Lowe (JZ) using a population of steelworkers at Ebbw Yale and Port Tnlbot, with smoking and chronic bronchitis dat.a presentecl in a subsequent, publication (31). It was noted that for each age group, c.hronic, bronchit,is was about three times more prevalent amon g men ~110 smoked 25 or more cigarettes per clay, than among those who had never smoked. Cigarette smokers appear to be more adversely affected by lmlnlonary exposure to dusts at work than the nonsmokers. The. authors pointed out tha.t st,udies to evaluate the interaction between smoking and industrial air pollution require occupational subgroups large enough t.o permit standardizat.ion for both age and smoking habits. In tllis way, the interaction between smoking and ot.her air pollut,ants cwi be am- lyzed more definitively.

Most surveys hare been of ad&s, but. Holland, et. al. (,$%) reported the findings of an investigation of smoking and reripiratory symptoms among more than 10,000 school children, age eleven or more, in Eng- land. The survey was conducted in 1965 and repeated in 1966. Ciga-

69

rette smoke.rs (at least one cigarette per week) more fvuently report&l symp,toms of cough and phlegm production than nonsmokers and the prwalence of symptoms increased with increases in the aanount smoked. Children who smoked one year but did not smoke in t,he subsequent year had a lower frequency of symptoms in the second year.

The relationship between smoking and pulmonary infection is un- clear. It, is e.rident that ciga.rette smoking is a ma.jor cause of chronic bronchitis. Much of the symptomatolo,T of chronic bronchitis of smokers, partic.ulnrly cigaret.te smokers, results from the harmful effects of inhaled tobacco smoke on t.he bronchia. ciliary a,pparatus and the mucous glands. These effects tend to impair mucous rwnoval from the bronchial and bronchiolar airwa.ys and possibly may, in turn, increase susceptibility to pulmonary infections.

In a study of 191 boys, age l-2 t.o 19, in a prepara.tory school, the incidence of all respiratory illness over a one-yea,r period was posi- t.ively correlated with smoking habits within each age group. “Severe” (purulent, sputum) lower respiratory tract illnesses were nine times more frequent in regular smokers than nonsmokers (age- adjusted) (2.4).

A4 study in Cairo of t,lle relation between smoking and infection and appearance of mucous gland hypertrophy in the main bronchi was reported by Megalled and his colleagues (34). They studied 50 men with c,hronic bronchitis and found sul~stnntially more n~ucous gland hypertrophy among the iR smokers than the 7 nonsmokers. This hypertrophy seemed unrelated to the presence of potential pathogenic orga- nisms isolated from a single bronchial lavage, although the authors believed that infection might have an initiating or potentiat,ing effect.

Fletcher (17) studied the relationship between frequency of Espira- tory illness as measured by sputum purulence and histories of “chest illnesses” a.nd “chest, colds” and the rate of decline of FEY in slightly more than 900 men who were followed at least four years. He concludes that il1ncsse.s and sputum purnlence have no significant eflect on FEV regression. (This study will be discussed again later in this chapter).

It, appears t.hat, in patients with chronic obst,ructive bronchopulmonary disease c.aused by cigarette smoking or other pulmonary irri- t,ants, superimposed infections may cause exa.cerbations of the c.hronic tlisease process. Them is no s~~l>st;\l~tii~l e\-itlenre that infed ions per se cause much of the chronic obstructive l~~~o~iclio~~ulmon:~r~ disr:we seen in cigalxtte smokers.

Wynder (63) reported that the hyperplnst~ic and met.al)last,ic effects of Swine influenza virus could not, be enhanced by subsequent e.xposure

70

of mice to cigarette smoke. Previous literature indicates that the se- quence of events may be of some importance, since there have been reports that cigarette smoke incream t,he bronc.hial epit.helial reaction to influenza virus. Spurgash (53) reported that pre-exposure to cigar&e smoke did not, hare any significant etfect on resistance of mice. to subsequent influenza virus infection inoculated by aerosol inhalation. But, the subsequent e,sposure of pre-infected mice to cigarette smoke resulted in significantly higher mortality rates, thus suggesting that cigaret,te smoke can aggravate a.n existing respiratory viral infection. Ho\Tever, smoke-expwd mice subsequently challe.nged with ces- tain ba.cteria, KlebnieUn pwwwaine or Diplococc~ts pneunzoniae, also exhibited a decreased resistance to respiratory infection as shown by a decreased survival t.ime and a higher mortality (53).

The tobacco plant can be diseased by a variet.y of fungi (3). Of these the AZterndu species and Aspergillus niger, were recent.ly shown to increase the toxicity of cigar&e smoke (20). Mice exposed to smoke from hay previously inoculated with AZtwnnrin. or ,4spergillw~ niger. showed progrmsire pulmonary congestion, edema and tissue destruction confirmed by autopsy. Those mice in a hay-smoke control group were normal clinically and showed only chronic, pulmonary inflammation on autopsy.

SMOKING AND BROXCHOPULMONARY PHYSIOLOGY

ANIMAL AND EXPEFSMEXTAL STUDIES

The ciliatoxic effects of cigaret.te smoke were presented in the 196J (59) and 1967 Reports (57). Discussants in a recent symposium (29)) pointed out that both volatile a.nd particulate c.ompone.nt.s of cigarette smoke can adversely affect ciliary activit.y. In short-term in V~WO experiments, Dalhamn (II) showed t.hat the ciliostatic effect of cigarette smoke was direcly related to the “tar” content if the gas phase was held constant.

Rylander (&) reported that in guinea pigs exposed to cigarette smoke, the reduction of killed, radioactive bacteria was lower than in c,ontrols, presumably due to a decrease in mucus flow. There was no significant difference in reduction of viable bact,eria.

,4 study by Dalhamn, et al. (10) suggests that lack of oxygen in the external environmental in vitro can reduce ciliary act,ivity. The main problem in the evaluation of studies related to ciliary activity is to determine to what, extent the in vitro studies can relate to the in viva st,udies in animals and in man. For instance, the ciliatoxic effects of hydrogen cyanide in cigarette smoke were dose-related in experiments on clam gills in w&o, but the same results could not be reproduced with in viva experiments in cats (22). Volatile (gas phase) components have bee.11 shown to be retained to a large extent by met surfaces (as)>

315-1310-66-6 71

which raises the question of how much of the volatile ciliatoxic agents in cigarette smoke entering the moist oral cavity actually enter the lower respiratory tract.

Davis, et al. (1.3) in experiments with respiratory irritants including cigarette smoke in guinea pigs, have. implicated the nasopharynx and larynx as sources of receptor stimulation leading to increased upper airway resistance, and decreases in respiration rate and minute volume. These effects were not present when a tracheostomy was performed to bypass the smoke directly into the trachea. However, Guillerm ($3) noted increased airway resistance and decreased compliance in the tracheotomized and spinal guinea pig after smoke inhalation.

-1viado and his co-workers ( 2. 3. 4, 19> 38. 45, 46, 47, 48) have continued their studies on bronchoconstriction and bronchodilation in animals and recently have further investigated the role of histamine in a study of inhibitors for histamine decarboxylase in rabbits, dogs, and cats (39). These species have variations in response to cigarette smoking as previously noted. Cats hare a uniphasic bronchoconstrictor response to inhaled cigarette smoke (somewhat like man’s) and dogs hnve a biphasic response. Rabbits were observed to behave differently than rats or dogs. Histamine has been implicated as mediating part of the bronchoconstrictire effect of cigarette smoke. The rabbit. does not respond to histamine by bronchoconstriction. This study (.X9) suggests that the rabbit lacks a histamine sensitive system in the airways, in contrast to cats and dogs. -Upha-hydrazino histidine, which inhibits the enzyme histamine drcnrbosylnse, was demonstrated to prevent much of the bronrhocollstri~tive effect in cats and dogs. By analogy, this suggests the possibility that histamine may mediate some of t,he l~ronclioconstricti\-fs respowe to inhaled tobacco smoke noted in htmians. Pretreatment I\-ith atropine has been shown to block the bronchoconst ricat ion caused by cigarette smoke (36) and by histamine inhalation in humans (7, 8, :Z).

There is experimental evidence (48) in dogs, that the pulmonary exposure to illhaled cigarette smoke or injected nicotine can result in pulmonary ~-;lsocollstric~tion, causing increased pulmonary arterial pressure. This effect is thought to be due to histamine relensc from lung tissue (48). -1utops.v studies in humans, by .~uerbnch (I), showrd considerably greater fibrous thickening of the arterioles and sn~nll artcries in smokers? ownrring not, only in the lungs, but other organs as well. The degree of fibrous thickening increasecl with age and the arnollnt of cigarette smoking.

Participants in il recent international symposium on the mechanism of eli&ation of deposited particles from the lungs (15), discussed the relationships among alveolar surfactant, alveolar macrophages, the alveolar transport mechanisms, and the mucocilinry apparatus ; wlii~ll may also relate to the pathoetiology of pulmonary emphysema.

72

Giammona (22) reports that cigarette smoke consistently lowers the maximal surface tension without altering the minimal surface tension of lung extracts after in vitro exposure to cigarette smoke. In ,viz*o changes were noted in guinea pigs, but not in dogs or cats, which he thou&t may hare been due to insufficient exposure. -4dditional information concerning surfactnnt has been discussed by Sekulic, et al. (@, 50). Meager, et al, (63) have reported that cigaret.te smoke has a depressant effect on protein synthesis of human alveolar cells in vitro.

STITDIES m HUMANS

Fletcher (17) in the study mentioned earlier in this chapter, correlated the rate of decline of FRY in over 900 mm followed for at least four years, with respect to starting FET’, cigarette smoking, sputum purulence, and histories of respiratory infections. He tested FEV’s in response to the acute effect of smoking cigarettes, and found that the mean regression of FEV in those subjects who had a higher preralcnce of cough and sputum was not significantly different from those with a lower prevalence. The men with higher initial standardized levels of FEY had less steep regressions than those with lower levels. Cigarette smoking had a significant effect on decline of FE\‘. Sputum eosinophilia was also related but apparently to a lesser degree, and Fletcher stated that there was no confirmation of the possible role of tobacco allergy in chronic obstructive bronc.hitis. With regard to the decline in FEV, more information on controls and on the quantity of cigarettes usually smoked would be helpful. While contributing important information, this study does not fully describe the pro- gression of declining FEV in cigarette smokers in relat.ion to the quantity that they smoked before and over the time-period studied. In a detailed study of 58 bronchitics (W of whom had positive smoking histories) Simonsson (51) found a positive correlation between the de.gree of obstructive stiLtus and the react.ivity to espowre to nebulized acet,ylcholine ; and noted that a larger decrease in airflow seems to occur in previously obstructed airways than in normal ones.

Peterson (Q) studies pulmonary function in a group of 12 individuals who had stopped cigarette, smoking for 18 months, and com- l)aretl their pulmonary function test before and after cessation. These individuals shokved signific:Rnt impro\-ements in their pulmonary func- tions as measured by timed vital c.apacity and expiratory flow rates. Ex-smokers reported a clecrease in cough and breat,hlessness after cessation of smoking. (This study confirms the findings of Krumholz reported in the 196’7 report). The mean FEV of Peterson’s ex-smokers was markedly greater than that observed in anotl1e.r group of individuals who had continued to smoke cigaret.tes during the same 18 month period, me.asure.d at the same time intervals.

73

Wilhelmsen (SO) found in a small study of 16 persons who had smoked over 10 cigarettes a day for a mean of 25 years that cessation of cigarette smoking for an average of 40 days was accompanied by a marked decrease of sputum production, coughing and wheezing, and a significant. increase in FEV1.

Bates (5,6) has reviewed the reliability and constancy of pulmonary function tests. He notes the importance of making ,pathological diag- n0se.s with lungs inflated at autopsy. Morphologic considerations of e~mphysema are correlated with functiona. abnorma1itie.s and current. biochemical research. He discusses derangement of pulmonary ventilation-perfusion distribution in relation to bronchial and/or alveolar damage from cigarette smoking with c.onsequent stresses on right ventricular fun&on. He emphasizes the fact. that obstructive bronchitis appears to lead more frequently to right heart. failure than does “pure” emphysema.

Although instances of “pure” emphysema or “pure” bronchitis exist, most patients with respiratory obstruction appear to have bot.h emphysema and bronchitis. Bat.es suggests the theory that one of cigarette smoking’s harmful effects may be destruction of bronchiolar st.ruc,ture. This could lead to disturbed vent.ilat,ion-perfusion (V/Q) relationships. As enough lung tissue breaks down, c.ausing centrilob- ular emphysema, there is impairment. of gas equilibration within the cent,rilobular spaces. Increasing derangement, of the V/Q distribution in turn can lead to hgpercapnia and hypoxemia. Clinically, what may seem to be respiratory decompensntion, may act.ually be incipient cardiopulmonarv decompensation due to the deranged V/Q and gas imbalance resulting from the obstructive bronchiolitis.

Postural h~posemia has also bee,n noted (55) in young asymptomatic cigarette smokers with no evidence, of chronic lung disease when in the supine position as compared with nonsmoking controls.

THEOR.IES ISTERREL-%TIXG CIGARETTE SMOK- IK’G AXD CHROSIC ORSTR17CTIVE RRONCHO- PI-LMOS*i\RT DISEASE WITH PI’LMONARY IITPERTESSIOS A9D COR P‘C-LMONALE

Hypercnpnin and hypoxemia are capable of causing pulmonary vasoconstriction with a result.ant increase in pulmonnry arte.rial pressure ancl right ventricular work. Stuart-Harris, in a review article (X), relates these phenomena to the clinical picture of pulmonary hypertension and right heart. failure seen in patients with pulmonary insufficiency caused by chronic obstructive bronchitis. Since the pathologic changes in the small pulmonary vessels are not’ usually as seve,re as those found in congenital heart disease, it is believed that the pulmonary hypertension seen in chronic. obstructive lung disease is of the \.asOcOiistri(‘ti\-e type . hlthongh most ljatients with severe chronic

74

bronc.lii#tis hare some emphysema, it is the airway obstruction of chronic bronchitis which may relate. most strongly to the development. of car pulmonale. It is now apparent that. car pulmonale can be a sequel to severe obstructive bronchitis without emphysematous changes (9,17, 35,37). Studies (16, 18,433) indicate that patients with hyper- c’nlmix mid hyl)oxemia due to abnormal ~nilmonar~ ventilation- l)erfusion relationships are likely t.o de\-elop cardiac complications. As inc1icnte.d in the preceding section of this report, recent studies (JO, 41? 43) have demonstrated the presence of ventilation-perfusion imbalances in patients with chronic bronchitis-the extent of imbalances being related to the severity of bronchitic process. Penman, et, al. (41) determined tile gas tensions in expired air and arterial blood and used them t,o calculate the alveolar clead space and alveolar blood shunt, 1)eimittinp estimation of tJiree theoretic;~l “c~oml”l~‘tnients” of the lung : (1) 1’entilated but unperfusetl (alveolar &ad space) “com- lwtment,” ( 2) unventila.ted perfused (alreolar blood shunt) “corn- partment” and (3) “normal” ventilated perfused “compartment.” (‘hronic. bronc,hitics were found to llave :~lmorn~nlities of ventilation and perfusion with a marked reduction in the “normal’? “compartment .*’ In patients Tvitll decompensnted (‘or pulmonale, further studies of the correlations between cardiac output, arterial oxygen tension, and arterial carbon dioxide tension nit.11 the above “compnrt.me~lts” lead Penman, et. al. (42) to believe t,hnt in cases of decom’pensated car pulmonale a considerable fraction of the cardiac out’lmt, is shunted wit,hout exposure to aerated alveoli.

It. was further 1lypothesize.d that tllis increased shLmting of blood through non-aerated regions of lung would result in increasing hyposemia and hylwrcapnia with consequent furt,her constriction of the pulmonary \-nsculafure and further encroac.hment of the alveolar dead spac,e capon the normally ventilated and perfused lung. X’illiams, et al. (61) in determining the acute. effects of cigarette smoking, found an inc.rease in the “alveolar dead space” in 11 patients with obstruotire airway disease. They postulate this to be due to “the effect of nicotine on the vasculaturwof the lung in this group of ptiellt,S.”

Since pUlIllOll~i1~~ vasoconstridion will also increase the pulmonary arterial ljressure ant1 right ventricular work, it may also lead to right. ventricular failure and the. classic picture of car pulmonale. The beneficial effects of c.orrec.ting (to the extwt that this is po&ble) the ventilatory problems in these patient,s is well hiown, and it is thoughts that the basis of the improvement is the correction of t.he hypoxemia ant1 llypercapnin which allows a reversal of the pulmonary \-asocollstriction, thereby permitt.inp better perfusion of untlerper- fused arezls and also decwasing the Aworkload of the right ventricle. Stuart-Harris also pointed out that the relief of myocardial anoxia with a.I~l3rOpI‘iate therapy may lielp the riglit ventricle recompensate.

75

T,ong-term continuous oxygen therapy in hypoxemic patients with chronic airwy ol&ruct.ion has been noted to have a beneficial effect of reducing pulmonary arteriolsar resistawe (30) .

It, is lwrtinent to note at this point that there is a developing body of experimental evidence discussed in previous Reports and in this c1mpte.r t.hnt cigarette smoking may have acute delet-erious effe&s on airway re.sistnnce and pulnlonnr~ vasoconstrictiSon which can be espe- Aally hnrmful t.o the patient whose pulmonary funct,ion is already compromised. The disordered pulmonary ventilation-perfusion relationships and pulmonary hypertension found in some patients with severe chronic bronchitis can only be lvorsened by further broncho- nonst,riction and possibly by pulmonary vasoconstriction caused by continued cigarette smoking. These. can enhance cardiopulmonary dccompcnsation and lead to heart failure from car pulmonale.

Further research is necessary to clarify more precisely t.he inter- re.lationships between the disturbances of veiltilatioll-~rfusion clawed by chronic obstriicti\-e ~~ro~ic~l~ropi~li~io~i~~~~y disexses ant1 cwtlio\-ascular abnorn~nlities as they relate to cigaret,te smoking.

SIXMARY A\NT) RESJLIRCH SGGGESTTONS

AIc~dit.ion:~l evidence compiled since 1967 c,onfirms previous positive fintlinm and estends our knowledge about, some of the. effec,ts of cipnre,tte smoking on pulmon:lr;v function. There has been furthe.r clnrific~;ltion of some of tlw illt.err~lntionships between chronic obstruc- tire broncllitis n11d ;ltl\-t:rae carcliopulmon;~ry cffe.ct.s indioaling that pulmon:~r;v hJ.pertrtlsion ant1 (*or pulrnon:~le map result from the more se,vere fornls of vltronic ol)strllvtive l)rollc,llopnmonnry disease. Smok- ing is :I tlwjor cxure of clironic~ l~roncliopnlmonnr~ disease and in wlditioii nr:l\- 11:11-r pnrt.iculnrly harmful c~nrdiopulmorrary e.ffects in t,liose lwtieiits wit11 severe chronic ol)structi\-e lwoncliitis.

Researc~h suqcst iow : ( 1) I,oilg-trrni followup studies on clinrqes in pultnou:~ry fllwt ion aurollg wnt iuning ci,rlrettc smokers as compared to those ~-110 11:1rr WI-PI* wloketl viqltvttrs and those who have discon- tinrietl cnig:nrrtte 5nlokiug. (2) T~oi~gilritliu:~l studies of relxtive.ly young I)eol)le l~rior to the initiation of snwkinp in order to conll)are pulmo- 11ary fulwtion heforv :\ntl after the taking up of smoking.

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76

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(2f) FREN-R, P., C~~-DR~Y, P., RO~YSSEI.. .4., SERIRF,. A. Les bronchites chroniques et l’insuffisancr rrspiratorie dans l’agglomeration de Bordeaux. Journal de Jledecine de Bordeaux l-%3( 2) : 18651879, December 1966.

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Si3. SIMON. G. R:ltliolopy and vmphywmx (‘linic.al Radiolog 1.7 : XC%-306, October 1964.

ST-L S~~osssos. R. G. Clinic:\1 xnd physiological studies on chronic bronchitis. I. (‘linicxl tlt*5c,rilltion of thcb pntirnt mntrri:~l. .\ct;l ~~llt~rgologirn 20 (4) : 257-300, 19G.

84

577. STANESCU, D. C., PILOT, L., GAVRILESCU, N., TECULESCU, D. B., CRITESCU, I. Aspects of pulmonary mechanics in arc welders siderosis. British Jour- nal of Industrial Medicine 24(2) : 143-147, April 1967.

S78. STERLISG, G. M. Mechanism of bronchoconstriction rawed b.r cigarette smoking. British Medical Journal 3 : XT-277. July 29, l!MX.

RTR. STRIEDER, D. d., RAZE&II, H. Effect of body position on the alveolar-arterial PO* difference in smokers. Clinical Research 16(2) : 474, April 1968.

SSO. STRIEDER, D. J., MURPIIY, R., KAZEMI. H. Hyposemia in as;vmgtomatic smokers. Clinical Research 16(2) : 376, April 1968.

SRI. SCKT~~IALCIIASTRA, T.. \VII,LIAMS, 31. H., Jr. Serial studire of pulmtmarr function in patients with chronic obstructive pulmonary disease. Ameri- can Journal of Medicine 39 (12) : 941-945, December 1965.

8x”. R~TIsEs, 8.. (‘IIRISTDFOKII~IR. A. a.. Kr.x-nor. (:. A., ~‘R~TT. 1’. (‘. Rlwnt,wno- logic criteria for the recognition of nonqmptomatica pulmonary emphysema : Correlation between roentaenologic findings and l~ulnionary pathology, American Review of Respiratorg Diseases 91 : 69-76, 196.5.

SM. TALAMO, R. C., BLESSERIIASSETT. J. R., AVSTES, K. F. Current concepts: Familial emI)hysrma and hlI)l~:ll-.~lltir~I)sill tlefic~irnc~~. Sew England Journal of JIrdicine 27.51 Z3 1 : 1301-130~. I)wember X. 19%

SR4. THCRLRECR. 1%‘. >I., ASGUS. G. E. The variation of Reid index measurements within the major bronc*hial tree. .%mcrican Review of Rrspirator~ Diseases 95 (4) : 551-555, April 1967.

SK.Ti. Trsr. G., WOLFE. IV.. FAILAT. I<., S.UXL .I. I<olv rbf Oi nncl (‘( b1 in rt~v+?rt;al of changes in mechanical properties of the lung follolvinF: lmlmonnr~ ra.wular owlusion. Clinical Research lB(2) : 376. April lM8.

S86. TOYANEK, A., FISER. F. Rronchoskopicke nalrz~ II kuraku. Rozhledr v Tuberknltrse a v Semwech 1’licnic.h 2i ( 10) : 6X7-U!).;, 19%.

S87. WALSHE. M. hr., HAYES, J. A. Respiratory symptoms and smoking habits in Jamaica. American Review of Respirat0r.v Diseases M( 4) : 640-644, October 1967.

SW. ZANEI., S., Tor~ss~.~. H. H., I’MME. F. J, .\irway resistanc,e ;rlld lwak e’s- piratop flow-rate in smokers and non-smokers. Lwcet 1 (i293) : 1237- 1238, June 8,196.X

SX!h ZE~BEHC.. I,. I)., 110~~0~. R. .J. >I.. I,aso.\r-. 11. The Sashrille Air I’o1111- tion Studs. V. Mortality from diseases of the respiratory system in relation to air pollution. Archives of Environmental Health 15(Z) : 214 224, August 1967.

S90. ZWI, S., SLUIS-CREMER, G. K., Du PREEZ, I,. -4 survey of pulmonary function in male office workers. Medical Proceedings 13( 23) : 369-554, So- vember 11, 1967.

85

CHAPTER 3

Smoking and Cancer Contents

Introduction_-__--______-________________-___-___-_-__- Conclusions of the 1964 Report- - _ _ - _ _ _ _ - _ _ _ - - _ _ _ _ - _ - Highlights of the 1967 Report_--_--__---___----------

General Aspects of Carcinogenesis-____~-___--___--__------ N-Nitrosamines_--_~-------____---_~---_---__---__-~ Polonium-210_-------____________________--~--~~-~~ Selenium---___---_-----~--.____~-__~--___~-__~----- Tobacco Pesticides and Growth Inhibitors- - - _ _ _ - - - - - Possible Fungal Contamination of Tobacco - _ _ - - _ _ - - - - -

Experimental Aspects of Carcinogenesis- - - - - - - - - _ - - - _ _ Passive Inhalation of Tobacco Smoke- - - - - _ - - - - _ - - - _ Active Inhalation of Tobacco Smoke- _ _ _ _ _ - - - - _ - - - _ _ - -

I~ungCancer--__-__--__----__--___---_---_----__--___-~ Illortality-__-__~-_----_--_-__--------_---~__- ______ Retrospect’ive Studies ______ -_----_--~__- _____ ~__~___ Prospective Studies- _______ -__--------~----__--_____ Lung Cancer Relat#ionships in Women- _ - - _ _ - - - - - _ - - - - Additional Considerations and Conclusions_ _ - - - - - - - - _

Cancer of the Oral Cavity____--__-_~--_--_-_---~_----_-- Cancer of the Larynx-_---~__-_---~---~---------~~-~~~~~~ Cancer of the Esophagus---~_-_~~-_~~--________________ Cancer of the Pancreas ______ -~---~-~--~----_--~__-~ _____ Genito-urinary Cancer__----_-_~--~~---_______________

Cancerof theBladder------__~ __.____ ~-_~--__---~_-- Cancer of the Kidney ________ -------------___- ______

Cited References-__-------____________________~.~~~~~ Supplemental Cancer References-_-~--~__--~_________

Page 89 89 90 90 91 92 92 92 92 93 93 93 94 94 94 96 97 97 99

101 102 103 104 104 105 106 112

87

INTRODUCTIOS

The pri.mary purpose of the 1968 Supl~lemental Report is t.o re\-ien the pertinent literature that has become a\-ailable subsequent to the 1967 Report. Brief mention of the, conclusions of the lS6-f Report and the hiph1ight.s of the 1967 Report is made to facilitate an understanding of the significance of the most recent information.

The current, research findings should beg considered in the perspec- t,ive of the B?Sf2i\ITll cGtlencr previoiisly reported in tlw lS64 ($1) and lSG7 (92) Reports.

1. Cigarette smoking is causally related to lung cancer in men: t,he magnitude of the effect, of cigarette smoking far outweighs all other factors. The data for n-omen, though less estensive, point in t,he same direction.

2. The risk of developing lung cancer increases wit,h duration of smoking and the number of cigarettes smoked per day, and is dimin- ished by discontinuing smoking.

.3. Tie risk of developing cancer of the lung for the combine41 group of pipe smokers, cigar smokers, and pipe and cigar smokers is pwater than for nonsmokers. but much less than for cigarette smokers. The data are insufficient. to warrant a conclusion for each group individually. Ornl Cancfv

1. The causal relationship of the smoking of pipes to the development of cancer of the lip appears to be est.nblished.

2. Although there are suggestions of relationships between cancer of other specific sites of the oral cavity and the several forms of tobaxo use, their causal implications cannot at prese.nt be stated. Laryngeal Cancer

E~aluntion of the evitlrncc Icads to ilp ,jutlpnwilt thilt, c*iprrtte smoking is a significant factor in. the causation of laryngeal cancer in the male. Esoplbag~al Guncc7~

The evidence on the tobacco-esol)ha~eal cancer relatlonshlp supports the belief tilat an association exists. However, the dat,a are not adequate to decide nliet.her the relationship is c.nnsa,l. i’unciv of Urin.ary B?ad&r

Xvailable data suggest an association bet.ween cigarette smoking and urinary bladder cancer in the male but, are not sufficient to support, judgment on the causal significance of ‘this a.ssoc,int.ion.

89

So relationship ha.s been established bet,ween tobacco use and stomach cancer.

HIGHLIGHTS OF TITE 19S7 REPORT (92)

1. -\ditional epidemiological, pathological, and experime.ntal data uot, onlv confirm the conclusions of the Surgeon Gneral’s 1964 Repovt regartlicq lung cancer iii men l)llt stwngthen the causal relationship of smoking to lung cancer in women.

2. Cessation of cigarette smoking sharply reduces the risk of dying from lung cancer rrlatiw to the risk of those who c.ontinue,.

R. ,1lthough additional experimental studies substantiate previous experimental data, ntltlitiou:~l resenrc9~ is needed to specify the tumor- initiating and tnmor-l)ro”‘otiil,v agents in tobacco smoke and to elucidate the basic mechanisms of t.he pathogenesis of lung cancer. La~ryngca7 Can.rc,

The. conclusion of the Surgeon General’s 1964 Repent that cigarette wiokinp is a. siqlificallt factor in the causation of laryllgeal cancer iu the male is supported 1)~ additional e.piclemiological evidence. Other Cancer8

Additional evidence supports the conclusions of t,he Surgeon Gen- eral’s 1964 Report and indicates a strong association between various forms of smoking and cancers of the bucal cavity, pharynx, and esophagus. In tlic absriic~~ of f1irthe.r information concerning the interaction of smoking Stli other facto15 known or snspectacl as causative agents, further cowlasiolls canntrt be made at this time, although a causative relntionsliip seems likely.

Aidditionnl [,I’itlt~nliolopical? clinical, and experimental data strengthen the asswint ion between cigarette smoking and cancer of the urinary bl:~dtlcr~ but the presently :~vailnble data are insufficient, to infer that the relationship is causal.

Since the IN7 report. recent nclrances iii the tobacco chemistry field were revieIved in Tao articles (65,8.%‘). The chnracteriza,tion of tobacco smoke by gas chronlntc~~ral,hv and digital comp\~ter opened a new areniie for the csploratiol 1 of tobacco smoke. Thr first. preliminary data indicate the l)resence of several thousands of compounds in to- I);~tw sn10ke. ‘I‘lli 1i111i11wi~ f:ti. rswcds thil 700-x00 compounds presently identified ($3).

The 1067 Reljort discuswd the major concepts of experimental tobacco carcinogensis. Al recent nlo~lo~rapl~ 1,~ n’ynder and Hoffmann (10-j) tlioroiiglilv describes and :~nnl~zes experimental carcinogencsis as it relates to tobacco and tobarco smoking. The reduction of tumorigenicity is of particular concwn. This can be accomplished by : (1) iwluc’t ioii of total “tar” wnteut, and (2) reduction of specific tuniori-

90

genie agents. It has been well established that experimental tumor production is close-related to the amount of “tar’* in cigarette smoke condensate (7). The a.mount of “tar!’ yield varies with parameters xwh as: (1) type of tobacco, (2’) curiiqg and l~iwccssing. and (3) filtration. It, has been demonstrated that by selecting. curing and blending as we.11 as by using specific filter mx~terials and cigarette pal)erl one can significantly reduce the “tar” yield of mainstream cigarette smoke (39: 83,88).

Over the, past. 15 years there, has been a general decrease in the amount of ‘%ar” and nicot.inc content of cigarettes (97. 1O.j). One. reason probably is the decreased nicotine ant1 ?ar” content in the “lighter” tobaccos now being grown . ,Inotlier is the increased public de.mand for “filtered” cigarettes.

Increased nitrate content of tol)ncco and the addition of nitrate to cigarettes has been reported t.o reduce the tumor yield in cslwriniental animals ( 10-i). kSniokc from air-curccl tol~~cco is less tumorigrnic than flue or sun-cured tobacco (,W. I0.j ) and cigarettes using more sheets and st.ems rather than whole leaf have been shonn to be less tumori- genie (64,104).

Also, more porous cigarette palmer (TO), and the atldition of nitrate, citrate, or phosphate to cigarette pper increases tlw burning rate of the cigarette, t.hereby lowering the number of p11tl.5 taken l)er itnit of cigarette (104).

Filtration \Till decrease the total “tar” yield ((il. 67. 96. 104). but except for the phenolic component, conunerical filters do not, selec- tively filter specific carcinogenic components from the “tar”.

It has been shown that. “tars” of tobacco extracts have increasing carcinogenic proper&s in direct, relationship to the. teml)erature of pyrolysis (lU.$) .

It is important to note that tobacco extract itself contains relatively high amounts of tumor promot,ers. The tumor promoting activity of tobacco extracts is of the same magnitude as thnt of tobacco smoke condensate (104) but so far no clear tumoripcnic relationship is evident between them (6).

Despit,e recent publications on the presence. of N-nitrosamines in tobacco (76) a.nd cigarette smoke (55)) the l)resent el.idcnce must be regarded as insufficient. because of the high lnobnbility that this is arti- fact,ual (66). The studies described so far hare failed to identify these a.gent.s in fresh tobacco smoke ($5. C6). However, since sercral of the N-nitrosamines are strong carcinogens (58) and tobacco smoke con tains several dozen secondary amines and oxides of nitrogen which may be precursors for nit,rosnmines (6~. 76. 80, I&T), tobacco smoke should be regarded as a potential source of S-nitrosamines.

91

POLONIUM-210

Kew data. on polonium-210 in t,obacco leaf and cigarette smoke have originated from various countries (8: 13,26,.%‘7, ~38~ 51: 52,68,89). The polonium-210 values vary between l-50 picocuries per 1.0 g. tobacco; 3-50 percent of it is recovera.ble, in the mainstream smoke of cigaret.tcs without filter tips, Using speci~al filter material, up to 90 percent of the polonium-210 can be filtered out of the mainstream smoke (8). One major source for polonium-210 in tobacco was reported to be phosphate fertilizer (89). Analyses of human tissues demonstrated that. lung, blood, and liver of smokers contain higher concentrat.ions of polonium-210 than t.he corresponding organs of nonsmokers (B7,@, 41. 57. 68). Rajewsky et. al. (68)estimate a daily polonium-210 inhalation rate of 2 picocuries for a. smoker of 20 cigarettes per clay. Their autopsy studies indicate an alpha dose exposure for the basal cells of the subsegmental and twminal bronchi of 41 mrem and 79 mrem per year, respectively, in smokers of 20 cigarettes per day. In view of the fact, that, Jacobi (44) calculated a dose rate in these same basal cells of l-2 rem per year from the deca.y of naturally occuring radon and thoron in the air, Rajewsky, et al. (68) consider it. unlikely that cancer is caused by the inhalation of polonium-210, in tobacco smoke. In a review of the role of radioactive substances on the effect of smoking, Casarett, was of a similar opinion (Id).

SELENIUM

At, present, there is still no substantial evidence implicating selenium as a respiratory carcinogen, although this is still somewhat disputed (29,lUO. 101).

Tor~\c:co PESTICIDES AM GROWTH INHIBITORS

The most widely used sucker growth inhibitor is maleic hydrazide. This agent was recently reported-to be carcinogenic (25). Tobacco leaf and ciyare.ttc smoke are known to contain organic pesticides (32, 104). The first identified carcinogenic pesticide in tobacco and cigarette smoke is l,l-dichloro-2- (o-chlorophenyl) -2- (p-cholorophenyl) ethane (o,p’-DDD) ($3. X), whicli is it technical by-1)roduct of the commer- cial insecticide p,p’-DDD. At present there is no known evidence of chlorinated insecticides contributing to tobacco carcinogenesis.

POSSIBLE FUNGAL CONTAMINATION OF TOBACCO

The mold Aspergi77aus fEnz*us is knownto synthesize the carcinogens of the afla.toxin group (17). However, a recent. investigation reported

92

the absence of these agents in tobacco and cigarette smoke (9U). h’ever- tIleless, further studies are indicated to evaluate the possibility that, some tobaccos may be contaminated with carcinogens produced by fungi.

EXPERIMENTAT, ASPECTS OF CARCIKOGENESIS

PASSIYE INIT.UATIOK OF TOBACCO SNOHE

In attempting to reproduce lung cancer in experimental animals, the limitations of presently arailnblc bioassnys? mninl~ passive inhalation studies, I~:I.IY I)ew cliwlssctl in tllv pre\.ious Rel)orts (91. 92). T,argc scale studies in whirl1 :I variety of animals have been exposed to the passi\-e inhnlntion of tobnccw smoke have essentially failed in producing squan~oas ccl1 cancer of the lung (204).

The dificultics wit11 I)assive illh;llation studies ill animals relate in part to the tosivity of (‘ill’l)Oll nlonositlc and nicwtine. The defensive “filtri~tiOl1” cnpal)ilities of the nasal l)nssngc5 alId the epithelium of the 1lpJm respirator? tract, necessitate rclntively higIl exposure kdSy

which in the case of tobacco smoke cannot adequately be accomplished by passive inhalation methodologies.

Some laboratory studies failed to produce squamous cell cancer in (‘5’7 black mice even though some of the animals were previously inoc.ulated wit.h Swine influenza virus (10(i). Harris and Srgroni (&), in experiments with C57 black mice, some of which were inoculated with viruses, achic\-ed sonic enlJ:~JJcenleJl~ of i ldCllO~RI’CiJ10JJl~l~ hit did

not. produce :ms pr0wn sqnanwus wll caners. T,ong-term cigarette smoke exposures in hamsters led only occa-

sionally to tracheal papillomas and not to squamous cancer (20). However, one could sensitize these animals with diethylnitrosamine and enhance the tumor production initiated by this carcinogen by a variety of volatile irritants including tobacco smoke.

Active tobacco smoke inhalation studies as reported in the 1W Report. (92) have shown that hyperplastic and metaplastic changes can be produced in the lungs of dogs. These studies are expensire and ic is difficult to keep the dogs alire long enough to permit the expected development of ncoplastic transformation. Auerbach, et al. (4) in continuing experiments with “smoking* clogs, have shown all the bronchial epithelial changes including tlysplasial n+i& is the most advanced stage of prc-mali~~nnt change. More research is needed to elucidate the biomechanisms involved in the pathogenesis of lung cancer caused by tobacco smoking.

93

LUNG CANCER

MORTALITY

The annual number of deaths in the United States from cancer of the lung (ICD Code 162, 163) increased from 18,313 deaths in 1950 to 48,483 in 1965 (95). During the same period of time the crude death rate rose from 12.2 deaths per 100,000 population to 25.0 deaths per 100,000 population. The lung cancer age-adjusted mortality rate for males increased from 18.5 per 100,000 population in 1950 to 39.2 per 100,t)OO 1)opulation in 1965: while in the females, the age-adjusted rates increased from 3.9 to 6.4 per 100,000 population over the same period.

The age-specific death rates for males show an increase with age up to the 65 to 74 year age group, and then a decline. On the other hand, the female lung cancer death rates show a relatively steady increase with age, averaging approximately 7 additional deaths per 100,000 population between each ten year age group. As a result, the male to female mortality ratio varies from a low of 2.0 for the 25 to 34 year age age group, to a high of 8.5 for the 65 to 74 year age group.

TABLE l.-Death rates per 100,000 population for lung cancer, by age

-i-

and sex, 1965

3% 2634 35-44 lb54 5H.4 6674 years Yem YKUS YCWS years

__~ -i- ~

Males--------~~.~... 1. 2 13. 2 ~ 58. 2 159.2 269. 3 Females-.----------. 0. 6 4. 4 / 13. 7 22. 1 31. 6 Ratio M/F--_----... 2. 0 3. 0 4. 2 1 7.2 ~ 8. 5

I I / -

7.wu 85 years years and over

~-

226. 4 152. 7 36. 5 45. 6

6. 2 3. 3

SOURCE: Satioml Center for Health Statistics (95).

RETROSPEXTICE STUDIES

Studies in Iceland uniquely support the evidence that t.he increase in lung cancer is related to the increase in cigarette consumption. Iceland is a small country with a total popukion of about 200,000. There is relatively lit,tle air pollution, due mainly to the use of hot water springs instead of the combustion of fuel <as a source of heating. Dungal (21) in 1950 noted a beginning rise in lung cancer in Iceland, associated with the rise in cigarette consumption during and after World War II. He predicted t,hnt if the cigarette consumption continued to rise, t.he 20 to 30 year lag in lung cancer death rates would begin to become apparent during the decade 1960-1970. Thorarinsson, et al. (81) reported a large increase in the lung cancer incidence in Iceland from 1931 to

94

1964, corresponding to a marked increase in per capita cigwette sales. The average annual incidence of lung cancer during the lo-year period, 1955-1964, was 12.1 in men and 6.5 in women per 100,000 population. However, comparing the first and second 5-year intervals, there was a 30 percent inwease in lung cancer incidence in men and a 52 percent increase in women (table 2) .

TABLE 2.-Average annual incidence rates for cancer of the lung, by sex: Iceland, 1955 to 1964

[Rate per 100,000 population]

Males ______ -_-___-___--_-_-___-______________ Females _______ -.__-___-__-_-_-_---____________

SOURCE: Thorarinsson, H. et al. (87).

Although the total number of deat,hs was small, 88 percent of the histologic.ally classifiable tumors were of the squamous, undifferentiated, or oat-cell varieties. Ninety percent of the squamous, 82 percent of the oat-cell cancers, and 33 percent of the undifferentiated or adenocarcinomas occurred in smokers.

A small study by Guillan, et al. (31) again illustrates that cigarette smoking is also associated \vith adenocarcinoma of lung cancer. Of 24 cases of adenocarcinoma of t.he lung in men, a smoking history could be determined in 22 cases. Of these, 91 perce.nt were smokers.

In a large retrospective study of 1,787 lung cancer patients in Japan by Ishikaaa (.&‘), adenocarcinoms was the most frequent histologic type noted in both males and females who did not, smoke. Squamous cell carcinoma n-as the most frequent, histologic type in male cigarette smokers and undifferentiated carcinoma the most frequent type in female cigarette smokers.

Of the male and female lung cancer pat,ients, 22.6 and 2.9 percent, respectively, were smokers of over 30 cigarettes a day. Ishikawa compared this to the corresponding smoking habits of patients in a large ongoing prospective study of Hirayama (discussed later) which showed only 4.3 percent. of the adult males over age 40 and 0.1 percent of the adult females over age 40 smoking 30 cigarettes a day or more.

Abelin, et al. (1) showed that the relative risk of lung cancer in Switzerland was associa.ted with heavy cigar and pipe smoking (as well as cigarette smoking) to a much greater degree than previously reprte.d. Most other studies hare not, shown a high association of lung cancer with cigar and pipe smoking. The authors suggest that their findings might be due t,o differences in either the amount smoked and/

95

or the carcinogenicity of Swiss and German cigars as compared to American cigars. The diflarence might also be explained by the greater use and more frequent inhalation of small cigars in Switzerland as compared ,to other countries where larger cigars are more commonly smoked but rarely inhaled.

PROSPECTIVE STUDY

The major, long-term, prospective studies vere reviewed in the 1967 Report. The Doll and Hill (18? 19) study is still in progress, but no new data have become available. Data collection for the Best, Ham- mond, and Dorn studies (5,34,4S) are completed, but various asp&s are still being analyzed and new information a411 appear in the future.

Preliminary data from a large scale prospective study (3’7) of 265>118 men and Jvomen in Japan show that the death rate from lung cancer is significantly higher in cigarette smokers as compared to nonsmokers for both males and females. There is also a posit’ive correlation between lung cancer death rates and both the amount smoked and the

I-

l-

l-

l-

)-

I-

,-

,-

BY sex and smoking habit

: : :. +

~

.:: ‘: ,::

Non- Smoker NOW 1-24 25. smoker

-- smoker cigarettes per day

Number 3 studied

-346 9 J 23350 119136 97047 17473 23350

m Male m Female

-20 21 22--

21 36912 7

9 16644 34769

FIGTXE l-Death rates for lung cancer, among persons age over 40 years, classified by sex and extent of cigarette smoking, and by age smoking began : Study of 29 Health Center Districts in Japan, danuary 1966 to March 1967.

SOUBCE: Hirayama, T. (37)

96

age smoking began, but the number of deaths is too small for adequate analysis at. this time.

LUNG CANCER RELATIONSHIPS IN WOMEN

Critics have tried to throlr- doubt on the smoking-lung cancer relationship by saying that the lung cancer death rates for u-omen have increased only slightly as compared to the greater relative increase in the number of women smokers.

It is true that the lung cancer death rates for women are presently much lower than the corresponding rates for men. Women presently account for onl,y about one-sixth of the total deaths from lung cancer. But since 1930 the lung cancer death rate in women has increased over 400 percent. Over the past 14 years alone this increase has been over 50 percent (94). ,Z most likely reason for the difference in male/female lung cancer death rates is that women still have not had the same degree of total exposure to cigarettes as haw men. For instance, as late as 1955. only 24.5 percent of the adult female population (age 18 and over) were regular smokers compared to 52.6 percent of the adult. male populat.ion (33). In 1966 the figures show only 33.6 percent of the adult females smoking (age 21 and over) as compared to 51.8 perwnt of the adult males. Also, the female smoker’s per capita consumption was about 26 percent less than that of the male smoker in 1955, and about 20 percent less in 1966 (93). In adclition, it has been show-n that women smoke differemly than men do (c9t9). They do not, smoke cigarettes as far to the end, where proportionally more nicotine and “t,ars” are inhaled than from the first part of t.he cigarett.e.. Won1e.n smoke more filter-Cl> cigarettes than men, and smoke more “low tar and nicotine” cigarettes than do men. They also inhale less frequently and deeply than men. Furthermore, cigarette smoking still tends t.o be heavily concentrated in those women under the age of 50 years, prior to the age at, which lung cancer is mostly likely to occur.

An anlysis of the Iun g cancer death rates (94) shows that,, “Vntil 1960 the rat,io of the death rate in the male population for this cause to the corresponding death rate in the female population continued upward. But after 1960 this ratio leveled off, reflecting the greater relative rise in mortality from lung cancer in the female population.”

ADDITIONAL (‘IoNSIDEIL~T~O~‘S ‘IND CONCLVSIONS

Filter cigarettes, in general, have lower “tar” and nicotine ra1ue.s than comparable non-filter cigarettes. In this respect, a study by Brass (9), shows preliminary evidence that smokers who switched to filter cigarettes have a decreased risk of developing lung cancer.

(;raham (3’0) studied the smoking habits of male lung cancer patients and controls. Previously he showed, on smoking machines, that dif-

97

fcrent, patterns of cigarette smoking gave different “tar” yields. His lung cancer patients had significantly greater high “tar?’ yield cigarette smoking patterns than the controls. The risk of lung cancer increased with increase in : (I) the mean number of puffs per cigtwette, (2) t.he average length of time taken to smoke a cigarette (except in the highest, number of puffs category) and (3) taking more puffs towards the end of the cigarette. These findings add further support to t,he dose-response relationship between lung cancer and cigarette “tar” exposure.

As pointed out in the 1964 and 1967 Reports, there appear to be several other factors which may also contribute to the etiology of lung cancer, especially in the presence of cigarette smoking. However, there has been no evidence to refute the statement in the 1964 Report. that, “Cigarette smoking is causally related to lung cancer in men; the magnitude of the effect of cigarette smoking far outweighs all other factors. The data for n-omen, though less extensive, point in the same direction.”

Of particular interest are the studies of Ruell, et al. (II, 12). They reviewed various prospective and retrospective studies which shelved that the urban-rural differences in lung cancer death rates in nonsmokers n-ere of the range of 2 : 1 to 4.4 : 1. However, the much greater effect. of smoking on increasing the lung cancer death rates was evident by their statement “that smoking can act independent.ly of the urban factor, the gradients among rural dwellers rising to as much as 10 to 15 fold for heavy smokers.” TJ?th regard to the high levels of photochemical air pollutants in Los ,Ingeles, they concluded: ‘With controls for cigarette smoking and length of residence, the risk of pulmonary canc.er in Los ,Inpeles, where photochemical air pollution levels are highest, was not greater than in other major met.ropolitan areas of California.”

hlthough photochemical air pollution might not be a contributing factor to lung cancer mortality in man, as is the “sulfur dioxide” air pollution found in most industrial areas, it may be too early to ascertain any effects. since air pollution in TAX Angeles only became a problem between 1945 and 1960.

Storks (@. 85) shows that per capita solid fuel consumption has a positive correlation with lung cancer death rates but to a much lesser degree than per capita cigarette consumption. He sug,mts, therefore, that air pollution from solid fuel combustion is related to lung cancer death rates and that this might possibly be independent of cigarette smoki~lg. However, Stocks did not de.termine the specific smoking histories of indiriduals ~-ho died from lung ca.ncer.

Concurrent st,udies of cigarette smoking and air pollution, in the same populations with precise smoking histories on individuals who have died from lung cancer, might serve to clarify the probable interaction between cigarette smoking and air pollution or possible inde-

98

pendence of cigarette smoking from air pollution as they relate to the etiology of lung cancer.

The preponderance of evidence [ 1964 Report (91). 1967 Report (5%‘)) and this report] continues to indicate that most lung cancers occur in cigarette smokers and that cigarette smoking is the major cause of lung cancer. A majority of lung cancer cases are of the squamous cell rnriety and most investigators are in agreement that squamous cell carcinoma is rare in the male nonsmoker (3. 15, 103). The elimination of cigarette smoking would in time eliminate most lung cancer. That this is a real goal is supported by the study of British physicians (18, 2,9) reriewed in the 1967 report..

It is not, disputed that some cases of lung cancer can occur in those people who have never smoked ciparette,s or inhaled any form of tobacco smoke. In these cases air pollution possibly pln~s a larger role in the cawation, but in most cases, it appears that it is the ciga.ret,te smoker nho is especially susceptible to whatever additional risk for lung cancer may be presented by certain types of air pollution or other fnctors such as asbestos or uranium dust inhalatSion.

‘l’he 1967 report showed that the overall death rates for oral cancer remained about the same during the period 1950-1964. This was influenced somewhat by recent changes in the ICD Code.

It is intere&ing to note that the incidence rates of oral cancer have also remained relatively constant over the period 19X-19&2,* in spite of increased cigarette smoking (24). This may be explained, in part, by the fact that the numerators of such rates often include neoplasms coded to the International Classification of Disease, rubrics 140 through 148. These rubrics identify many oral and pharyngeal diagnostic sites which do not contribute equally to either the. morbidity or mortality experience resulting from the use of tobacco, For example, preliminary findings in an unpublished study by Keller (47) suggest that. salivary cancers (ICD rubric 142), unlike tongue and floor of mouth cancers, are not associated with the tobacco habit,. The fact that pipe and cigar smoking in this country began to be replaced by ciparette smoking among men born subsequent to 1900 may also be significant, although this trend has leveled off and may even have been re- versed since the health consequences of smoking cigarettes first came to public attention in the mid-1950’s. In the population which accounts

‘There is no ntitional ctata collection on inddenw rates of ddseam. Sewral &ates have mncer wgi&-ier whirh have information cm the incidence of caner in that particu1a.r state. Thr data from Connecticut are generally thought to reflect the ch~ngiing patterns of cmcer incidence throughout the I:nited States. It is realized that there might he individual state differences. Krfcrencw to incidence rates in this chapter section are taken from the Connecticut Dunn unless otherwise specified.

99

EUCCALCAVlTYANDPHARYNX

0 I I I I I

1935 1940 1945 1950 1955 1960 YCXS

- Maler ---Females

FIG~RF. Z-Age-adjusted rates of the iucidence of caucer of the buccal cavity aud pharynx, for males and females : Connecticut, 19351962.

SOURCE : Eisenberg, et al. (24).

for the bulk of oral cancer cases-men over 45-there has been a greater change in the form in which tobacco is used than in the proportion of men using tobacco.

Since pipe and cigar smoking is associated with oral cancer, with mortality ratios not very different from those for cigarette smokers, the constant incidence rates may reflect the fact that the proportion of t,obacco users among men over 45 has been fairly stable.

A review of the recent retrospective studies shows a relationship of oral caucer to all forms of the tobacco habit (22. 2%. .53,5$. 77, 78. 79, 98). This includes the use, in the nlucobuccal fold, of either snuff, among n-omen (lo, 22, 71, 7.2, 81), or the betel nut quid with tobacco, among the residents of India and Southeast Asia (~6, j$,77: 78,79,,%?).

Reddy has 1noduce.d tumors in mice by daily instillation of a “pan” mixture with tobacco (the same mixture used for chewing) into the vaginas of virgin mice (69) .

There is evidence that in the presence of tobacco consumption, alcohol may also be a factor in the etiology of oral cancer (48, 4.9> 50, 97). In a recent study on male veterans, Keller concluded, “* * * heavy smoking, heavy drinkin g and liver cirrhosis (either alone, or as a measure of heavy drinking) are associated with cancer of the

100

mout,h and pharynx” (48). Since most. people who drink large amounts of alchohol regularly are also heavy users of tobacco, it is difficult to identify the relative contribution of these two factors or t’he role of Ihe nutritional problems often associated with heavy alcohol use.

,4dditional data have, been reported by Moore (&?), on patients developing second primnrv mouth and throat cancers, after having heen cured for at. least thrie years prior to development. of the cancer. These patients were all asymptomatic for at least three years prior to development of the second cancer. Of 117 patients with adequate, smoking histories only 4 of Ji-1 (0 ljercent) who quit smoking after the first, cancer, developed a new ljritnary. On the other hand, 27 of 74 patients (36 percent) who continued to smoke del-eloped a second primary cancer. These data supl)ort the important contribution of smoking to the etiology of mouth and throat cancer.

Roth, et al. (73. 74) recently have shown that the dTe-binding capacit,y of DSA of oral epithelial cells is significantly enhanced in cigarette smokers in contrast to nonsmokers, probably reflecting an increase in the DSA content of oral epithelial cells in smokers. This suggests some alteration in the Ds.1 which ma\- be a factor in oral carcinogenesis. Smokers had \-alues of dye-binding capacity inter- mediate between nonsmokers and 21 patients with proven oral cancer. Those smokers who refrained from smoking for up to nine months showed a significant. decrease towards more normal I-alues.

It is clear that people who use tobacco hare higher rates of oral cancer than those who do not. Research is needed to identify the dose relationships, to determine whether or not there are dosage thresholds, and to clarify the relationships between dosage, style of tobacco use, and part of the mouth affected.

It seems likely that factors such as alcohol consumption, nutritional problems, and oral hygiene mas be interrelated with the tobacco habit in a fairly complex pattern. More resenrrh is needed to clarify these relationships.

For patients with oral cancer, and probably for those at a high risk of oral cancer because of other exposures, cessation of tobacco use can make an important contribution to reducing the, risk of a new primary cancer.

CA?;CER OF THE LARYNX

Cancer of the larynx is mainly a disease of male smokers. Of t,he 2,629 deaths in 1965, over 88 percent, were men. The 1067 report noted that the death rate for cancer of the larynx had not, increased significantly since 1950. The incidence rates, however, have shown a steady increase since 19%

101

FIWRE &.Ige-adjusted rates of the incidence of cancer of the larynx, for males and females : Connecticut, 193&1962

SOURCE : Eisenberg et al. (24).

The American Pancer Society (2) estimates the occ.urence of 6,000 new cases of cancer of t.he larynx in 1968 but only about, 2,800 deaths, due to relative curability of t,his disease if diagnosed early.

Several retrospective studies have again shown the extremely high rate of smokers [ 98 percent (86)) 92 percent (75) ] among paCents with cancer of the larynx.

CAKCER OF THE ESOPHAGUS

As reported in the 1967 Report (92) the death rates for cancer of the esophagus have increased only slightly in the period 1950-1964. The large scale prospective studies (18, 19> 34, 4s) showed mortality ra.tios up to 11 in heavy cigarette smokers, while pipe and/or cigar smokers had ratios up to 5.

Preliminary data from a prospective study (37) in Japan also indicate an increased frequency of death from cancer of the esophagus among smokers as compared to nonsmokers.

No further information has become available on the relationship of esophageal cancer to alcohol and/or other confounding variables as discussed in the 1967 report.

102

CANCER OF THE PANCREAS

The 196’i report implied a rellat,ionship between smoking and pancreatic cance,r due to the somewhat higher mortalit,y ratios observed in three of the. large scale prospective epidemiologic studies.

The ,Imerican Cancer Society estimates that. deaths due to cancer of the pancreas will total 15,000 in 1968 with a male/fe.male ratio of approvimate.ly :< : 2. The overall death rate for cancer of the pancreas has shown a steady rise; from 7.2 to 8.4 in males ( + 17 percent.) and et.4 to 4.9 ( fll percent) in females, for the time period 1953~55 to 196-65 (a). The incidence rates have increased almost 50 percent in males since 1935, with no apparent increase for fernala.

In the past. year? preliminary evidence from two retrtrqwtive studies (&3,102?) has showi that only 10 percent of the patients with cancer of the pancreas are nonsmokers. The risk of developing cancer of the pancreas appears to increase in proport ion to the amount smoked.

Preliminary data from a prospective study (37) in Japan also shops a significantly higher frequency of deaths from pancreatic cancer among smokers a.s compared to nonsmokers.

PANCREAS

- Male --- Female

FIGURE -l--Age-adjusted rates of the incidence of cancer of the pancreas, for males and females : Connecticut, 19X*1962.

SOURCE: JGisenberg, et al. (24).

?J5-Ii31 0-68-S 103

These st.ndies st,rengthen the earlier indications of an ass&&on be- t\wen smoking and pancreatic cancer, but. further research is needed in this are.a to elucidate the significance of this association.

GENITO-URINARY CANCER

CANCER OF THE BLADDER

As stated in the 1967 Report, there has been no increase in male or female death rates for cancer of the bladder over the 15 year period 1950-1964. However, t.he incidence rates for males have increased orer 75 pe.rcent in the 25-year period from 1935-37 to 1960-62, and about 26 percent. in the 15 year period from 19454i to 1960-62.

Deeleg, et al. (16) reported on a retrospective study of 127 patients with cancer of the bladder and 126 patients wi-it.h lung cancer, all matc.hed with controls. The smoking “factors” (amount times duration of smoking) were significantly greater among cases than controls for both cancer sites. Even by age-groups, the “mean smoking factor” for either cancer n-as higher for cases than for controls. Preliminary data

FICLTLE Z-Age-adjusted rates of the incidence of cancer of the bladder, for males and frmalw : (‘onwcticut, l%~l!W2.

SOURCE: Eisenberg, et al. (24)

104

from a prospective study (37) in ,Japan shows a higher frequency of deaths from bladder cancer among smokers.

Certain amino acids, as found in tobacco, form trace amounts of alpha- and be&naphthylamines upon pyrolysis (59). The latt.er agent is an estab1ishe.d bladder carcinogen. So far, howewr, only it.s isomeric alpha-naphthylamines ‘has been identified in cigarette smoke (GO. 67).

Further investigat,ion is ne.eded on the carcinogenic metabolites of tryptophan which have been shown to be inere.ased in the urine of cigarette smokers (9%‘).

CANCER OF THE KIDNEY

The 1967 Report did not, mention the association between smoking and cancer of the kidney.

The U.S. Veterans study (4~) shops increasing mortality ratios for cancer of the kidney with the amount of cigarette smoking. There is no apparent relationship with pipe and/or cigar smoking.

TABLE 3.-Mortality ratios and death rates for cancer of the kidney in U.S. ,ueterans, by age, type and amount smoked for current smokers only

1 , Number of cigarettes smoked per day

Pipe and/or Cigars

0 1-9 l&20 21-39 40 and Pipe

cigars over

__- -1

Mortality ratios- _--_ 1. 00 97 1. 34 1. 68 2. 75 1. 15 77 1. 32 Death rates:

Age45-54_.._-_.__.._____.___..~..- _._--_ ---__- ~.._~..___._._____ Age 55-64._----_ 8 5 Age 65-74__mm--_ 14 7 Age 75-W---- 7 -_-._--_---- --_--_ ---__-

Somce: Kahn, IX. A. (46).

TABLE 4.-Mortality ratios and death rates for cancer of the kidney in male cigarette smokers, by speci$ed age groups

Cigarette smokers -

Age 4564 Age 65-79 -

Mortality ratios_--~.--~.~---~---~~--------~----~--- 1. 42 Deathrates---_--- _.___._. --_---~_--_~---~.---.-___; ’ (416

, 1. 57 1 (15)23

1 Numbers in parentheses indicate death rates for persons who have never smoked regularly SOURCE: Hammond, E. C. (S4).

105

Hammond (34) has also demonstrated higher mortality ratios in cigarette smokers for cancer of the kidney.

Preliminary evidence from a &respective study in progress (It%) suggests t.hat> cigarette smokers, espec.ially t.hose who smoke over 35

cigaret.tes a day, are over-represented in those patients with cancer of the kidney. More research should be done t,o try to ascertain if there is a meaningful relat,ionship between smoking and ca.ncer of the kidney.

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