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 conclu-
sions 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 re-
quired. 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.

o 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 can-
cer that has become a.vailablc since TAe Henlt?~ Conxeprtewcs of Xm.ok-
ing, 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 evi-
dence 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 re-
search, 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 ciga-
rette smoking is the main cause of lung cancer in men. Cigarette smok-
ing 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 can-
cer 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 in-
creased 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 non-
smokers? 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 non-
smokers, 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 PSillll~)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 be-
tween 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 smok-
ers 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 prob-
lem 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 non-
smokers 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

regu-
larly

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 concern-
ing 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
ill~~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 associ-
ated with s1ii0kiii.g were priniarily cxpl~ained 1)y cancer of various site,s.
Only Ii! percent of tlie excess dentlis were associated with cardio-
vascular causes. This prospective study of %.5,118 adults over the age
of 40 encompassed ;I followup period of 15 months. -1dditional follow-
up by TJirayanla slwuld yield useful tlnta with respect to smoking and
excess mortality from cardiovascnlar diseases in this ,Japnnese popu-
lation 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

o 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 asso-
ciation 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 inci-
dence 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 asso-
ciated 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 differ-
ences in rates between smokers and nonsmokers are greater for myo-
cardial infarction than for angina; however, t.he risk ratios are
similar.
In a ret,rospective study, Heyden-Stucki et al. (61) found no asso-
ciation 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 smok-
ing 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 clas-
sified 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 ciga-
rette smoking, together or separately, were present in over 80 percent
of these patients.

In the major prospective studies, when both smoking and hyper-
tension 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 non-
smokers with respect to cholesterol levels and other lipids were not
statistically significant.

A recent report (A'/;) describes some of the variability of interrela-
tionships 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 pres-
ence 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 differ-
ences 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 substan-
tially 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 rela-
tively 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 differ-
ent 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 statis-
tical 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 sig-
nificant 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@) dis-
cussed the studies by Cedcrlof on Swedish t\yin pairs (In. 30). His
data on American twin pairs was recently prcscnted and showed re-
sults 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 differ-
ences identified ns significant in the large-scale population studies.

TIM fact' that discordance for smoking does occur ;unong monozy-
gotic twins certainly indicates that the snlokinp habit cannot be deter-
mined by genetic factors alone. Txl-in studies with further bophi&ca-
tion 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 "in-
consistencies" 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 smok-
ing 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 nonsmok-
ers. 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 lipopro-
tein 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 bio-
chemical 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 throm-
bus 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 "plate-
let" 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 sub-
stance 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 oc-
currence 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 cate-
cholamine 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 sub-
normal 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 de-
creased rise in linoleic acid (long-chain unsaturated) after 5 hours.

These findings may be related to the effect of saturated and un-
saturated fatty acids on blood coagulation and suggest' further re-
search 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 con-
traction, and these effects: of nicotine are itlentic21 to those of norepine-
phrine. 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 deter-
mine 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 lllu~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 dur-
ing 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 adminis-
tration of nicotine, as measured by electrocardiographic changes, than
were normal dogs, especially in the acute stage of myocardinl infarc-
tion (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, elec-
trolyte, 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 con-
ditions. 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 smok-
ing 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 in-
crease 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 smok-
ers 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 con-
trols. 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 post-
infarction 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) find-
ings 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 ade-
quate 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 hemo-
globin 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, sug-
gesting 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, in-
dicates 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 relation-
ships 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 ob-
struction, 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 smok-
ing 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 coro-
nary 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 im-
portant in cellular respiration of all body cells. In view of the ex-
tremely 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 myo-
cardial 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 ciga-
rette smokers, both male and female, had approximately a 10 mg. per-
cent 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 glu-
cose tolerance n-as pathologic in 46 percent as compared with 10 per-
cent 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 dis-
cussed 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 in-
crease 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 increas-
ing 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 develop-
ment 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 ~~hysio-
logical 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 coro-
nary heart disease, cigarette smoking may "trigger" myocardial oxy-
gen 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 contrac-
tion, 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 pul-
monary function from chronic obstructive bronchitis.
5. The impairment of coronary blood flow as a result of the in-
creased blood viscosity associated ATit h~perlipemia or hemoconcen-
tration.

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 hemo-
concentration 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 ciga-
rette 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 cerebro-
vascular 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 associa-
tion 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 approxi-
mately 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 rela-
tive cerebral hypoxia; ;I situation n-ltich could be il factor in the
etiology of stroke.
            CITED REFERESCEP

(I) ARDLIE, N. G., GLEW, G.. SCHWARTZ:, c. .J. Influrnce of c!Fitec~lokU~illeS
   on nucleotide-induced platelet aggregation. Saturr I London J  212
    ( .mN) : 41.i-417. I )c~tl)lwr 2. l!WXi.

(2) .%STRI-I'. I'.. KJELDSEN. K., WAXSTR~-1,. J. Enhancing influence of (*arbori
   monoxide on the develqment of atheromator;is in ~~lrolr~str~rl)l-frtl rab
   bits, Journal of Atherosclerosis Rwearvh i : 334%XA. 1%;.
(8) .%VERBACH. 0.. HAMWND, E. c., GA~1~~rsm:r.. I,. Thiclkening of walls of
   arterioles and small arteries in relation to age and smoking habits.
   Sew E~~)glaud .J))~irnal of ~t~~tlic.i)ie L'i,\j I,\) : !lhO !)S4, JI:lS 2. l!lfiS.
(4) ATRES. S. M. Personal communication. 3larc.h 1068.
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60


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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 understand-
ing 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 bron-
chitis 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 ciga-
rette 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 occupa-
tional 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

                     IISC 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 sim-
ilar observations. In all instances? smokers had respiratory symptoms
such as cough, l)hlegm pmcluc-tion , :lnd clyspnca more often than non-
smokers 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 rela-
tionship 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 impor-
tant 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, publi-
cation (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 indus-
trial 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 re-
port&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 sub-
sequent 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 hyper-
trophy 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 con-
cludes 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 bronchopul-
monary 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 reac-
tion 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 inhala-
tion. 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 infec-
tion. 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 destruc-
tion confirmed by autopsy. Those mice in a hay-smoke control group
were normal clinically and showed only chronic, pulmonary inflamma-
tion 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 ciga-
rette smoke can adversely affect ciliary activit.y. In short-term in V~WO
experiments, Dalhamn (II) showed t.hat the ciliostatic effect of ciga-
rette 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 experi-
ments 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 con-
tinued 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 con-
trast 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 infor-
mation 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, cor-
related 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 smok-
ing 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 indi-
viduals 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 indi-
viduals 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 ventila-
tion-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 bron-
chitis 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 asymp-
tomatic 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 pres-
sure 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'? "compart-
ment .*' 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 hypos-
emia 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 rela-
tionships 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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    224, August 1967.

S90. ZWI, S., SLUIS-CREMER, G. K., Du PREEZ, I,. -4 survey of pulmonary func-
   tion 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 understand-
ing 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 develop-
ment 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 ade-
quate 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 eluci-
date 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 esoph-
agus. 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 pres-
ently identified ($3).

The 1067 Reljort discuswd the major concepts of experimental to-
bacco 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 tumori-
genicity 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) fil-
tration. 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. rea-
son 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 evi-
dent 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 ciga-
ret.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 inhala-
tion 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 inhala-
tion 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 ildCllO~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 ap-
parent 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 pe-
riod, 1955-1964, was 12.1 in men and 6.5 in women per 100,000 popula-
tion. However, comparing the first and second 5-year intervals, there
was a 30 percent inwease in lung cancer incidence in men and a 52 per-
cent 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, undifferen-
tiated, or oat-cell varieties. Ninety percent of the squamous, 82 per-
cent 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 com-
pared 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 non-
smokers 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, classi-
fied 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 rela-
tionship 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-re-
sponse 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 non-
smokers 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 photo-
chemical 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 ascer-
tain any effects. since air pollution in TAX Angeles only became a prob-
lem 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 inter-
action 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 in-
fluenced 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 diag-
nostic 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 cipar-
ette smoking among men born subsequent to 1900 may also be signifi-
cant, 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 indi-
vidual state differences. Krfcrencw to incidence rates in this chapter section are taken
from the Connecticut Dunn unless otherwise specified.

99


EUCCALCAVlTYANDPHARYNX

?        ?         ?         ?         ?         ?
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 signifi-
cantly 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 indi-
cate 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 pan-
creatic 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 pan-
creas 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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