U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE

Public Health Service
Center for Disease Control


      THE
HEALTH CONSEQUENCES
   OF SMOKING

JANUARY 1974

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


Honorable Carl Albert
Speaker of the House of Representatives
Washington, D.C. 205 15

Dear Mr. Speaker:

Enclosed is the 1974 report on the health consequences of smoking
submitted to you as required by Section 8(a) of the Public Health Cigarette
Smoking Act of 1969. As you will see, it confirms the evidence in previous
reports that cigarette smoking is a serious health hazard and broadens our
understanding of the mechanisms by which smoking contributes to the
development of various forms of cancer, cardiovascular disease, and respiratory
disease.

Under this Act, I am also required to submit to you such recommendations
for legislation as I deem appropriate. This Department has previously taken a
position in support of legislation which would authorize the regulation of
cigarettes through the power to ban the manufacture and sale of cigarettes
exceeding what are considered excessively hazardous levels of tar, nicotine,
carbon monoxide, and other ingredients shown to be injurious to health. The
extent to which the cigarette smoking public has over the years spontaneously
moved towards this kind of self protection suggests that it would welcome the
additional protection such legislation would bring. This Department, therefore,
recommends to the Congress that it consider legislation providing this
Department or some other appropriate agency with the authority to set
maximum permissible levels of hazardous ingredients in cigarettes.

With kindest regards.

Sincerely,

Caspar W. Weinberger
  Secretary

For sale by the Superintendent of Documents, U.S. Government Printing
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PREFACE

This report is the eighth in a series issued by the Public Health
Service reviewing and assessing the scientific evidence linking
cigarette smoking to disease and premature death. The current
report is devoted to recent research that enlarges the evidence
on which our knowledge is based and broadens our understanding
of the mechanisms whereby smoking contributes to the develop-
ment of various forms of cancer, cardiovascular disease, and
respiratory disease.

It is now 10 years since the Advisory Committee of the Surgeon
General issued its famous report of January 11, 1964, and 20
years since scientific evidence indicating that cigarette smoking
is a major health problem came to widespread public attention.
In the past 20 years substantial changes have taken place in the
smoking habits of the American public. In the early 1960's
cigarette smoking had reached its peak as a habit among men in
their 20's and was rapidly increasing as a habit among each suc-
ceeding generation of women.

As a result of the continuing growth of scientific evidence on
the hazards of cigarette smoking and the educational programs
to disseminate this knowledge, millions of people have stopped
smoking, and millions of others who would otherwise have taken
up smoking have not done so. A further gain in reducing the
hazards has been the substantial decline in the "tar" and nicotine
content of cigarettes in the past 20 years. Despite population in-
crease and increase in the rate of smoking by young women, there
has been a very real reduction in exposure to cigarettes in some
portions of our society.

The evidence is cIear that people who have stopped smoking
cigarettes have lower death rates from smoking-related diseases
than those who continue to smoke. If these reductions continue
we can look forward to the time when the rapid increase of
diseases associated with smoking will halt and begin a decline
that will result in fewer deaths during the most productive years
of life.

Charles C. Edwards, M.D.
Assistant Secretary for Health

. . .
111


TABLE OF CONTENTS

PREFACE _-_____-____________--------------------

TABLE OF CONTENTS  __ _ _ _ _ _ _ _ _ _ _ __ __ __ _ _ __ _ _ __ _ _
Preparation of the Report and Acknowledgments - _ _ _ _ - _

Chapter 1. CardiovascuIar Disease  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

Chapter 2. Cancer  _ _ __ _ _ __ __ __ _ ___ __ __ __ _ _ _ _ _ _ _ _ _ __
Chapter 3. Non-neoplastic Bronchopuhnonary Diseases - _

INDEX __-________-_--__-__-----------------------

Page
  . . .
111

V

vii

1


35

71

119

V


PREPARATION OF THE REPORT
AND ACKNOWLEDGMENTS

Previous Reports

"Smoking and Health. Report of the Advisory Committee to the
Surgeon General of the Public Health Service," subsequently re-
ferred to as the "Surgeon General's Report," was published in
1964. The National Clearinghouse for Smoking and Health, estab-
lished in 1965, has the responsibility for the continuous monitor-
ing, compilation, and review of the world's medical literature
which bears upon the health consequences of smoking. As .called
for by Public Law 89-92, three subsequent reviews of the medical
literature on the health consequences of smoking were sent to the
Congress :

1. "The Health Consequences of Smoking, A Public Health
Service Review : 1967" (submitted July 1967).

2. "The Health Consequences of Smoking, 1968 Supplement to
the 1967 PHS Review" (submitted July 1968).

3. "The Health Consequences of Smoking, 1969 Supplement to
the 1967 PHS Review" (submitted July 1969).

Public Law 91-222 was signed into law on April 1, 1970, and
called for an M-month interval between the 1969 supplement and
the next report. During this period, a comprehensive review of
all of the medical literature available to the Clearinghouse relat-
ing to the health consequences of smoking was undertaken, with
an emphasis upon the most recent additions to the literature. The
product of this review was : "The Health Consequences of Smok-
ing, A Report of the Surgeon General : 1971," submitted to the
Congress in January of 1971.

Subsequently, reviews of the medical literature, which had
come to the attention of the Clearinghouse since the publication
of the 1971 report, were published as, "The Health Consequences
of Smoking, A Report of the Surgeon General, 1972," and `The
Health Consequences of Smoking, 1973," and were submitted to
the Congress in January of the corresponding years.

vii


Every report published since the original "Surgeon GeneraYs
Report" has contained a review of the medical literature relevant
to the association between smoking and cardiovascular disease,
non-neoplastic bronchopulmonary disease, and cancer. Several of
the reports included reviews of `the relationship between smoking
and peptic ulcer disease (1967, 1971, 1972, 1973) and cigarette
smoking and pregnancy (1967, 1969, 1971, 1972, 1973). Other
topics relating to the use of tobacco have received special em-
phasis in single reports :

1. Noncancerous Oral Disease (1969).
2. Tobacco Amblyopia (1971).
3. Allergy (1972).

4. Public Exposure to Air Pollution from Tobacco Smoke

(1972).

5. Harmful Constituents of Cigarette Smoke (1972).

6. Pipe and Cigar Smoking (1973).
7. Exercise Performance (1973).

The 1974 Report

The present document, "The Health Consequences of Smoking:
1974," includes reviews of the relationships between smoking and
cardiovascular disease, chronic non-neoplastic bronchopulmonary
disease, and cancer, which are based upon medical literature
which has become available to the Clearinghouse since the publi-
cation of the 1973 report. Each chapter is organized in a similar
fashion :

1. Introduction. Each introduction comprises a series of state-
ments of the separate lines of evidence which converge to
support a causal relationship between tobacco use and the
specific diseases under consideration in the chapter. Each
separate statement reflects critical reviews of the data
available from the pertinent medical and scientific literature
as presented in previous publications of "The Health Con-
sequences of Smoking."

2. &~siort. The body of each chapter contains critical re-
views of two types of articles which have come to the atten-
tion of the Clearinghouse in the interval since the publica-
tion of "The Health Consequences of Smoking: 1973."
a. Those articles which either extend our understanding of
   the relationships between tobacco use and the specific

. . .
vlu


disease under consideration, beyond the position reflected
in the introduction, or provide additional confirmation
of previously suggested, but less well-established, rela-
tionships.

b. The articles which present new data which do not
demonstrate the definite relationships between tobacco
use and specific diseases identified by the critical review
of previously available data.

3. Summary. The summary of each chapter includes state-
ments of the most significant new contributions to the
understanding of the relationships between tobacco use and
specific diseases.

4. Bibtiomphy. Each bibliography is divided into two parts.
The first contains references to the studies discussed in the
text; the second primarily contains references to those
studies which form the bulk of the articles reviewed by the
Clearinghouse, which have provided data confirming well-
established relationships. Although these studies are not
discussed in the text of the chapter, accession numbers from
the "Smoking and Health Bulletin", published by the Clear-
inghouse, have been provided. The Bulletin contains ab-
stracts of all of the articles obtained by the Clearinghouse
each year, and the accession numbers provided in the sup-
plemental bibliography of each chapter will direct the
interested reader to the appropriate abstract. The Bulletin
can be obtained from the Clearinghouse upon request.

Identijkation of Articles

For each report, the continuous monitoring and compilation of
the medical literature on the health consequences of smoking has
been accomplished through several mechanisms :

1. An information science corporation is on contract to extract
articles on smoking and health from the medical literature
of the world, This organization provides a semimonthly
accessions list with abstracts and copies of the various
articles. Translations are called for as needed. Articles are
indexed and classified according to subject and filed in
accession number order.

2. The National Library of Medicine, through the MEDLINE
system, sends the National Clearinghouse for Smoking and
Health a monthly listing of articles in the smoking and
health area. These are reviewed, and the articles not

ix


identified by the information science corporakon are
ordered.

8. Staff members review current medical literature and
identify pertinent articles. Inevitably each year, articles
containing important new data come to the attention of the
Clearinghouse after the drafts of chapters have been sub-
mitted. Such articles are incorporated into the following
year's report.

Review of Chapter Drafts

All of the articles so compiled reIated to cardiovascular disease,
bronchopulmonary disease, and .cancer were reviewed, and the
first drafts of the chapters prepared by the medical staff of the
National Clearinghouse for Smoking and Health. The first drafts
were then sent to reviewers for criticism and comment with re-
gard to the format, the thoroughness of screening the available
literature, the selection and review of articles, and conclusions.
The final drafts were reviewed as a whole by the Director of the
National Clearinghouse for Smoking and Health, the Director of
the National Cancer Institute, the Director of the National
Heart and Lung Institute, the Director of the National Institute
of Environmental Health. Sciences, and by additional experts
both within and outside of the Public Health Service.

ACKNOWLEDGMENTS

The National Clearinghouse for Smoking and Health, Daniel
Horn, Ph. D., Director, was responsible for the preparation of
this report. Medical Staff Director for the report was H. Stephen
Williams, M.D., Assistant Medical Staff Director was Paul I.
Schneider-man, M.D., and consulting editors were Elvin E. Adams,
M.D., Daniel P. Asnes, M.D., and John H. Holbrook, M.D.

The professional staff has had the assistance and advice of a
number of experts in the scientific and technical fields, both in
and outside the Government. Their contributions are gratefully
acknowledged. Special thanks are due the following:

ANDERSON, WILLIAM H., M.D.-Chief, Pulmonary Section, School of Medi-
cine, University of Louisville, Louisville, Ky.
AUERBACH, OSCAR, M.D.-Senior Medical Investigator, Veterans Administra-
tion Hospital, East Orange, N.J.
AYRES, STEPHEN M., M.D.-Physician in Chief, Saint Vincent's Hospital and
Medical Center of Worcester, Worcester, Mass.

x


BOCK, Fnm) G., Ph. D.-- Director, Orchard Park Laboratories, Roswell Park
Memorial Institute, Orchard Park, N.Y.
BORES, HOI&IS G., M.D.-Medical Investigator, Veterans Administration
Hospital, Tampa, Wa.

Bomb, Rosu%LL K., M.D.-Professor of Oncology, McArdle Laboratory
for Cancer Research, University of Wisconsin, Madison, Wis.
FERRIS, BENJAMIN G., JR, M.D.-Professor of Environmental Health and
Safety, School of Public Health, Harvard University, Boston, Mass.
GO,,DSMITH, JOHN R., M.D.-Medical Epidemiologist, Health and WeIfare
Agency, California State Department of Health, Berkeley, Calif.
HIGGINS, IAN T. T., M.D.-Professor of Epidemiology, School of Public
Health, University of Michigan, Ann Arbor, Mich.
HOFFMAN, DIE'M~ICR, Ph. D.-Chief, Division of Environmental Carcino-
genesis, American Health Foundation, New York. N.Y.
KELLER, ANDREW Z., D.M.D.-Chief, Epidemiologic Studies Section, Veterans
Administration Central Office, Washington, D.C.
Knuntuor,Z, RICHARD A., M.D.-Medical Director, Institute of Respiratory
Diseases, Kettering Medical Center, Kettering, Ohio.
LENFANT, CLAUDE, M.D.-Director, Division of Lung Diseases, National
Heart and Lung Institute, National Institutes of Health, Bethesda, Md.
MCLEAN, ROSS, M.D.-Professor of Medicine, Bowman Gray School of Medi-
cine, Wake Forest University, Winston-Salem, N.C.
MCMILLAN, GARDNER C., M.D.-Associate Director, Etiology of Arteriosclero-
sis and Hypertension, Division of Heart and Vascuiar Diseases, National
Institutes of Health, Bethesda, Md.

NETTESEEIM, PAUL, M.D.-Group Leader, Respiratory Carcinogenesis, Biol-
ogy Division, Oak Ridge National Laboratory, Oak Ridge, Tenn.
PAFFZNBARCER, RALPH S., JR, M.D.-Chief, Epidemiology Section, Bureau
of Adult Health and Chronic Diseases, California State Department of
Public Health, Berkeley, Calif.

PETTY, THOMAS L., M.D.-Associate Professor of Medicine and Head, Divi-
sion of Pulmonary Diseases, University of Colorado Medical Center,
Denver, Colo.

RAUSCHER, FRANK J., M.D.-Director, National Cancer Institute, National
Institutes of Health, Bethesda, Md.

RENZETTI, A'ITILIO D., JR., M.D.-Professor of Medicine, Pulmonary Disease
Division, University of Utah Medical Center, Salt Lake City, Utah.
Smrmr, UMBERTO, M.D.-Associate Scientific Director for Carcinogenesis,
Division of Cancer Cause and Prevention, National Cancer Institute,
Nationai Institutes of Health, Bethesda, Md.
SCnuMAN, LEONARD M., M.D.-Professor and Head, Division of Epidemiology,
School of Public Health, University of Minnesota, Minneapolis, Minn.
SHIMKIN, MICHAEL B., M.D.-Professor of Community Medicine and Oncol-
ogy, Department of Community Medicine, School of Medicine, University of
California, La Jolla, Calif.

WYNnm, ERNEST L., M.D.-President, American Health Foundation, New
York, N.Y.

The following additional staff members of the National Clearinghouse for
Smoking and Health contributed to the preparation of this report: Richard
H. Amacher, Elaine Bratic, Emil Corwin, Lillian Davis, Sandy Harris,
Gertrude P. Herrin, Nancy S. Johnston, Theresa Klotz, Mary Mitchell,
Donald R. Shopland, Kathleen H. Smith, and Elsie Van Valkenburg.

xi


CHAPTER 1

Page

CARDIOVASCULAR DISEASES
CORONARY HEART DISEASE (CHD)

Zntroduction --_-___-____________------------
Epidemiologic and Autopsy Studies _ _ _ _ _ _ _ _ _ _ _ _
   I. Studies in Men Demonstrating a Re-
     lationship Between CHD and Smok-
      ing  -_____-_--__--- - _ _ - _ _ - - ______-
   II. Studies Failing to Demonstrate a Defi-
     nite Relationship Between Smoking
       and CHD ________________________
  III. Studies in Women Relating CHD and
      Smoking  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ -
Carbon Monoxide (CO)

  Introduction ____________________------------
  Epidemiologic Studies  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Experimental Studies in Man - - _ _ _ _ _ _ _ _ _ _ _ _ _ - -
Nicotine _______-____________-----------------
Experimentul Studies _ _ _ _ _ _ - _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
PERIPHERAL VASCULAR DISEASE  _ - - _ _ _ _ _ _ _ _
Epidemiologic Studies  _ _ _ _ _ - _ _ _ _ _ _ _ _ - _ - _ _ _ _ _ _
Experimental Studies _ _ _ _ _ _ - _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
CEREBROVASCULAR DISEASE (CVD)  _ - _ _ _ _ _ _
  Epidemiologic Studies  _ _ _ _ _ _ _ _ _ _ _ _ - _ _ _ _ _ _ _ _ _ _
CIGARETTE SMOKING AND ASSOCIATED CHD
RISK FACTORS __- ______________ -- _____ -_-__
THROMBOSIS  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
SUMMARY OF RECENT CARDIOVASCULAR
FINDINGS  _ _ _ _ - _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
CARDIOVASCULAR DISEASE REFERENCES _ _ -
CARDIOVASCULAR DISEASE SUPPLEMENTAL
REFERENCES  -_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ___ _ _ _ _ _ _ _ _ _ _

3
4

4

8

9

10
11
11
13
13

14
14
16

16
16

17

18

19
19

22

1


List of Figures

Figure l.-Mortality for men with and without ven-
    tricular premature beats (VPB), according to
    presence or absence of smoking as a risk factor.
    Bars show percentages of men who died during
     3-year period _-- ________ - _________ --- ____    6

Figure Z.-Relative odds of developing atherothrombotic
    brain infarction (ABI) , coronary heart disease
    (CHD), or intermittent claudication (IC) ac-
    cording to levels of cigarette smoking -__ _ __

16

Figure 3.-Serum cholesterol levels of cigarette smokers
     and nonsmokers in the Belgian military service _

18

J&t of Tables

Table l.-1968 serum cholesterol, diastolic blood pressure,
    cigarette smoking status, and 12-year mortal-
    ity-cohort of 903 men, age 40 to 69 in 1958,
    free of evidence of organ system disease and
    ECG abnormalities and followed long-term with-
    out systematic intervention. Peoples Gas Com-
    panyStudy,1958to1970 ___-- ____ -___-- _____    7

Table Z.-Cigarette smoking and sudden death from CHD
     in women -__--____-_____-__--____________    10

Table 3.-Standardized multivariate regression coefficients
    of intermittent claudication on various charac-
    teristics _____-_-__-_____-_________________ 15


CHAPTER 1

CARDIOVASCULAR DISEASES

CORONARY HEART DISEASE (CHD)

Introduction

One million deaths per year are attributable to diseases of the
cardiovascular system in the United States. Arteriosclerotic car-
diovascular disease (ASCVD) is the leading cause of death in this
country, accounting for greater than 50 percent of annual deaths ;
coronary heart disease (CHD) alone is responsible for 600,000
deaths per year. Cigarette smoking, hypercholesterolemia, and
hypertension have been identified as major risk factors for the
deveIopment of CHD.

Epidemiologic, autopsy, and experimental evidence presented
in past editions of this report (1964, 1967, 1968, 1969, 1971,
1972, 1973) support a causal relationship between cigarette
smoking and cardiovascular morbidity and mortality, as sum-
marized below:

1. Both retrospective and prospective epidemiologic studies
have demonstrated a strong relationship between cigarette smok-
ing and increased CHD morbidity and mortality, with approxi-
mately a twofold higher risk of dying from CHD for all male
cigarette smokers compared to nonsmokers.
2. A dose-response relationship has been demonstrated between
cigarette smoking and CHD morbidity and mortality in men.
3. Cigarette smoking acts both independently of and synergis-
tically with the other two major risk factors to produce these
effects on CHD morbidity and mortality.
4. The above relationships between cigarette smoking and
CHD morbidity and mortality have been demonstrated in Black
and Asian, as well as Caucasian, populations.
5. The relative importance of cigarette smoking in the develop-
ment of CHD in young men (less than 50 years old) is greater
than that for any other risk factor.


6. Most prospective and retrospective studies suggest that pipe
and cigar smokers exhibit a slightly higher risk of development
of CHD than nonsmokers (but a significantly lower risk than
cigarette smokers), while some studies demonstrate no such rela-
tionship.

7. Prospective epidemiologic studies document that cessation
of cigarette smoking results in reduced mortality from CHD.

8. Autopsy studies reveal greater frequency and severity of
coronary and aortic atherosclerosis among cigarette smokers than
nonsmokers ; cigarette smokers have been reported to have greater
myocardial arteriolar wall thickening at autopsy than non-
smokers.

9. Experimental evidence in humans suggests that cigarette
smokers with preexistent angina have a greater impairment in
cardiac work capacity than nonsmokers. The role of cigarette
smoking in the etiology of angina is unclear.

10. Experimental studies on humans and animals have shown
that the pathophysiologic changes commonly observed in patients
with CHD may be aggravated by cigarette smoking ; contribu-
tions from both nicotine and carbon monoxide have been demon-
strated. In addition, some of the biochemical and anatomical
abnormalities seen in CHD have been induced by cigarette smoke,
carbon monoxide, and nicotine.

Most of the studies reviewed in the last year confirmed the
knowledge of the relationship between cigarette smoking and
CHD. A listing of these studies appears in a separate section of
the Supplemental Bibliography. A number of studies extended
the knowledge of the association between cigarette smoking and
CHD, but several studies presented data which were either par-
tially or wholly inconsistent with the known relationships; these
two types of studies are reviewed below.

Epidemiologic and Autopsy Stud&

I. Studies in Men Demonstrating a Relationship Between CHD
and Smoking.

The Coronary Drug Project Research Group studied, by mul-
tivariate analysis, 2,035 survivors of myocardial infarction in a
prospective investigation to determine the relationship of placebo-
treated premature beats and other known risk factors to sudden
coronary deaths and total mortality (CV 12). Nonsmokers with
ventricular premature beats (VPB) had a significantly higher
total mortality than nonsmokers without VPBs (P <.05), and
smokers with VPBs had a higher incidence of sudden coronary

4


deaths than smokers without VPBs (P <.Ol). Among patients
without VPBs there was a significantly higher mortality rate in
smokers compared to nonsmokers (P <.05). Even in the presence
of VPBs, smokers had significantly higher total mortality (P
<.05) than nonsmokers. A higher incidence of acute coronary
deaths in smokers with VPBs compared to nonsmokers with
VpBs was also found, but the difference was not statistically
significant (P h.08). Thus, in survivors of myocardial infarc-
tion, smoking was associated with a significantly increased mor-
tality, and when complicated by the presence of ventricular pre-
mature beats, resulted in an incidence of sudden death greater
than the sum of the mortality from sudden death attributed to
either risk factor (cigarette smoking or VPB) alone (figure 1).
In this study, "lethal interactions" of this nature were found
only for smoking, digitalis therapy, cardiac enlargement, and
heart failure. These results indicate that cigarette smoking is an

0

Deaths From All Causes
Sudden Coronary Deaths

26.6t **

VPB 0" ECG c   -      + J          -
                w                       -  + J

Number           Nonsmoker                    Smoker

of men      1,116          137           684           98

   o P < .05, o *P < .Ol (Comparison of men with and without VPB)
    v <.05      (Comparison of men with and without risk factor)

FIGURE I-Mortality for men with and without ventricular premature beats
(VPB), according to presence or absence of smoking as a risk factor. Bars
show percentages of men who died during 3-year period.

SOURCE : Coronary Drug Project Research Group (CVft).

5


important risk factor in the occurrence of sudden death as well
as death from all causes among patients with known CHD.

In a recent article, Mennotti and Puddu (CV 26) reported on
the lo-year follow-up data of the 1,717 men between the ages
of 40 and 59 who were part of the Seven Countries Study.
Whereas at five years, no relation could be found between the
incidence of CHD and cigarette smoking, the lo-year follow-up
data revealed a correlation between cigarette smoking and CHD,
with a relative risk of 1.30-1.62 for smokers of greater than 10
cigarettes per day ; the relative risk varied with the stringency
of criteria for diagnosis of CHD and the degree of smoking. In
these two populations, the incidence of CHD was far below that
found in the United States, yet the current data suggest that
cigarette smoking is a significant risk factor in the development
of CHD in Italy.

With regard to the relative risks of the various risk factors,
analysis of the 12-year follow-up data from The PeopIes Gas
Company Study (CV 81) revealed that in the cohort of 903
men free of CHD at the initial examination, the risk factor
which was associated with the highest 12-year mortality from
all causes was cigarette smoking, whether alone or in combina-
tion with the other risk factors (table 1). For all "CVR"
(cardiovascular-renal), sudden, and CHD deaths there was a
trend toward increased mortality in the smokers, but the total
number of cases in each category was small.

Carlson and Bottiger (CV IO), in the Stockholm Prospective
Study, examined 3,168 men and found that, over a g-year follow-
up period, the development of fatal and nonfatal myocardial in-
farction and other coronary deaths was related to cigarette smok-
ing, elevated serum cholesterol, and elevated serum triglyceride
concentrations. The incidence of new events of ischemic heart
disease was significantly higher for all smokers (P <.Ol) and
for smokers less than 60 years old (P c.001) compared to non-
smokers. Smokers aged 36 to 60 had significantly higher serum
cholesterol and triglyceride levels, and higher blood pressure
readings than nonsmokers.

In terms of CHD morbidity and mortality, cigarette smoking
exerts its most potent effect on men under 60. Blacket, et al. (CV
7')` in a retrospective study of 70 men in New South Wales with
CHD, diagnosed between the ages of 28 and 40, demonstrated
that 27 percent of this "coronary group" smoked more than 30
cigarettes per day as compared with 11 percent of the controls
(P <.OOl). A total of 23 percent of the coronary group smoked
more than 40 cigarettes per day (P < .Ol).

6


TABLE l.-1968 serum cholesterol, diastolic blood pressure, cigarette smoking status, and B-year mortality-co-
hort of 903 men, age 40 to 59 in 1968, free of evidence of organ system disease and ECG abnormalities and
followed long-term without systematic intervention. Peoples Gas Company Study, 1968 to 1970.

                                                             lbYeuYortdity
iYE;   I%ic2'=   sz%is    ":A?
            PramW3'                             All uuMs   %i!azz    "2~         CW         Stroke

  NH       NH       NE        208      16,t  69.9$    2,   8.1     0,   0.0    2,   8.1    0,   0.0
  H         NH       NH       106      11,   80.4    6,  40.2     1,   7.8    8,  21.8    1,   6.6
  NH        H        NH        40       3,   72.6     1,  23.8     1,  28.8     1,  23.8     0,   0.0
  NH       NH       H         289      88,  136.3    17,  61.3     6,  21.1    13,  46.6     4,  14.7
  H         H         NH        34      4,  83.9     1,  20.8     0,   0.0     1,  20.8    0,   0.0
  H        NH       H         164      26,  172.2    16,  98.2     7,  44.8    10,  63.6     4,  26.6
  NH        H        H         40      8,  170.7     2,  42.1     1,  22.4     1,  22.4    1,  19.7
  H         H         H         32     10,  819.8     4, 118.0     1,  26.3    8,  76.4    1,  41.6
  1 only high                     436      62,  118.0    23,  63.2    8,  18.7    17,  39.4    6,  11.2
  Any 2 only high                 228      38,  162.8    18,  78.6     8,  36.9    12,  53.6    6,  20.4
  Any 2 or aI1 3 high               260     48,  182.2    22,  84.1     9,  36.3    16,  67.6     6,  22.2
  All                          so!3     116,  124.1    47,  61.8    17,  19.3    84,  37.7    11,  11.7

o ??? ?o?? o??? ?? ???? ??? *?*? eihokt& Z-SO au/dl at amtry 0#68): for diublk blood D-, zso mm Ns et autrr flB66); uld for et8uwtb uaokiar.
210 cirmetta/~ et mltry ~19W.
tNumtwr of datb.
:Ae- datll rdemoo.
8OUltcE: Btamlar, J.. et al. (CV 81)

4


The Boston Collaborative Drug Surveillance Program conducted
a retrospective study on the prevalence of coffee drinking and
cigarette smoking in 276 patients with a diagnosis of acute
myocardial infarction (CV 8) and another study on 440 patients
with acute MIS (CV 21) comparing these patients with hospital-
ized controls. On the basis of their data, they suggested that
the association between coffee drinking and acute myocardial
infarction was stronger than that between cigarette smoking
and acute MI. There was observed an almost twofold risk of
developing acute MI in noncoffee drinking patients who currently
smoked more than 1 pack per day as compared with noncoffee
drinking nonsmokers.

Hrubec (CV 20) reviewed data from the veteran twin panel of
The National Research Council on patients with angina pectoris
diagnosed by questionnaire, and found no significant correlation
between coffee consumption and angina, except in the group
smoking more than 11/ packs .of cigarettes per day (P <.03).
There was a significant relationship (P c.06) between cigarette
smoking of any magnitude and the presence of angina.

II. Studies Failing to Demonstrate a Definite Relationship Be-
tween Smoking and CHD.

Cotton, et al. (CV 13)) in a retrospective study, examined 91
men with a past history of myocardial infarction (4 months to
10 years). Case material was obtained from the files of two
referring physicians in England, and controls were chosen from
a regional transfusion service. These workers found no increased
prevalence of MI among current smokers, but did report a sig-
nificantly increased prevalence of MI in men with a past history
of smoking (P <.OOl). The authors concluded that the lack of
significant difference between the patients and controls in their
"current" smoking habits ". . . probably reflects the fact that
some of the patients gave up smoking or reduced the amount
smoked after their coronary attacks."

Durakovic and Saric (CV 15), in a retrospective study of 998
Yugoslavian industrial employees, found no statistically signif-
icant correlation between cigarette consumption and the preva-
lence of angina pectoris.

Malhotra (CV 25) found no difference between current smok-
ing habits in 44 patients with myocardial infarction and 88 hos-
pitalized age- and sex-matched controls in an Indian population.
A significant difference was found between cases and nonhospi-
talized healthy controls (P = .02).

Bruschke, et al. (CV 9) reported follow-up from 5 to 9 years
after coronary arteriography of 590 consecutive patients with

8


significant coronary artery obstructive disease, and found a
higher mortality rate in smokers compared to nonsmokers, but
the difference was not statistically significant.
In New Guinea, Sinnett and Whyte (CV 29) reported a very
low prevalence of CHD in a rural tribal area. The incidence of
other known coronary risk factors was low, but tobacco was
smoked by 73 percent and 20 percent of males and females, re-
spectively. However, the authors emphasized that the tobacco
leaf is dried and rolled into a bamboo pipe at least 6 inches long
"and the smoke is not inhaled."

De Soldati, et al. (CV IS) conducted a retrospective study
on 66 patients with recurrent myocardial infarction in Buenos
Aires, and found a statisticahy significant correlation between
cigarette smoking and recurrent myocardial infarction, but also
reported that the nonsmokers had a significantly shorter inter-
val between infarctions than the moderate or heavy smokers.

III. Studies in Women Relating CHD and Smoking.

Most of the studies on the relation between the various risk
factors and CHD morbidity and mortality have been done with
male populations. Data from large-scale studies have shown a
relationship between CHD mortality and smoking in women. In
a recent retrospective series of 182 women who died suddenly and
unexpectedly, Spain, et al. (CV 30) reported a significant corre-
lation between cigarette smoking and sudden death attributed to
CHD. In this study, there were 29 CHD-related deaths. There
was a significantly greater number of nonsmokers dying of non-
CHD causes than of CHD (P <.Ol) (table 2). In addition, 62
percent of the women dying suddenly from CHD smoked greater
than 1 pack per day, as opposed to 28 percent of the control
group composed of women dying suddenly of other causes (P
<.Ol). In the CHD group, there was an inverse relationship
between the degree of cigarette consumption and mean age at
death, i.e., heavy smokers died of CHD at an earlier age than
nonsmokers. The statistical significance of this observation was
not recorded. The authors reported that the mean age at the time
of sudden death for the entire group of 182 women was 19 years
less for heavy smokers compared to nonsmokers. The authors also
reported that in their autopsy populations the male:female mor-
tality ratio for sudden death due to CHD was 11:l for nonsmok-
ers and ~3.8:1 for all smokers.

9


TABLE Z-Cigarette smoking and sudden death from CHD in
                        wornen

                                          CHD sudden death
                         Population*
                      Number/percent   Number/percent Mean a&range
Smoking habits
Nonsmoker             81/53       3110       67/60-76
<20 cigarettes/day         29/19       8/28       55/52-61
220 cigarettes/day         43128       18162      48132-58
Total                 153/100      29llOO      54/32-76

*All deaths exclusive of CHD.
SOURCE: Spain. D. 1.. et al. GV 30).

Wink and Hager (CV 35)) in a retrospective study of 10 pre-
menopausal women with myocardial infarction, showed that
there was a significantly higher incidence of cigarette smok-
ing in this group of women than in postmenopausal women with
acute myocardial infarction seen in the same clinic (P <.OOl).

CARBON MONOXIDE (CO)

Introduction

The importance of the effects of low levels of exposure to carbon
monoxide on the pathophysiology of CHD is well recognized
(1967, 1968, 1969, 1971, 1972, 1973).

It is known that the gas phase of cigarette smoke contains
approximately 1 to 5 percent CO and that the concentration of
CO increases as the cigarette burns down. Heavy cigarette smok-
ers develop significantly higher COHb concentrations than non-
smokers, reaching levels of 4 to 15 percent. Arterial hypoxemia
may develop following CO exposure, and myocardial metabolism
may be significantly altered under the conditions of CO exposure,
thus limiting myocardial work capacity. A significant decrease in
exercise performance in patients with angina has been induced
by smoking non-nicotine cigarettes, with increases of carboxy-
hemoglobin concentrations to approximately 8 percent. Some of
the mechanisms responsible for these effects have been reviewed
in previous editions of this report.

In experimental studies, CO increases coronary flow and heart
rate in normal subjects, increases oxygen debt, and results in
myocardial hypoxia. Carbon monoxide has also been implicated
by some workers as an etiologic factor in the development of
atherosclerotic lesions. Recent studies have contributed signifi-
cantly to our understanding of the role of CO in the development
and pathophysiology of CHD.

IO


Epidemiologic Studies

Wald, et al. (CV 34) found, in cross-sectional analysis of 950
Danish smokers, a correlation between the development of athero-
sclerotic diseases and carboxyhemoglobin levels. They concIuded
that COHb levels were better indicators than smoking history
of a person's risk of developing ASCVD, including CHD. The
heavy smokers had a higher prevalence of ASCVD than the nil
and light smokers combined (P c.001). Only 8 of the 58 subjects
had a past history of myocardial infarction.

Experimental Studies in Man

Aronow, et al. (CV 3) studied the effect of carbon monoxide
exposure on myocardial work capacity and angina. Ten men
with known CHD and angina, aged 40 to 56, who were exposed
to heavy morning freeway traffic in Los Angeles for 90 minutes,
performed cardiopulmonary tests in the pre-exposure, immediate
post-exposure, and 2-hour post-exposure states. Each man served
as his own control by breathing purified compressed air on a
similar go-minute excursion in heavy morning traffic. After
breathing the freeway air, all 10 men developed marked increases
in expired-air carbon monoxide levels (P <.OOl), and arterial
carboxyhemoglobin levels (P <.OOl), both immediately and at
2 hours post-exposure. No differences were found in these param-
eters when the patients breathed compressed air. The mean exer-
cise performance of the 10 men was significantly impaired in the
immediate post-exposure period (P <.OOl) and also at 2 hours
post-exposure (P c.05). The mean exercise performance was
significantly increased from the immediate post-exposure period
to the 2-hour post-exposure period (P <.05), corresponding to
significant decreases in mean expired CO and percent COHb at
2-hours post-exposure. Significant decreases in heart rate (P
<.OOl) , systolic blood pressure (P <.Ol) , and the product of
the systolic blood pressure times the heart rate (P <.OOl) de-
veloped in relation to the onset of angina in the immediate post-
exposure period, and significant decreases were noted at the time
of onset of angina at the 2-hour post-exposure periods for heart
rate (P c.001) and the BP x HR product (P <.OOl). No sig-
nificant differences in any of these values were found when the
patients breathed compressed air. Three of the 10 patients devel-
oped ischemic ST segment depression during the ride of carbon
monoxide exposure ; none of the 10 patients developed such
changes during exposure to compressed air. As the BP x HR
product is one measure of cardiac work capacity, these results
strongly suggest that "less work can be done before the onset of

11


exercise-induced angina in patients with elevated carboxyhemo-
globin levels" (as manifested by diminution of both cardiac
work measurements and actual exercise performances). Pollu-
tants other than carbon monoxide may have contributed to the
findings in this study.

Using a double-blind design, Aronow and Isbell (CV 4) stud-
ied the effects of the administration of purified CO and purified
compressed air on 10 men with stable angina. All the subjects
were nonsmokers. Administration of the compressed air for 2
hours resulted in a significant decrease of venous COHb (P
<.OOl) from a mean of 1.07 percent to 0.77 percent and no
significant changes in mean exercise time until onset of angina,
systolic blood pressure (BP), heart rate (HR), or the BP x HR
product. Administration of 50 p.p.m. CO for 2 hours resulted
in a significant increase in venous COHb (P <.OOl) from a
mean of 1.03 percent to 2.68 percent, and significant decreases
in mean exercise time until onset of angina (P <.OOl) systolic
blood pressure, heart rate, and the BP x HR product at the time
of angina (P <.OOl) . It is important to note that the levels of
carboxyhemoglobin observed in the groups of patients from these
two studies were below those frequently attained by cigarette
smokers.

In a related study, Fortuin, et al. (CV 1, 2, 16) analyzed mid-
and post-exercise ECG changes in "normal" subjects and pa-
tients with stable angina before and after exposure to purified
CO. In the "normal" subjects, venous COHb concentrations of
5.7 to 7.1 percent were obtained, and exercise performance, as
measured by time period of exercise before attaining a specified
heart rate, was significantly impaired in both young (P <.005)
and middle-aged subjects (P <.Ol) . Seven of the 26 older "nor-
mal" subjects demonstrated some abnormality in their ECGs at
some stage in the study, and all of these ECG changes (including
ST segment abnormalities and arrhythmias) were exaggerated
after CO exposure. In the 10 patients with stable angina, venous
COHb levels were raised to 2.9 and 4.5 percent after exposure to
60 and 100 p.p.m. CO, respectively. The mean duration of exercise
before the onset of angina1 pain was significantly shortened follow-
ing CO exposure at both dose levels (P <.005), ST segment
depression was deeper in 5 of 10 patients, and, in general, had
an earlier onset and longer duration after CO exposure. In addi-
tion, duration of pain was significantly lengthened with exposure
levels of 100 p.p.m. (P <.Ol). These studies lend further sup-
port to the concept that CO exposure resulting in mild to moder-
ate elevations in COHb concentrations may exacerbate exercise-

12


induced myocardial ischemia in persons with preexisting clinical
or subclinical coronary heart disease.

NICOTINE

Nicotine has been found to increase heart rate, blood pressure,
cardiac output, stroke volume, and velocity of myocardial con-
traction. The cardiovascular effects of nicotine has been sum-
marized in The Health Consequences of Smoking (1971). Experi-
mental evidence suggests that these effects are mediated through
release of catecholamines from sympathetic ganglia and myo-
cardial chromaffin tissue, and that sympathetic ganglionic block-
ers inhibit these effects. There may also be neurogenic compo-
nents to the cardiovascular effects of nicotine, as well as effects
on regional coronary perfusion.

Experimental Studies

Bizzi, et al. (CV 6) studied the effects of nicotine on adipose
tissue in the rat. Rats were administered nicotine intraperitone-
ally and subcutaneously, and the responses of plasma free fatty
acids (FFA) and in vitro lipolysis were observed. Intraperito-
neal nicotine tartrate (NT) caused a transient rise in FFA, and
subcutaneous NT in 1 percent carboxymethylcellulose also re-
sulted in a rise in plasma FFA in a dose-response relationship.
Administration of the vehicle alone as a control was not per-
formed. Inhibitors of lipolysis (including beta blockers) inhib-
ited this stimulatory effect of nicotine on plasma FFA. Of
particular note was that in adrenalectomized rats, NT failed to
elevate plasma FFA, but did so when corticosterone was admin-
istered before sacrifice.

In vitro, NT added to a medium containing adipose tissue did
not result in enhanced release of FFA into the medium, thereby
implying an indirect effect of NT through enhanced catechola-
mine secretion as seen in the in vivo situation. Neither acute
nor chronic doses of NT resulted in elevated tissue triglyceride
concentrations.

These results confirm previous evidence of nicotine's ability,
both acutely and chronically, to elevate plasma FFA, this action
being mediated through enhanced catecholamine secretion. The
new findings concerning the role of adrenocorticoids are of un-
certain significance. The precise role of elevated FFAs in athe-
rogenesis remains to be elucidated.

13


PERIPHERAL VASCULAR DISEASE

A number of retrospective studies have implicated cigarette
smoking as one of the major risk factors in the development
and progression of peripheral atherosclerosis, arteriosclerosis ob-
literans (ASO) and thromboangiitis obliterans (TAO). The pa-
tency of peripheral bypass grafts may also be adversely affected
by cigarette smoking.

The increased incidence of peripheral vascular disease associ-
ated with smoking may be in part due to elevated COHb levels.
Experimental data suggest that cigarette smoking may chronic-
ally decrease peripheral flow capacity and acutely result in clos-
ure of precapillary sphincters, vasoconstriction, and decreased
blood flow in human connective tissue in vivo.

Recent prospective and retrospective epidemiologic evidence, as
well as experimental data add to our knowledge of the associa-
tion between cigarette smoking and peripheral vascular disease.

Epidemiologic StucZiee

The $6-year follow-up data of the Framingham Study (CV 18)
revealed strong relationships between cigarette smoking and the
development of the three major manifestations of atherosclero-
sis: CHD, atherosclerotic brain infarction (ABI), and intermit-
tent claudication (figure 2). The only exception to this was the
absence of correlation between cigarette smoking and ABI in
women, but for CHD deaths, MI, coronary insufficiency, and
intermittent claudication, the correlations were as strong in
women as in men. It appears that cigarette smoking is one of the
major risk factors in the development of intermittent claudica-
tion (table 3) (CV 24). A higher total incidence over the 16
years of follow-up and a higher annual incidence of intermittent
claudication occurred in smokers than in nonsmokers, the latter
statistically significant for all age groups of both sexes. When
the other risk factors were controlled for utilizing multivariate
analysis, the effect of smoking became even more pronounced.

In a retrospective study of 100 patients with peripheral vascu-
lar disease evaluated by peripheral angiography and selective
coronary angiography, Tomatis, et al. (CV 82) found that 98 *
percent of patients with aortoiliac disease, 91 percent of those
with femoropopliteal disease, and 93 percent with abdominal
aortic aneurysms had a history of smoking.

In a population of nondiabetic smokers with evidence of peri-
pheral vascular disease, Linhart, in Astrup, et al. (CV 5), found

14


Cigarette Smoking (Men, ages 45-74)

Number of Standard Deviations From Mean Value

FIGURE P.-Relative odds of developing atherotbrombotic brain infarction
(ABI), coronary heart disease (CHD), or intermittent claudication (IC) ac-
cording to levels of cigarette smoking.

SOURCE : Gordon, T.. Kennel, W. B. (CV 18).

TABLE 3.-Standurdized multivariate regression coeficients of
. intermittent &u&cation for various characteristics

Regr63aion coetlicient

CbSmt&StiC

Age 46.64   Age 66-64  Asfe 66-74     Yua (end
                       standsrd error)

Men
Cigarettes/day
Glucose intolerance
Serum cholesterol
Systolic blood pressure
Left ventricular
hypertrophp (ECG)

Women
Cigarettes/day
Glucose intolerance
Serum cholesterol
Systolic blood pressure
Left ventricular
hypertrophy (ECG)

0.362    0.618    0.016   0.451 (0.116)
0.323    0.410   -0.115   0.351 (0.076)
0.303    0.314   - 0.103   0.269 (0.092)
0.105    0.318   - 0.412   0.178 (0.107)


0.118    0.016    0.231   0.080 (0.087)


0.731    0.270    0.462   0.406 (0.126)
__--     0.442    0.232   0.390 (0.101)
0.404    0.286    0.113   0.334 (0.096)
0.640    0.247    0.420   0.356 (0.136)


0.242    0.223    0.304   0.247 (0.097)

Note: Incidence of iotczmittent chndication:
              46.64   66-64   66.74
  r&n           zo     46    16
  womca               61 12
SOURCE: Ksanel, W. B.. kutleff, D. (CV 24).

16


a significant correlation between frequency of severe intermittent
claudication and consumption of greater than 15 cigarettes per
day (P <.Ol). There was no difference between these heavy
smokers and the other smokers for development of gangrene, nor
did development of claudication vary with number of years smok-
ing or total number of lifetime cigarettes consumed. Of his 112
patients, 57 stopped smoking after initial diagnosis and treat-
ment, and subsequent progress of their claudication was retarded
with no fresh gangrene developing in any of these subjects. The
55 patients who continued smoking suffered from the same rate
of complications as seen before treatment.

Experimental Studies

Goldman, et al. (CV 17) reported that the amount of heat
loss from the hands of 10 normal subjects was found to be sig-
nificantly Iess on exposure to cold after subjects smoked two
cigarettes, when compared to the control state (P <.05).
Smoking exerted no effect on heat loss from the feet of these
subjects. These results corroborate previous reports of the
vasoconstrictive effects of smoking on the peripheral vascula-
ture. The differences in heat loss between upper and lower ex-
tremities were explained by differences in reactivity to vasomotor
stimuli, differences in total blood flow, and greater vasoconstric-
tor tone in the lower extremity.

CEREBROVASCULAR DISEASE (CM))

Retrospective studies have revealed a correlation between cig-
arette smoking and morbidity and mortality from CVD in men.
No correlation has been found previously for women.
Acutely, cigarette smoking has/been reported to increase cere-
bral flow and decrease cerebrovascular resistance. The exact role
of cigarette smoking in the pathogenesis of CVD is unclear. Re-
cent studies are summarized below:

Epidemiologic Studies

Data from a restrospective series of 598 nonpregnant women,
ages 15 to 44, with a diagnosis of stroke (CV II) revealed that
73 percent of the women with strokes were cigarette smokers as
opposed to 43.4 percent of the nonhospitalized control group
(P <.OOl) and 60 percent of the hospitalized control group (P
<.OOl). The combined effect on thrombotic episodes in this study
population of both smoking and oral contraceptives was greater

16


than that exerted by the use of oral contraceptives alone. It was
coucluded that cigarette smoking contributes significantly to the
development of stroke in women, and enhances the effect of oral
c&raceptives on the development of thrombotic cerebrovascu-
]ar events.

Analysis of the 16-year follow-up data of the Framingham study
(CV 23) revealed an increased risk of ABI attributable to smok-
ing in men, with a sixfold excess risk in male smokers aged 45
to 54. The numbers of cases are still too small to draw any firm
conclusions from the data. No correlation between smoking and
cerebrovascular events was found in women.

In a prospective study of 3,991 longshoremen followed for 18
years, Paffenbarger (CV 28) found no correlation between fatal
stroke and cigarette consumption. Included in the study group
were 59 cases (from a total of 132) of intracerebral hemorrhage.

CIGARETTE SMOKING AND ASSOCIATED CHD RISK FACTORS

There is conflicting evidence concerning the role of cigarette
smoking in the chronic elevation of serum lipids. Results from
studies of the acute effects of smoking on blood lipids, including
FFA, cholesterol, and triglycerides, have also been contradictory.
A negative correlation between cigarette smoking and mean
systolic and diastolic blood pressures has been shown in some
studies and not others. This apparent correlation has been ex-
plained by the negative association between smoking and relative
weight.

Recent contributions in this field are summarized below:

In a retrospective study of 42,804 military men in Belgium
(CV 33), multiple regression analysis revealed that in all age
groups smokers of greater than 20 cigarettes per day had a
higher serum cholesterol than nonsmokers. This finding was of
statistical significance in age groups 20 to 29 (P <.Ol), 30 to 39
(I' <.OOl), and 40 to 49 (P c.01); i.e., the years of greatest
risk of CHD for the combination of hypercholesterolemia and
cigarette smoking (figure 3).

Mundy and Cutforth (CV 27) studied 85 patients with myo-
cardial infarctions who had survived their infarctions for at
least six months. They found no correlation between "lipid levels"
and smoking. Only lipoprotein electrophoretic abnormalities were
reported, although the authors stated that serum cholesterols
and triglycerides were determined.

17


EPID.MHB

Chol. mp%

SERUM CHOLESTEROL VALUE

260 -              Smokers vs. Never-smokers

250 -

240 -

o   P < 0.05
o ?   < 0.01
o ?? ?????o

230 -

- - - Nonsmokers
       WCig/ D

     <20

w 251
w--e 280
      "S

20-29         w-39         40-49         3-50

2.615        4,551         3,252          089
1,083         2,069         1.029          370
*            .             o           nb
?            o             ?
             ?

FIIXXE 3.- Serum cholesterol levels of clgnrette smokers and nonsmokers in the
              Belgian military service.

SOLXCE : Van Hotrte, 0.. Kestrlont. H. (CT' 3.V).

In a prospective study of 10,000 male Israeli civil service
workers, aged 40 and up, Kahn, et al. (CV 22) found a positive
relationship between smoking habits at the start of the study
and the incidence of hypertension over a 5-year follow-up period
(P <.Ol).

THROMJ3OSIS

The role of cigarette smoking in promoting thrombosis has not
been well defined. Hawkins (CV 19). conducted experiments on
platelet functions of 30 healthy men and found that the bi-
phasic electrophoretic mobility change of platelets was altered
immediately after smoking and returned to normal at 15 minutes.

18


mole blood coagulation (P <.05), rates of initial clot forma-
tion, maximum clot tensile strength (P <.05), and clot retrac-
tion were all altered in the smokers in the direction of favoring
hypercoagulability as compared with nonsmokers, but were not
altered further in the smokers either immediately or 15 minutes
after smoking one cigarette.

SUMMARY OF RECENT CARDIOVASCULAR FINDINGS

1. Data from recent epidemiologic studies suggest that cigarette
smoking acts independently of and in conjunction with cer-
tain cardiac arrhythmias to increase the risk of mortality
from coronary heart disease in men. Smokers also have a
greater probability of dying from CHD at an earlier age than
nonsmokers.
2. New epidemiologic data suggest that women who smoke cigar-
ettes have a greater risk of sudden death from CHD than do
nonsmoking women.

3, The results of experimental studies demonstrate that the ele-
vated levels of carboxyhemoglobin frequently seen in smokers
may result in significantly decreased cardiac work perform-
ance and precipitation of ischemic electrocardiographic
changes and arrhythmias in patients with clinical and sub-
clinical CHD. Carboxyhemoglobin levels may be of value in
determining a person's risk of developing arteriosclerotic car-
diovascular disease.

4. Findings from experimental studies confirm that nicotine acts
indirectly to cause elevations of plasma FFAs. The relative
role of sympathetic versus adrenocortical stimulation of the
rise in FFAs remains to be determined.
5. Epidemiologic data reveal strong associations between cigar-
ette smoking and development of peripheral vascular disease.
6. Data from epidemiologic studies support a strong association
between atherosclerotic brain infarction and cigarette smok-
ing in premenopausal women and in men of all ages. No asso-
ciation between ABI and smoking has yet been demonstrated
in menopausal women.

CARDIOVASCULAR DISEASE REFERENCES

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  heart disease. Annals of Internal Medicine `79(l) : 46-50, July 19'73.

19


2. ANDERSON, E. W., STRAUCH, J. M., ANDELMAN, R. J., FORTZnN, N. J.,
  KNELBON, J. H. Effects of low level carbon monoxide exposure on
  human cardiac function. II. Subjects with angina pectoris. Preliminary
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3. hONOW, W. S., HARRIS, C. H., ISBELL, M. W., RoKAw, S. N., IMP-TO,
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4. ARONOW, W. S., ISBELL, M. W. Carbon monoxide effect on exercise-
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5. ASTRUP, P., et al. Exercise and smoking. IN: Wolf, S. (Editor). The
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6. Brzzr, A., TACCONI, M. T., MEDEA, A., GARATTINI, S. Some aspects of
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7. BLACKET, R. B., LEFLARTHAEPIN, B., PALMER, A. J., WOODHILL, J. M.
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9. BRUSHKE, A. V. G., PROUDFIT, W. L., SONES, F. M., JR. Progress study
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10. CARLSON, L. A., BOTTICER, L. E. Ischaemic heart-disease in relation to
  fasting values of plasma triglycerides and cholesterol. Stockholm
   prospective study. Lancet l(7756) : 865-868, April 22, 1972.
11. COLLABORATIVE GROUP FOR THE STUDY OF STROKE IN YOUNG WOMEN. Oral
   contraception and increased risk of cerebral ischemia or thrombosis.
   New England Journal of Medicine 288(17) : 871-878, April 26, 1973.
12. CORONARY DRUG PROJECT RESEARCH GROUP. Prognostic importance of
   premature beats following myocardial infarction. Experience in the
   coronary drug project. Journal of the American Medical Association
   223(10) : 1116-1124, March 5, 1973.
13. COTTON, S. G., NIXON, J. M., CARPENTER, R. G., EVANS, D. W. Factors
   discriminating men with coronary heart disease from healthy controls.
   British Heart Journal 34(5) : 458-464, May 1972.
14. DE SOLDATI, L., BARBIERO, O., CHUTLIAN, A., ROMAN, M. I., MATTIAUDA,
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   66 Casos de Segundo Infarto de Miocardio. (The more common
   atherosclerotic factors observed in 66 cases of a second myocardial
  infarct.) Presna Medica Argentina 59(2) : 71-74, January 1972.
15. DIJRAKOVIC, Z., SARIC, M. Odnos Pusenja Prema Koronarnoj Bolesti u
   Grupi Aktivnog Stanovnistva. (Smoking habit in relation to coronary

20


  heart disease in a group of workers.) Arhiv sa Higijena Rsda i
  Tok&&giju 22 (4) : 309-316, 1971.
16, FoRTUIN, N. J., ANDERSON, E. W., S~ucn, J. M., KNELSON, J. N. Ef-
  fects of low level carbon monoxide exposure on human cardiac
  function. I. Normal subjects. Preliminary paper-Environmental Pro-
  tection Agency and the C. V. Richardson Laboratory. November 24,
   1972.

17. GOLDMAN, R. F., NEWMAN, R. W., WILSON, 0. Effects of alcohol, hot
  drinks, or smoking on hand and foot heat loss. Acta Physiologica
  Scandinavica 87(4) : 498-606, 1973.

16. GORDON, T., KANNEL, W. B. Predisposition to atherosclerosis in the head,
  heart, and legs. Journal of the American Medical Association 221(7) :
  661-666, August 14, 1972.

19. HAWKINS, R. I. Smoking, platelets, and tbrombosis. Nature 236(6348) :
   450-452, April 28, 1972.

20. HRUBEC, 2. Coffee drinking and ischaemic heart-disease. (Letter). Laneet
  l(7802) : 648, March 10, 19'73.

21. JICK, H., MIETMNEN, 0. S., NEFF, R. K., SHAPIRO, S., HEINONEN, 0. P.,
  SU)NE, D. Coffee and myocardial infarction. New England Journal
  of Medicine 289(2) : 63-67, July 12, 1973.
22. KAHN, H. A., MEWALIE, J. H., NEUFEW, H. N., RISS, E., GOLDBOURT, TJ.
  The incidence of hypertension and associated factors: The Israel
  ischemic heart disease study, American Heart Journal 81(2) : 171-182,
   August 1972.

23. RANNEL, W. B., GORDON, T., WOLF, P. A., MCNAMAUA, P. Hemoglobin
  and the risk of cerebral infarction: The Framingham study. Stroke
   3(4) : 409-420, July-August 1972.
24. KANNEL, W. B., SBURTLEFF, D. The Framingham Study. Cigarettes and
  the development of intermittent claudication. Geriatrics 28 (2) : 61-68,
   February 1973.

25. MALHOTRA, S. L. In search of causes of ischaemic heart disease. British
   Heart Journal 35 (1) : 17-23, January 1973.
26. MENOTTI, A., PUDDU, V. Epidemiology of coronary heart disease. A 10
  years study in two Italian rural population groups. Acta Cardio-
  logica 28(l) : 66-88, 1973.

27. MUNDY, G. R., CUTFORTH, R. H. The relationship between serum lipid
  abnormalities and other major risk factors in myocardial infarction.
   Australian and New Zealand Journal of Medicine 2 (1) : 8-11, 1972.
28. PAFFENBARCER, R. S., JR. Factors predisposing t,o fatal stroke in long-
  shoremen. Preventive Medicine l(4) : 522-528, December 1972.
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  land population, Tukisenta, New Guinea. Cardiovascular disease and
  relevant clinical, electrocardiographic, radiological and biochemical
  findings. Journal of Chronic Diseases 26(5) : 266-290, May 1973.
36. SPAIN, D. M., SIEGEL, H., BIUDESS, V. A. Women smokers and sudden
  death. The relationship of cigarette smoking to coronary disease.
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   14, 1973.

31* STAMm, J. BERKSON, D. M., LINDB~RG, H. A. Risk factors: Their role
  in the etiology and pathogenesis of the atherosclerotic diseases. IN:
  Wissler, R. W. Geer, J. C. (Editors), The Pathogenesis of Athero-

21


  sclerosis. American Association of Pathologists and Bacteriologists
   Williams and Wilkins, Baltimore, 1972. pp. 41-119.
32. TOMATIS, L. A., FIERENS, E. E., VERBRUGGE, G. P. Evaluation of sur-
  gical risk in peripheral vascular disease by coronary artiography:
  A series of 100 cases. Surgery 71(3) : 429-435, March 1972.
33. VAN HOUTE, O., KESTELOOT, H. An epidemiological survey of risk factors
  for ischemic heart disease in 42,804 men. I. Serum cholesterol value.
   Acta Cardiologica 27(5) : 527-564, 1972.
34. WALQ N., HOWARD, S., SMITH, P. G., KJELDSEN, K. Association between
  atherosclerotic diseases and carboxyhaemoglobin levels in tobacco
  smokers. British Medical Journal l(5856) : 761-766, March 31, 1973.
36. WINK, K., HAGER, W. Myokardinfarkt bei menstruierenden Frauen.
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   67(11) : 364-372, March 17, 1972.

CARDIOVASCULAR DISEASE SUPPLEMENTAL REFERENCES

Part Z

(Articles which were reviewed but not discussed in the text, providing data
confirming well-established relationships between smoking and cardiovascular
disease.)

73-0400. ADAMS, J. D., ERICKSON, H. H., STONE, H. L. Myocardial metabolism
    during exposure to carbon monoxide in the conscious dog. Jour-
     nal of Applied Physiology 34(2) : 238-242, February 1973.
72-1061. ALAUPOVIC, P. ET AL. Distribution of arteriosclerosis in various
    populations. IN : Wolf, S. (Editor). The Artery and the Proc-
     ess of Arteriosclerosis : Measurement and Modification. The
     second half of the proceedings of an interdisciplinary conference
      on fundamental data on reactions of vascular tissue in man.
     Lindau, West Germany, April 19-25. 1970. New York, Plenum
     Press, 1972. pp. 21-76.

73-0068. BADRAN, A. M., SOROUR, A. H. A retrospective study of some risk
     factors in the epidemiology of myocardial infarction in Egypt.
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      231, 1972.

73-0656. BAREZ~~D~ HERNANDEZ, F. J., JALIRAQUE, L. M., JIMENEZ, D. L.,
     SIJZBERT, M. F., ORTIZ VAZQUEZ, J. El infarto de miocardio juvenil.
     Revision de nuestra experiencia en la unidad coronaria. (MYo-
     cardial infarction among young people. A review of new results
     in a coronary unit.) Revista Clinica Espanola 129(2) : 157-168,
      April 30, 1973.
72-0780. BARBORIAK, J. J., RIMM, A., TRISTANI, F. E., WALKER, J. R., LEPLEY,
     D., JR. Risk factors in patients undergoing aortocoronary by-
     pass surgery. Journal of Thoracic and Cardiovascular Surgery
     64(l) : 92-97, July 1972.

73-0608. BOLLINCER, A., LICRTLEN, P., KAINDL, F., MANNEEIMER, E.
     Koinzidenzuntersuchungen beziiglich peripherer Arteriopathie und
     Koronarsklerose. (Coincidence study on peripheral arteriopathy

22


    and coronary sclerosis.) Wiener Zeitschrift fiir Inner@ Medizin
    und ihre Grenzgebiete 53 (9) : 465-456, 458-462, 1972.
73~071. B@r'rxGER, L. E., CARLSON, L. A, Stockholm Prospective Study II-
    Nio ars uppfcljning. (Stockholm Prospective Study II-Nine
   year follow-up.) Lakartidningen 69(41) : 4640-4644, October 4,
       1972.

734072. Bni.lc~~nNoVlj, 0. KuoEeni u dlouhodobf! sledovanpch nemocnych s
    is chemickou chorobou dolnich konretin. (Smoking in a long-term
    follow-up study in patients with ischemic disease of the lower e.x-
    tremities.) Vnitfni ukarstvi 18 (6) : 537-541, 1972.
71-0362. CANO, J. P., CATALIN, J., BADRE, R., DUMAS, C., VIAIA, A., GIJIL-
    LERME, R. Dhtermination de la nicotine par chromatography en
    phase gazeuse. II. Application. (Determination of nicotine by
    chromatography in gaseous phase. II. Applications.) Annales
    Pharmaceutiques Francaises 28 (11) : 633-640, 1970.
73-0319. CORELLI, F. Buerger's disease: Cigarette smoker disease may always
    be cured by medical therapy alone. Uselessness of operative
    treatment. Journal of Cardiovascular Surgery 14( 1) : 28-36,1973.
73-0073. DAMM, G., TRAUMANN, K. J. Risikofaktoren und Arteriosklero-
    sezeichen bei Diabetes mellitus. Rheographische Untersuchungen
    an 100 Diabetikern. (Risk factors and signs of arteriosclerosis
    in patients with diabetes mellitus. Rheographic examination of
    100 diabetics.) Medizinische Klinik 67(16) : 687-591, April 21,
       1972.

73-0182. DELAEAYE, J. P., BESSET, C., TOUBOI.TL., P. Evolution spontan& et
    pronostic des arteriopathies ath&oscl&euses des membres in-
    ferieurs. (Spontaneous evolution and prognosis of atherosclerotic
    arterial diseases of the lower limbs.) Archives des Maladies du
    Coeur et des Vaisseaux 63 (12, Supplement 1) : 64-78, 1970.
73-0323. DICK, T. B. S., STONE, M. C. Prevalence of three cardinal risk
    factors in a random sample of men and in patients with
     ischaemic heart disease. British Heart Journal 35(4) : 381-386,
     April 1973.

72-0785. DARKEN, H. Zur Epidemiologie und Klinik des Herzinfarktes.
    (Epidemiology and clinical aspects of myocardial infarct.) In-
     ternist 13(8) : 310-317, August 1972.
73-0613. EKBLOM, B., HUOT, R. Response to submaximal and maximal ex-
    ercise at different levels of carboxyhemoglobin, Acta Physiologica
     Scandinavica 86 (4): 474-482, 1972.
73-0325. FINGERLAND, A. Eliminate koui;eni v prevenci chorob kardiovas-
    kularnich. (Elimination of smoking in the prevention of cardio-
    vascular diseases.) Ceskoslovenske Zdravotnictvi 29 (8) : 312320,
       1972.

73-0342. GREEN, P. W, B., HAWKINS, B. S., IRVINE, W. T., JAMIESON, C. W.
    An assessment of above- and through-knee amputations. British
     Journal of Surgery 59 (11) : 873-875, November 1972.
72-0966. HALL, G. H, Effects of nicotine, carbon monoxide and tobacco
    smoke on regional blood flow in the cerebral cortex. European
    Journal of Pharmacology 19(3) : 385-388, September 1972.
72-1110. HANSTEEN, V., LORENTSEN, E. Induced hypertension in the treat-
     ment of severe ischemia of the foot. Circulation 46(5) : 976-982,
      November 1972.

23


73-0669. HIGGINS, I. T. T., IOXNIIN, J. D., GILBON, J. C., COCHRANE, A. I+
     CAMPBELL, IL, WATERS, W. E., FEIUUS, B. G., JK, OH, Y.,
     HIGGINS, hf. W. Coronary disease in Staveley, Derbyshire, with
    an international comparison with three towns in Marion County,
     West Virginia. Journal of Chronic Diseases 26(10/11) : 567-530,
       November 1972.

D-0839. HILTGEN, M., GUERMONPREE, J. I,., BAFUULLON, A., MAUIUCE, P.,
     LENEGRE, J. Relations entre le de& des l&ions art+%ieiIea
     coronaires, la douleur cardique et les facteurs de risque dans
     100 cardiopathiea isch&niques explor&s par cinbangiographie
     coronaire shlective. (Relationship between the degree of coronary
    artery lesions, cardiac pain and risk factors in 100 IXEW of is-
    chaemic heart disease explored by selective coronary cineangiog-
     raphy.) Coeur et M&iecine Interne ll(3). 521-533, July-Sep-
       tember 1972.

73-6670. hACSSON, S.-O. CaIf blood flow and smoking. IN: TmBLIN, G.,
     Keys, A., Werk6, L. (Editors). Preventive Cardiology. Proceed-
     ings of an International Symposium, Skovde, Sweden, August
     21, 1971. New York, John Wiley and Sons, 1972. pp. 171-179.
72-6668. Jouvn, A., SOWMER, A., AVWINOS, C. Epid&niologie de l'athero-
     s&rose coronarienne. Les enqu&ea prospectives. (Epidemiology
     of coronary atherosclerosis. Prospective studies.) Gazette M&id-
      icaie de France 79 (13) : 2046, 2046, 2049, 2050, April 7, 1972.
72-1112. KARVONEN, M. J. Sydiin-ja verisuonitaudit-ehisy ja varhainen
     toteaminen. (Coronary heart disease-prevention and early diag-
     nosis.) Suomen LiiHkPrilehti 27 (1) : 76-82, 1972.
72-0635. KEYS, A., ARAVANIS, C., BLACKBURN, H., VAN BUCHEM, F. S. P.,
     BUPNA, R., DJORDJEVIC, B. S., F~ANW, F., KARVONEN, M. J.,
     MEN~ITI, A., PIJ~JDU, V., TAYLOB, H. L. Coronary heart disease:
     Overweight and obesity as risk factors. Annals of Internal
     Medicine 77 (1) : 15-27, July 1972.

73-0081. KHACHADURIAN, A. K., RUBEIZ, G. A., SAWAYA, J. I. Coronary
     artery disease. in the young. A study of risk factors in 100
      consecutive cases in Lebanon. Lebanese Medical Journal 26 (4) :
      263-267,1972.

73-6329. KLENSCFI, H., hNFT, C., HARRO, W. Die diagnostische Vaienz
     einiger Risikofaktoren-Tests sur Friiherkennung koronarer
     Erkrankungen. (The diagnostic value of several risk factor tests
     for early diagnosis of coronary diseases.) Zeitschrift Piir
     Kreislaufforschung 61(11)  : 995-1003, November 1972.
73-081. KYI, K. M., MING, C. K. An epidemiological study of ischaemic
     heart disease in the Rangoon General Hospital. Union of Burma
     Journal of Lie Sciences 3(3) : 337341, 1970.
72-1116. LIGHTS, N. F. Chronic carbon monoxide exposure. Proceedings
     of the Royal Society of Medicine 65(Q) : 16-17, September 1972.
73-0843. Lrrr~~, J. M., PETBITsI-JONES, D., ZYUTRA, P., WILLIAMS, R., KERR,
     C. A survey of amputations for degenerative vascular disease.
     Medical Journal of Australia l(7) : 329334, February 17, 1973.
72-0970. MARTELLI, A., PINELLI, G., MARIGNANI, A., RIMONDINI, S. L'Infarto
     de1 miocardio al di sotto dei 40 anni. (Studio clinico-elettro-
     cardiografico su 22 casi). (Myocardial infarct in people under
     forty [Clinico-electrocardiographic study of 22 cases.]) Acta
     Gerontologica 22(3) : 3-18, 1972.

24


i2-12Q6. MIHAIL, A., POPESCU, P., RI~ESCU, M., CARUNTU, M., BALAUTA, S.
    Influenta factorilor de rise si de agravare asupra evolutiei in-
    farctului miocardic acut. (Risk factors that aggravate the
     evolution of acute myocardial infarction.) Medicina Interna
     24 (3) : 291303, March 1972.

73-051g. NEUFEI~), H. N., MEDALIE, J. H., RISS, E., GOLDBOURDT, U. Selected
    findings of the Israeli ischemic heart disease study. Geriatrics
     28 (2) : 134-136, February 1973.

72-0387. NIMALASURIYA, A., WIMALARATNE, K. D. P. A clinico-pathological
    study of coronary heart disease in Ceylon. Ceylon Medical Journal
      17 (1) : 86-90, June 1971.

7~-1118. NUSSEL, E., HEHL, F. J. Rauchen und koronare Herzkrankheit.
    (Smoking and coronary heart disease.) Rehabilitation, Prii-
    ventivmedizin, Physikalische Medizin, Sozialmedizin 26 (l/2) :
      12-15, 1972.

72-1135. OSTAPOWICZ, G. Das sogenannte Raucherbein. (The so-called "smok-
    ers' leg".) Rehabilitation, Prlventivmedizin, Physikalische Medi-
     zin, Sozialmedizin 25 (l/2) : 20-21,1972.

73-0848. PAULSON, 0. B., PARVING, H. H., O-EN, J., SKINHOJ, E. In-
     fluence of carbon monoxide and of hemodilution on cerebral
    blood flow and blood gases in man. Journal of Applied Physiology
     35 (1) : 111-116, July 1973.

73-0162. PERNOT, C. L'infarctus du myocarde en milieu ferroviaire. As-
    pects medico-professionnels B propos de 100 cas. (Myocardial
     infarction in railway men. Medico-professional aspects con-
    cerning 100 cases.) Archives des Maladies Professionnelles de
     MBdecine du Travail et de S&uritB Sociale 33(12) : 611-620,
       December 1972.

73-0087. PREIMATE, E. Y. Rasprostranene nekotorykh faktorov riska i ikh
     sochetanii pri ishemicheskoy bolezni serdtsa v Rige. (Frequency
      of some risk factors and their combination in ischemic heart
     disease in the city of Riga. Epidemiological study.) Terapevti-
     cheskii Arkhiv 44(Q) : 35-38, 1972.

73-0089. RICORDEAU, G. Traitement m&Cal de 1'atheroscMrose obliterante
     des membres inferieurs. (Medical treatment of arteriosclerosis
     obliterans of the lower limbs.) Revue du Praticien 22 (29) :
     4037-4038, 4041-4042, 4045-4046, November 11, 1972.
73-6191. RIOS-MOZO, M. Arteriosclerosis femoro-poplitea. Clinica y diagnos-
     tico. (Femoro-Popliteal arteriosclerosis. Clinical symptoms and
     diagnosis.) Angiologia 24 (5) : 186-195, September-October 1972.
72-0792. RISSANEN, V., P~ORAI,A, K., HEINONEN, 0. P. Cigarette smoking
     in relation to coronary and aortic atherosclerosis. Acta Path-
     ologica et Microbiologica Scandinavica. Section A 80 (4) : 491-
      500,1972.

73-0677. ROSEN, A. J., DEPALMA, R. G., VICTOR, Y. Risk factors in periph-
     eral atherosclerosis. Archives of Surgery 107(2) : 303308,
      August 1973.

72-0391. SERAFIMOVA, J. Koronarnata bole& i pusenjeto niz iskustvata
     na kardioloskoto oddelenie na intemata. (Coronary disease and
     smoking-experience of the cardiologic department.) Godisen
     Zbornik na Medicinskiot Fakultet vo Skopje 17: 709-715, 1971.

26


72-0974. STAMLER, J., BERKSON, D. M. Prospects with multifactorial ap
     proaches emphasizing improvement in life style. Advances in
     Experimental Medicine and Biology 26: 213-243, 1972.
72-1123. STOCKSMEW, U. Vergleich physiologischer Parameter bei zigaret.
     tenrauchenden und nichtrauchenden Infarktpatienten. (A com-
     parison of physiological parameters in cigarette smoking and ~
     nonsmoking infarct patients.) Rehabilitation, Prliventivmedizin,
     Physikalische Medizin, Sozialmedizin 25 (l/2) : 69-60, 1972.
72-0795. SWIATKOWSKA, K. Szansa wyksztalcenia sie miazdzycy naczyn wien-
     cowych u osob palacych. Znaczenie tego czynnika u chorych z
     przewlekla patoligia ukladu oddechowego i u chorych na miazdzyce
     naczyn wiencowyeh. (The probability of development of coronary
     atherosclerosis in smokers. The significance of this factor in
     patients with chronic respiratory diseases and in patients with
     coronary atherosclerosis.) Polski Tygodnik Lekarski 27 (24) :
      911-913, June 12, 1972.

72-0939. SzAcHowm, J., hTIUcHA, Z., Wmz~~wsxx, H., PAWLISZEWSKA, J.,
     SZYMANSKI, W., BRZ~Z~WSKI, R., WYDIUYNSKI, L. Palenie ty-
     toniu a zawal serca. (Smoking and myocardial infarction.)
     Polski Tygodnik Lekarski 27(29) : 1126-1129, July 17, 1972.
72-0976. Txcurxscu, D., LILIS, R., HILT, M., ROVENTA, A. Cercetari epi-
     demiologice privind cardiopatia ischemica in industrie. Efectul
     incordarii psihice si al efortului intelectual. (Epidemiologlcal
     studies in ischemic heart disease in industry. Effect of physical
     strain and intellectual work.) Studii si Cercetari de Medicina
      Interna 13 (3) : 259-274,1972.

73-0194. THIIZL, H. G., PARKER, D., BRUCE, T. A. Stress factors and the
     risk of myocardial infarction. Journal of Psychosomatic Research
      17(10) : 43-57, January 1973.

72-0677. THORSTEINSSON, S. B., HARDE.U~ON, T., SAM~LSSON, S. 161
     sjuklingur medh kransaedhastiflu d lyflaeknisdeild Landspitalans
     1966-1968. (One hundred and fifty-one patients with myocardial
     infarct at the University Hospital of Iceland 1966-1968). Laekla-
      bladid 57(6) : 255-275, December 1971.

73-0684. TIBBLIN, G. Risk factors for developing myocardial infarction and
     other diseases. The "Men Born in 1913" study. IN: Tibblin, G.
     Keys, A., Werkij, L. (Editors). Preventive Cardiology. Pro-
     ceedings of an International Symposium, Skovde, Sweden, August,
     21, 1971. New York, John Wiley & Sons, 1972. pp. 33-42.
73-0092. VALGMA, K. A. Faktory, sposobstvuyushchie vozniknoveniyu ishe-
     micheskoi bolezni serdtsa. (Factors provoking ischemic heart
      disease.) Terapevticheskii Arkhiv 44 (9) : 38-40, 1972.
73-0686. VAN DEB STRICRT, J., GOLDSTEIN, M., FUMAND, J. P., BELENDER, J.
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     of Cardiovascular Surgery 14(l) : 9-16 January-February 1973.
72-0797. WWMJZR, L. H., M~DAR, G, Risikofaktoren der Atherosklerose.
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      656,1972.

73-0687. YAMAZAKI, N. Effects of hereditary and environmental factors
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      Journal 37(l) : 69-77, January 1973.

26


Part II

(Additional articles which were reviewed but not discussed in the text.)

7M23g. ALVAREZ, J. P., CLnnuc-, C. P., hONS0, J. M. A., MARTtiN,
     A. V. Action of tobacco on lipolysis and its modification by
     insulin. Experlentia 28(12) : 1453-1454, December 15, 1972.
72-1096. ALVA~~ DE Luoo, F. A. Metodo microcolorimetrico rapid0 para
     la valoracion de la carboxihemoglobina en la sangre. (Rapid
     microcolorimetric method for determination of the carboxyhemo-
    globin level in blood.) Revista de la Facultad de la Universitad
      Central de Venezuela 12(25) : 80-102, 1970.
734323. ANDERSON, T. W. Nutritional muscular dystrophy and human
    myocardial infarction. Lancet 2( 7824) : 298-302, August 11,
       1973.

73-0504. BIJZRENBAUM, M. L., FLEISCHMAN, A. I., RAKEELBON, R. I., HASTEN,
     T. WATSON, P. B. Ten-year experience of modified-fat diets on
    younger men with coronary heart-disease. Lancet l(7817) : 1404
     1407, June 23,1973.

72-1102. BIORCK, G. ET AL. Sudden cardiac death. IN: Wolf, S. (Editor).
     The Artery and the Process of Arteriosclerosis: Measurement and
     Modification. The second half of the proceedings of an inter-
     disciplinary conference on fundamental data on reactions of
     vascular tissue in man. Lindau, West Germany, April 19-26,197O.
     New York, Plenum Press, 1972. pp. 213-275.
72-1103. BRANTNEB F. Be&hen Zusammenliinge swischen konstitutioneller
     Aypotoine und Nikotinmissbrauch? (Are there correlations be-
     tween constitutional hypotension and nicotine abuse?) Rehabilita-
    tion. Prliventivmedisin, Physikalische Medisin. Sozialmedizin
     26( l/2) 31-32, 1972.

73-0320. CORONARY DRUG PRarEcr REs~is~ca GROUP. The Coronary Drug
     Project. Design, methods and baseline results. Circulation 47(3,
     Supplement 1) : I-l-1-50, March 1973.
    DAMM, K. H., Gxmrrwur, T., M-BALL, F., MUOBNY, G. Blut-
     suckerverhalten bei Kaninchen nach akutsr Kohlenoxidvergiftung
     unter atmosphlrischem Druck und unter Uberdruck. (Level of
     blood sugar in rabbits investigated under atmospheric pressure
     and high pressure after acute carbon monoxide intoxication.)
     Archiv fur Toxikologie 29(2) : 159-171, 1972.
73-0830. DAWBER, T. R., TEOMA~, H. E., Ja, MCNAMARA, P. M. Character-
     istics of the dicrotic notch of the arterial plus wave in coronary
     heart disease. Angiology 24(4) : 244-266, April 1973.
73-0324. DODU, S. R. A. Clinical aspects of ischaemic heart disease (IHD)
     in Ghanaians. Ghana Medical Journal 11(3) : 203-214, September
       1972.

72-1107. DOWER, G. E., OSBOBNE, J. A. Polarcardiographic study of hospital
      staff~bnormalities found in smokers. Journal of Eleetrocardio-
     logy 6 (3) : 273-280, 1972.

73-0408. GIN?& K. H. Muscle relaxation by drugs which stimulate sensory
     nerve endings. II. The effect of nicotinic agents. Neuropharma-
     cology 12(2) : 149-164, February 1973.

27


73-0326. GOULD, L., VENKATARAMAN, K,, GOSWAMI, M., GOMPRECHT, R. F.
     Cardiac effects of two cigarettes. Journal of Clinical Pharma,
     cology and New Drugs 13 (3) : 76-82, February-March 1973.
72-1236. JUCHAU, M. R., LEE, Q. II., BLAKE, P. H. Inverse correlation be.
     tween aryl hydrocarbon hydroxylase activity and conversion of
     cholesterol to pregnenolone in human placentas at term. Life
     Sciences; Part II: Biochemistry, General and Molecular Biology
     11(19) : 949-956, October 8, 1972.

72-0910. KJELDSEN, K., ASTRUP, P., WANSTRUP, J. Ultrastructural intimal
     changes in the rabbit aorta after a moderate carbon monoxide
     exposure. Atherosclerosis 16 (1) 67-82, July-August 1972.
72-0154. KUPKE, I. R. Biosynthesis of lipids in perfused dog aorta and
     coronary artery. II. Incorporation of [2-"C] acetate into lipids
     of two aortic layers and of the coronary artery under the influ-
     ence of nicotine. Journal of Molecular and Cellular Cardiology
     4 (1) : 27-38, February 1972.

73-0186. Lxzrx, I., MESSINGEX, H. B., ROSENMAN, R. H. A sociobiological
     approach to the study of coronary heart disease. Journal of
     Chronic Diseases 26(l) : 13-30, January 1973.
72-1114. LEON, A. S., ABRAM& W. B. The role of catecholamines in produc-
     ing arrhythmias. American Journal of the Medical Sciences
      262( 1) : 9-13, July 1971.
72-1115. LEVENE, D. L. Management of heart disease in the elderly. Canadian
     Family Physician 18(9) : 76-77, September 1972.
73-0844. Low, H. S. Cigarette smoking and the pathogenesis of atherosclero-
     sis-a hypothesis. Irish Journal of Medical Science 142 (4) : 174-
      178, July 1973.

73-0421. MITKOV, V., HALIPPETROVA, E., MADZIROVA, N. The effect of to-
     bacco smoking upon the blood supply of the brain in healthy
     persons. Folia Medica 13 (6) : 332-338, 1971.
73-0599. MITKOV, D., MILENKOV, H., KANTAREV, N. Influence of nicotine
     on the activity of lipoprotein lipase. Folia Medica 13 (6) : 328-
      331,197l.

72-6915. MORITA, T., BING, R. J. Lipid metabolism in perfused human
     coronary arteries. Proceedings of the Society for Experimental
     Biology and Medicine 140 (2) : 617-622, June 1972.
73-0264. RICHARDSON, D. R. Effects of "smoking" doses of nicotine on RBC
     velocity in mesenteric capillaries. Microvascular Research 5(2) :
      146-147,1973.

73-0268. SCOTI; R A., HENSON, D. E., L~SAK, A., TURNER, R. J., MALIKOVA,
      S., HASS, G. M. Relations between metabolic increase of plasma
     free fatty acids and the occurrence of arteriosclerotic thrombo-
     arteritis in rabbits. American Journal of Pathology 70(2) :
     209-233, February 1973.

73-6439. SEIGIZL, D. G., GREENEOUSE, S. W. Multiple relative risk functions in
     case-control studies. American Journal of Epidemiology 97(5) :
      324-331, May 1973.

73-0031. SLAYEN, B., JACKSON, A. F., PAPACDSTAS, C. A. The role of angio-
     tensin II in a pressor response to nicotine after phenoxybenza-
     mine. Proceedings of the Society for Experimental Biology and
     Medicine 142 (1) : 303-306, January 1973.

28


73-9313. STEBBINGS, J. H., JR. Two observed associations between respiratory
     allergies and hypertension in nonsmokers. American Journal of
     Epidemiology 97 (1) : 4-15, January 1973.
72-9627. TSUJJMOTO, A., KOJIMA, S., IKE~A, M., Doar, T. Excretion of nico-
     tin and its metabolites in dog and monkey saliva Toxicology and
     Applied Pharmacology 22 (3) : 365-374, 1972.
~3-0526. WALTON, K. W., CRAIG, G. M., PRIOR, P., WATERHOUSE, J. A. H.,
     SKILTON, J. Double-blind crossover clinical trial of pyridinolcarba-
     mate in peripheral arterial disease (arterio-sclerosis obliterans) .
     British Heart Journal 35(2) : 211-219, February 1973.

29


CHAPTER 2

CANCER

LUNG CANCER

  Introduction _-_- ______ - ________________ - ____
Lung Cancer in Men _______ - ______ -_-- ______
    Epidemiologic Studies  _ _ _ _ _ _ _ _ - _ _ _ _ _ _ _ _ _ _
   Histopathologic Studies ___-_- ____ ----_-__
Lung Cam3r in Women __-_-- ___________ - ____
   Histopathologic Studies  - _ _ - _ - _ _ - _ - - _ _ _ _ _ _
Relationships Between Pipe and/or Cigar
  Smoking and Lung Cancer _--- ________ -_-__
Secular Trenda qf Lung Cancer in Women - - _ _ _ _
Factors Involved in Reducing the Risk of Lang
  Cancer in Cigarette Smokers _ - _ - _ _ _ _ _ _ _ _ _ _ _ _
Occupationd Risks Contributing to the Develop-
  ment of Lung Cancer _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Experimental Studie.a _ _ _ _ _ _ _ _ _ - _ _ _ _ _ _ _ _ _ _ _ - _ _
   Experiments on Humans and Autopsy
      Material  _ _ _ _ _ _ _ _ - _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
   Respiratory Tract Carcinogenesis in Ani-
     mals _____-__________________________
   The Role of Infection in the Development
     of Lung Cancer __- _______ -_-_-- _______
   The Immune System and Lung Cancer _ _ _ _ _
Aryl Hydrocarbon Hydroxylaae Activity and the
  Role of Metabolites of Polyaromatic Hydro-
  carbons in the Development of hng Cancer _ _ _
    Studies in Humans ____ -_-_- _____________
    Studies in Animals  _ _ _ - _ - _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

ORAL CANCER

Introduction ____________________------------
Epidemiologic Studies  _ _ _ _ _ _ _ _ _ _ _ - _ - _ _ _ _ _ _ _ _ _

Page

35

37
37
38

39
39

39

40

40

41
43

43

46

47
43

49
49
49

52
53

31


CANCER OF THE ESOPHAGUS _- ____ ____ _-___ -  %e
                                 66

PANCREATIC AND GASTRIC CANCER _ _ _ _ _ _ __
CANCER OF THE LARYNX __ __ __ __ __ _ __- __ __ __
CANCER OF THE GENITOURINARY SYSTEM _ _ _
  Introduction __-____--______________________
  Epidemiologic Study  _ _ _ _ _ _ _ - _ _ _ _ _ _ _ _ - _ _ _ _ _ _ _
  Experimental Studies  - - _ _ _ _ _ _ _ _ _ - - _ _ _ _ _ _ _ _ _ _ _
     Humans ___-___________________________
     Animals  __- ______ - ______________ -- _____
SUMMARY OF RECENT FINDINGS ON THE
RELATIONSHIP OF SMOKING AND CANCER _ _
CANCERREFERENCES ____ -_--__-_---- ___..-_--
CANCER SUPPLEMENTAL REFERENCES _ _ _ _ _ _

List of Figuma

Figure l.-Trends in age-adjusted cancer incidence rates
for selected sites (1969-1969). White females _ _ _ _ - _ - -
Figure 2.-Trends in age-adjusted cancer incidence rates
for selected sites (1969-1969). Negro females _ _ _ _ _ _ - -
Figure 3.-Time trend : Age-adjusted mortality rates from
lung cancer (ICD 162 and 163) for men - - _ _ _ - _ _ _ _ - _ _ -
Figure 4.-Trends in smoking for U.S. men. Percentage of
smokers reported as "currently smoking cigarettes" on
surveys taken in 1966, 1966, and 1970, plotted by age
at survey and year of birth cohorts _--__-___- ___-----
Figure &-Time trend : Age-adjusted mortality rates from
lung cancer (ICD 162 and 163) for women _ - _ _ _ _ _ _ _ _ _ -
Figure 6.-Sex ratio of mortality rates from lung cancer
(ICD 162 and 163) for United States _ _ _ _ - - _ - - _ _ _ _ _ _ _
Figure 7.-Response of pulmonary macrophages in an
individual to cigarette smoking _ - _ - _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ - - _
Figure &-Effect of cigarette smoke on benzo(a)pyrene-
hydroxylase activity in rat lung _ - - _ _ _ _ _ _ - - _ _ _ - _ _ _ _ _
Figure 9.-Effect of actinomycin and puromycin pretreat-
ment on the induction of benzo (a) pyrene-hydroxylase
bycigarettesmokeintherat _______ -- ____ -__- ______-
Figure lO.-Time course for maximum induction of
benzo (a) pyrene-hydroxylase in lung after exposure of
rats to cigarette smoke - ____ -_-_- ________ -_----_-__

66
67
67
67
68
68
68
63

68
69
62

41

42

43

44


46

46

60

61

52

53

32


Figure ll.-The relationship between lung benzo(a)
pyrene-hydroxylase activity and the duration of exposure
tocigarettesmokeintherat ______ - _________________    64
Figure 12.-Relative risk of pancreatic cancer by number
of cigarettes smoked in males -__-___-___- ___________    66

List of Tables

Table L-Sites of origin of bronchial carcinoma and
deposition efficiency for particles in the segmental
bronchi ___-___---______-_-_____________________-- 45
Table 2.Relative risk of oral cancer according to level
ofexposuretosmokingandalcohol _-_-- _____________    54

33


CHAPTER 2

CANCER

LUNG CANCER

Introduction

An estimated 72,000 people died of lung cancer in the United
States in 1973 (CA 28). For males in the age groups 36 to 54
and 55 to 74, cancer is the second leading cause of death, and
the lung is the most common site of cancer in these age groups.
For men over 75, cancer is the third leading cause of death, and
lung cancer trails only cancer of the prostate as the most com-
mon cancer in this age group. For women of all ages, lung cancer
is now the fourth leading cause of death from cancer, and
for both sexes combined, cancer is the second leading cause of
death overall.

Cigarette smoking has been identified as the major cause of
lung cancer. Epidemiologic, autopsy, and experimental data re-
viewed in the original Surgeon General's Report and in previous
editions of The Health Consequences of Smoking (1967, 1963,
1969, 1971, 1972, 1973) strongly support this causal relationship
and are summarized below:

1. A strong relationship between cigarette smoking and lung
cancer mortality in men has been demonstrated in numerous
prospective and retrospective studies with risks for all smokers
as a group ranging from 7.61 to 14.20 times those of nonsmokers.

2. A dose-response relationship between cigarette consumption
and the risk of development of lung cancer for both men and
women has been demonstrated in numerous studies, with risks
in men for heavy smokers ranging from 4.9 to 23.9 times those
of nonsmokers.

3. Many investigators in the past have utilized Kreyberg's sys-
tem of classification of the histopathologic types of lung cancer

36


(Group I-Epidermoid and oat cell carcinoma ; Group II-Adeno-
carcinoma, bronchio-alveolar cell carcinoma, carcinoid tumor,
and mucous gland tumor). The resuhs from many studies in the
past have shown a strong association between Group I tumors
and cigarette smoking and data from some of these and other
studies have revealed an association between adenocarcinoma
(Group II tumors) and smoking. However, the association be-
tween adenocarcinoma and smoking is not as strong as that dem-
onstrated for Group I tumors, and not all data consistently dem-
onstrate such an association.

4. Although the incidence of lung cancer in women is lower
than that for men and data on lung cancer in women are sparse,
results from prospective and retrospective studies have demon-
strated an association between cigarette smoking and lung can-
cer mortality in females.'

5. The reIationships described above have been shown for
Caucasian, Negro, Japanese, and Arabic populations.

6. Mortality from lung cancer directly attributable to cigarette
smoking is increased in the presence of the "urban factor" and
occupational hazards, including uranium mining and exposure
to asbestos.

7. The combination of cigarette smoking and occupational
exposures to radon daughters in uranium mining or to asbestos
have been shown to produce additive and/or synergistic increases
in the risk of development of lung cancer.

8. Data from prospective and retrospective studies reveal an
increased risk of development of lung cancer in pipe and cigar
smokers compared to nonsmokers, but the risk is less than that of
cigarette smokers. The differences in mortality from lung cancer
between cigarette smokers and pipe and cigar smokers are con-
sistent for differences in inhalation patterns of these two groups
of smokers.

9. Dose-response relationships for amount smoked have been
demonstrated for pipe and cigar smokers.

10. Evidence has been presented which indicates that cessation
of smoking results in a lowered risk of mortality from lung
cancer in comparison with the risk of continuing smoking.

`Differences in the incidence in lung cancer of men and women may be
explained, at least in part, by differences in numbers of cigarette smokers,
amount of daily consumption of tobacco, inhalation patterns, use of filter VS.
nonfilter cigarettes, occupational exposure, as well as biologic differences in
susceptibility to lung cancer.

36


11. Results from autopsy studies have shown that changes in
the bronchial mucosa which are thought to precede development
of frank bronchogenic carcinoma are found more commonIy in
,mokers than in nonsmokers. Many of the studies demonstrated
dose-response relationships for these changes.

13. Experimental studies have demonstrated that dogs which
cllronically inhale cigarette smoke may develop lung tumors. In-
tratracheal instillation of several fract.ions of cigarette smoke
have resulted in the production of lung tumors in hamsters.
Sumerous subfractions of tobacco and tobacco smoke have been
shown to have skin-tumor promoting activity in mice.

13. Cell and tissue culture studies have demonstrated that
constitutents found in tobacco and cigarette smoke condensate
(CSC) may produce malignant transformation of tissues, as
well as nonspecific changes in cells.

14. Numerous complete carcinogens and cocarcinogens (tumor
promoters) have been isolated from and identified in cigarette
smoke condensate.

Most of the studies reviewed in the last year confirmed the
knowledge of the relationship between cigarette smoking and
cancer. A listing of these studies appears in a separate section
of the Supplemental Bibliography. A number of studies ex-
tended the knowledge of the association between cigarette smok-
ing and cancer, but several studies presented data which were
either partially or wholly inconsistent with the known relation-
ships ; these two types of studies are reviewed below.

Lung Cancer in Men

Epidemiologic Studies

Tokuhata (CA 32) collected data on the families of 270 lung
cancer patients and noted familial aggregations for both lung
cancer mortality and the cigarette smoking habit. He postu-
lated an autosomal recessive inheritance model for susceptibility
to development of lung cancer. However, when the familial ag-
gregation of lung cancer (familial host factor) was controlled
for, cigarette smokers still had approximately 5.3 times greater
mortality from lung cancer than nonsmokers.

Jha, et al. (CA 11) reviewed 25 histologically proven cases of
lung cancer in India and found that only 48 percent of the

37


patients were regular smokers (6 heavy and 6 light smokers),
A total of 36 percent of the tumors were adenocarcinoma and
large cell undifferentiated carcinoma.

Histopathologic Studies

In an analysis of the lo-year follow-up data from the Phila-
delphia Pulmonary Neoplasm Research Project, Weiss, et al. (CA
85) followed 6,027 men prospectively, including 330 nonsmokers,
with semiannual photofluorograms and observed the develop
ment of lung cancer in 121 men, 94 cases being proved histolog-
ically. All cases of lung cancer occurred among smokers. Anal-
ysis of the 67 cases of lung cancer occurring among the 2,680
men who were current smokers at the time of initial observa-
tion revealed dose-response relationships for number of ciga-
rettes smoked per day (P c.01). Utilizing the WHO criteria for
classification of histologic types of lung cancer, the authors found
dose-response relationships for smoking and squamous cell car-
cinoma in toto (P <.Ol), well-differentiated squamous cell car-
cinoma (P <.Ol), small cell (oat cell) carcinoma (P <.05,) and
adenocarcinoma (P <.05). No dose-response relationship was
demonstrated for poorly differentiated squamous cell or large cell
carcinoma. The dose-response curve for adenocarcinoma was based
on only 14 cases, and for oat cell carcinoma on only 8 cases.

Yesner, et al. (CA 62) reviewed 449 biopsies of autopsy-
proven cases of lung cancer seen at the Yale-New Haven and West
Haven Veterans Administration Hospitals between 1953 and
1959. By utilizing the current WHO criteria for classification
of lung cancer, the authors found a considerable number of dis-
crepancies in interpretation and classification of the histologic
material between the time of initial diagnosis and the present
review of the material. A total of 90 percent of the cases of
lung cancer occurred among cigarette smokers ; 62.4 percent of
the cigarette smokers with lung cancer had either epidermoid or
oat cell carcinoma, as compared with 19 percent of the non-
smokers (P <.OOl). A strong relationship was demonstrated
between smoking and the development of epidermoid and oat cell
carcinomas, but dose-response relationships could not be demon-
strated for epidermoid carcinoma. The authors suggested that a
reappraisal of associations between specific histopathologic fea-
tures of lung cancer and smoking may be warranted,

38


Lung Cancer in Women

Histopathologic Studies

Kennedy (CA 12) reviewed 168 cases of lung cancer in women
at the Sheffield Royal Infirmary diagnosed from 1955 to 1971.
smoking information was obtained from 112 charts. In each
d-year interval, there was an increased number of cases of lung
cancer compared with the preceding interval, with increases in
squamous cell and adenocarcinomas predominating. Unfortu-
nately, changes in the incidence of lung cancer at the Sheffield
Royal Infirmary cannot be determined, since the total number
of women autopsied during the different time periods was not
given. Kreyberg Group I tumors were about 4 times more fre-
quent than Group II tumors in smokers, but only 2.2 times more
frequent in nonsmokers. This difference was not statistically
significant. After combining the results of this study with those
of three other British studies, the author concluded that ciga-
rette consumption ". . . has little influence on the histological
appearance of lung cancer in British women." Limitations in the
analysis of the data restrict the conclusions which may be drawn
from this study, because of confusion in; the histologic classi-
fication of the cases of lung cancer cited in this article.

Relationships Between Pipe and/or Cigar
   Smoking and Lung Cancer

Wynder and Mabuchi (CA 39) reported on a retrospective
study of 30 male patients with lung cancer who smoked ex-
clusively cigars and/or pipes. A control group of current smokers
of pipes and/or cigars without smoking-related cancers was
matched with the cases for age. The authors found a 2.75 times
higher prevalence of Kreyberg Group I tumors than Group II
tumors in the lung cancer group. The average age of the pipe or
cigar smoking lung cancer patients with Group I tumors was
approximately 9 years greater than cigarette smoking lung can-
cer Group I patients; however, the cigar and pipe smokers began
smoking about one decade later than the cigarette smokers.
Among pipe and cigar smokers, the lung cancer patients in-
haled more frequently than the age-matched controls, but the
numbers were too small to draw statistically significant con-
clusions. The lung cancer group contained relatively fewer in-
dividuals who smoked both cigars and pipes (P <.025). A dose-
response relationship was demonstrated ; there was a significantly
greater percentage of heavy cigar smokers (greater than 4 cigars
per day, P <.005) and heavy pipe smokers (greater than 10

39


pipefuls per day, P c.05) within the lung cancer group than
among the controls.

Tidings and Bross (CA 21) studied 71 white male cigar/pipe
smokers with lung cancer from the Roswell Park Memorial In-
stitute and found no dose-response relationship for cigars, and
although the authors stated that no such relationship existed
for pipes either, there was a trend toward greater amounts of
pipe tobacco consumed in the lung cancer group, especially for
more than 10 pipefuls. In neither study did "occasional" cigar
smokers appear in the lung cancer group (P <.05).

Seculur Trend2 of Lung Cancer in Women

In an analysis of The U.S. Vital Statistics, Silverberg and Hol-
leb (CA 28) projected an 18 percent increase in deaths due to
lung cancer in males in 1973 and a 34 percent increase in deaths
from lung cancer in 1973 for females compared with 1968
statistics.

Analysis of recent data from Alameda County, California
(CA 1), confirms this increase in lung cancer incidence among
women (figures 1 and 2).

In a review of the national and worldwide statistics on mortal-
ity from lung cancer, Schneider-man and Levin (CA 25) ob-
served that the mortality rate from lung cancer in men con-
tinues to rise, although the rate of rise has diminished over the
past decade (figure 3), in concordance with the downward trend
in smoking being observed in men (figure 4). On the other
hand, the rate of rise in the incidence of lung cancer in women
continues to go up (figure 5), resulting in a narrowing of the
sex ratio from a high in 1960 to 6.8:l to a level of approxi-
mately 5.8:1 in 1967 (figure 6). The increase in the percentage
of women who smoke correlates well with this rising incidence
of lung cancer. The male:female mortality ratio is expected
to narrow still further, mostly due to the rising incidence of lung
cancer in women. The authors stated that the epidemic of lung
cancer in women has not yet reached its peak, and if women
continue to smoke, the incidence of lung cancer can be expected
to rise still further.

Factors Involved in Reducing the Risk of Lung Cancer
       in Cigarette Smokers

In a series of 88 lung cancer patients, Wynder and Hoffmann
(CA 37, 38) found that 73 percent of filter smokers and 65
percent of nonfilter smokers with lung cancer smoked more than

40


loo -

80 -


60-

40 -

20 -

4 -






2 -

- loo

      -40


CORPUS   -



BRONCHUS - 20

- 4






a 2

1960 1961 1962 1963 1964 1965 1966 1967 1968 1969

FIGUBX L-Trends in age-adjusted cancer incidence rates for selected s&s (19tW-
              69). White females.

SOURCL : A?elhnO, Y. 0.. et aL (Cd 1).

20 cigarettes per day compared to 50 percent of lung cancer pa-
tients who smoked similar amounts in 1950. The authors at-
tributed these findings to the reduced amount of carcinogens con-
tained in today's nonfilter cigarettes compared with 20 years
ago, and then concluded that the long-term smoker of today's
nonfilter cigarettes has a lesser risk of developing lung cancer
than the smokers of the nonfilter cigarettes of 1950 (all other
measurements of cigarette smoking dosage being equal). Meth-
ods of selection of patients were not presented.

Occupational Risks Contributing to the Development of
          Lang Cancer

In a recent prospective study of 11,656 male members of the
Insulation Workers Union in the United States and Canada

41


whose smoking habits were known (CA 15), a dramatic UlEer-
ence was found between the observed and expected incidences of
lung cancer among smokers. Among 2,066 men with no history of
cigarette use, 2 lung cancer deaths occurred where 5.98 deaths
were expected. Among the 9,590 cigarette smokers, 134 deaths
due to lung cancer were observed and only 25.09 were expected.
These results confirm the synergistic effect of asbestos ex-
posure and cigarette smoking on the risk of development of lung
cancer.

In a retrospective study of mortality among 93 female asbestos
workers who died between 1960 and 1970 and whose smoking
habits were known, Newhouse, et al. (CA 17) reported that 16
women died of lung cancer. Fourteen of these women had a his-
tory of smoking (87.5 percent), whereas only 65 percent of the
total number of deceased women were smokers. This difference
is statistically significant (P <.05). In a separate publication

100

80


60

40

20

   a- /------
,-
o ???????? ? ? ? ? ? ? ? ? ? ? ? ???????? ? a.-" ..-o-... ???? ???   CERVIX
                               `-. UTERI

1960 1961 1962 1963 1964 1965 1966 1967 1968 1969

-

-

loo

a0


E4

40

20

10

8


6

FIQUEE S.-Trends in age-adjusted cancer incidence rates for selected sites
             (1966-69). Nemo females.

SOURCE : Arellano, M. G., et aL (Cd 1).

42


(CA s), these workers reported that the interaction of ciga-
rette smoking and asbestos exposure in women, as well as in
men, appeared to be multiplicative.

Experimental Studies

Experiments on Humans and Autopsy Material

Heidendal, et al. (CA 8) used the Xenon-133 washout tech-
nique to detect and localize a clinically and radiographically
occult bronchogenic malignancy in one man by observing de-
creased pulmonary clearance of the radioisotope in the region of
the tumor. They then used the same procedure on 10 long-term
smokers with chronic coughs but no clinical signs of severe COPD

70

60

50

40

30

g 20
9
8
a
z
a
PI 10
s g
r" 8
s 7
   6

   5

I     I      I      I      I     I      I     I

JAPAN

1950-51   52-53   54-55   56-67   5849   50-61   62-63   64-65

                      Year

FIQUBE %-Time trend: Age-adjusted mortality rates from lung cancer (10
              162 and 163) for ma

SOURCE: Schneiderman, M. A., tipin, D. L. (OA 86).

43


and 10 non or ex-smokers and found no differences in their
pulmonary clearance of the radionuclide. The authors felt that
the Xenon washout scintiscan may be of use in high risk in-
dividuals for the detection and localization of occult lung car-
cinomas. This technique may be of special benefit to patients
with positive or highly suspicious sputum cytologies and nega-
tive chest roentgenograms and bronchoscopies.

In an experimental study using silastic casts of the human
tracheobronchial tree, Schlesinger and Lippmann (CA 24) were
able to show that for particles of varying sizes, the mean de
position efficiency of the segmental bronchi corresponded very
closely to the distribution of bronchogenic carcinoma in those
segments (table 1). The limitations of this experimental model
are discussed in detail by the authors.

     70






     60






     50





Y?
4     40
s
E
fJ     30
t





     20






     10

I-

L

  1940-49
*i/   \
o ?
- 1950

.
?
o ? 1690-99
\J
  \
          Prior
  \4-
      a

to 1890

i

I        I       I       I       I       I

18-24    25-34    35-M    45-54    55-64    65+

              Age et Survey

FIQURE 4.-Trends in smoking for U.S. men. Percentage of smokers reported as
"currently smoking cigarettes" on surveys taken in 1955 ( 0 ), 1966 ( i) , and
1970 (*), plotted by age at survey and year of birth cohorts.

SOURCE : Schnelderman. M. A., Levln, D. L (CA 86).

44


FIG

5  -                                   ,--0 JAPAN

3  -

                .-*
                  ,-
2  -

           .' .*
    ,.M'
       ,'
    -' .*
1-t      I      I      I      I      I      I      I

1950-51  52-53   54-55   56-57   58-59   60-a   62-63   64-65

                       Year

;URE 5.- Time trend: Age-adjusted mortality rates from lung cancer (ICD
            162 and 163) for women.

SOURCE: Schneiderman, M. A., Levln, D. L (CA 15).

Hoffmann (CA IO) has calculated that a heavy cigarette
smoker (greater than 30 cigarettes per day) living in a pol-
lutant free environment will inhale from his cigarettes approxi-
mately 300 times as much particulate matter (by weight),
and approximately 20 times as much benzo(a)pyrene (by
weight), as a nonsmoker living in a polluted city environment.
The author stated that as much as 95 percent of the pollutant
particles and benzo(a)pyrene will be retained within the lungs

TABLE 1.4Stes of origin of bronchial carcinoma and deposition
   eficiencg for particles in the segmental bronchi

Lobe Bronchus

Mean Percentwe of
Tote1 Careinomer
Originating in Lobar
Genqratioq which
&y;t.c m Each

Mean Efficiency (*'
ot Each Lobe
Bronchus *I
Percentage of
Total Ettlciency
of Lobar Generstion

Right upper               33.5               31.4
Right middle               7.5               6.2
Right lower               19.4              13.6
Left upper               26.0               29.6
Left lower                13.6              14.2
`Mean valuee for deposition edkieney were used beeauae of the range of particle sizes of
environmenti contrminante which could possibly eauee the production of leeions on the. reaPira-
tory epithelium.
SOURCE: Schleeinger. R. B.. Lippmsnn, M. (CA 24).

45


6

v I White
- Non-white

1950       53       56        59       62       65 67

Year

FIQUBE &-Sex ratio of mortality rates from lung cancer (ICD 162 and 168)

for united Statea

SOUlWE : Schneiderman, M. A., Levin, D. L (Ud 36).

of the smoker, while the city dweller retains a smaller fraction
of the inhaled material.

Respiratory Tract Carcinogenesis in Animals

In a follow-up study of carcinogenesis of the respiratory tract
induced by benzo(a)pyrene and ferric oxide in hamsters, Saffio-
tti, et al. (CA 22) found dose-response relationships for number
of tumors per tumor-bearing animal when varying doses of the
carcinogen were given in weekly doses intratracheally. Again, the
bronchus was the most affected site, and squamous cell carcinoma
the most common tumor induced. The latency period for deaths
of tumor-bearing animals varied inversely with the tumor dose.

Sellakumar, et al. (CA 27), using the same animal model,
maintained the concentration of intratracheal benzo (a) pyrene
at a constant level, but increased the amount of ferric oxide car-
rier two and threefold and found no change in the rate of
tumor production. Although ferric oxide appears to be necessary
for t.he production of lung tumors in hamsters, particularly when
small doses of benzo (a) pyrene are used (the mechanism
involves increasing the duration of contact with and the degree
of penetration of benzo(a) pyrene into the bronchial and pul-
monary tissue), the ferric oxide does not appear to be exerting
an independent carcinogenic effect, since no dose-response re-
lationship was noted when the amount of Fe,O, was varied.

In experiments in which benzo(a)pyrene was injected intra-
tracheally into Syrian Golden hamsters weekly for 52 weeks,
Feron, et al. (CA 4) found dose-response relationships for the

46


development of respiratory tract tumors, including squamous
cell carcinomas of the trachea, bronchi, and bronchiole-alveolar
pgions. No ferric oxide carriers were employed in this set of
exneriments. Although squamous cell carcinomas were not the
most common tumors produced, they appeared only in those
animals receiving the two highest concentrations of benzo(a)-
pyrene and in a dose-response relationship. When these re-
subs are compared with those from experiments in which ferric
oxide was used as a carrier for benzo(a) pyrene, a lower yield of
tumors and a longer latency period for the development of tumors
were observed. These experiments suggest that ferric oxide need
not be present for benzo(a)pyrene to produce lung tumors in
the Syrian Golden hamster.
Stanton, et al. (CA 29) described a new animal model for
the induction of epidermoid carcinomas of the lung. They in-
jected beeswaxtricaprylin pellets intrathoracically in rats and
observed that those pellets which contained cigarette smoke
condensate (CSC) or the heptane soluble fraction (HSF) of
CSC produced epidermoid carcinomas of the lung in 31 of 106
rats. Neither the pellets .by themselves nor inclusion of un-
smoked tobacco or tobacco ash within the pellets produced this
carcinomatous change. The authors concluded that this animal
model will be useful for detecting particular carcinogens found in
cigarette smoke condensate. The authors stated that, on the .
basis of their findings, the pulmonary carcinogen(s) found in
cigarettes "must be formed and contained in the smoke of the
burning cigarette."
Mohr, et al. (CA 14) described experiments performed on
10 common European hamsters in which weekly subcutaneous
injections of Ndiethylnitrosamine resulted in tumors of the
nasal cavities, larynx, trachea, and bronchi, including two
squamous cell carcinomas of the lung. "Most" bronchi showed
metaplastic changes. The two cases of lung cancer were found in
the animals who survived to 25 weeks. The authors postulated
that if longer survivals were achieved in some of the other
animals, more bronchogenic tumors may have been produced.
  The Role of Infection in the Development of Lung Cancer
Cigarette smokers have a higher incidence of chronic pulmo-
nary infect.ions than nonsmokers, Cigarette smoking has been
shown to be the major cause of chronic bronchitis. However,
the possible role of pulmonary infections in the development of
lung cancer is less clear, since cigarette smoking is the major
mse of chronic bronchitis and lung cancer. The ability of ciga-
rette smoking to contribute to the development of pulmonary
infections may also be responsible for some of the effect of


smoking on pulmonary carcinogenesis. Postulated mechanisms
include enhancing the repair processes of bronchial epithelial
cells, increasing the size of the transformation-susceptible pop
ulation of cells, disturbing pulmonary clearance of inhaled car-
cinogens, inhibiting pulmonary immune mechanisms, and enhano
ing or inhibiting metabolism of carcinogens (CA 16,26).

Nettesheim, et al. (CA 16, 26) conducted experiments on the
possible influence of pulmonary infection in the development of
lung cancer, utilizing several animal models and different in-
fectious agents. They reported that mice exposed to influenza
virus in conjunction with smog or CaCrO 4 had a reduced inci-
dence of pulmonary adenomas and adenocarcinomas compared to
that of mice exposed solely to the pollutants. The acute inflam-
matory response of the animal to this particular virus may have
been responsible for the decreased incidence of tumors in these
animals. In a study of rats with chronic murine pneumonia (CMP)
(CA 26)) addition of N-nitrosoheptamethyleneimine (a cyclic
nitrosamine) to the rats' drinking water resulted in an increased
incidence of squamous cell carcinomas of the lung in male rats,
as well as a higher number of tumors per animal in those with
CMP compared with uninfected male rats (P <.005). For fe-
male rats, the dose of carcinogen administered was very high,
which may have unintentionally obscured possible differences
between infected and uninfected rats. In studies designed to as-
sess pulmonary clearance, these authors found that animals
exposed to influenza virus had impaired lower respiratory tract
pulmonary clearance. This impairment of clearance was observed
acutely and chronically, and may have resulted from entrapment
in the inflammatory tissue (acute effect), and from scarring
(chronic effect).

The Immune System and Lung Cancer

Pinkerton (CA 19) investigated the effect of an experimental
animal's immunocompetence on the carcinogenicity of benzo (a) -
pyrene. After the subcutaneous administration of an adjuvant
(Freund's complete, incomplete, BCG, or pertussis vaccine) to
pregnant hamsters, there was an enhancement of carcinogenicity
of benzo (a)pyrene in the progeny as measured by frequency of
skin tumor development and weight of tumor. On the other
hand, prior administration of adjuvant to pregnant and non-
pregnant female hamsters resulted in diminution of tumorigenesis
induced by benzo(a)pyrene in those same animals. The author
postulated that induction of tumors by benzo(a) pyrene is in-
fluenced by T and B cell activity ; in the pregnant and non-


pegnant hamsters in which tumor formation was reduced by
treatment with adjuvant, the adjuvant elicited heightened T cell
response (cell-mediated antibody) and thus suppressed tumor
formation and growth. However, since T cells cannot cross the
placenta, a hypothetical humoral substance proliferated by the
activated T cells of the pregnant mothers may have crossed the
placenta, entered the fetus, and elnuted a B cell response (hu-
moral antibody). The author suggested that this humoral anti-
body may have resulted in increased susceptibility to tumor
formation and growth.

A& Hydrocarbon Hydroxylase Activity and the
  Role of Metabolities of Polgaromatic
   Hydrocarbons in the Developmnt
       of Lung Gamer

Studies in Humans

Cantrell, et, al. (CA 8) studied differences in aryl hydrocarbon
hydroxylase ( AHH) activity of pulmonary alveolar macrophages
(PAMs) obtained from 9 healthy smokers and 5 healthy non-
smokers. These investigators found a highly significant increase
in AHH activity in the PAMs from the current smokers corn-.
pared to those of the nonsmokers (P <.OOl) . The mean ages
and age ranges of the two groups of volunteers were not de-
scribed, nor were their places of residence (urban vs. rural)
stated. In one volunteer, AHH activity within PAMs was ob-
served over a period of time in which he began smoking 10 to
15 cigarettes per day; AHH activity was temporally related to
the presence, absence, and duration of smoking in this individual
(figure `7). The authors speculated on the role of AHH as a
protective mechanism against or, in contrast, as a promoter of
carcinogenicity of the inhaled polyaromatic hydrocarbons of
tobacco smoke.

Studies in Animals

Welch, et at. (CA 56) studied the effect of cigarette smoke
inhalation on pulmonary BP hydroxylase (AHH) activity in
rats, and reported the following: (1) When rats were exposed to
the smoke from 5 cigarettes per hour for 1 to 4 hours, an
initial decrease in AHH activity at 1 hour was observed, followed
by a substantial increase at 2, 3, and 4 hours (figure 8). (2)
This effect was blocked by actinomycin D and puromycin (in-
hibitors of RNA and protein synthesis) (figure 9). (3) After

49


0.05 1

      0.04


  *
2%
2 0   0.03
ti -
<2
13
g .z   0.02
  3



      0.01 ZZ'
        Y





             -115 10
                     0 20 30   40   50   50 70 30   90

FIOWE `I.-Response of pulmonary macrophages in an individual to cigarette
smoking. The shaded bar indicates duration of smoking. The vertical lines
indicate the range of duplicate determinations at each time period.

SOURCE : Cantrell, E. T., et al. (Cf.4 8).

4 hours of exposure to cigarette smoke, maximal AHH activity
was observed at 24 hours (2%fold increase) ; AHH activity then
dropped markedly at 6 days post-exposure, probably owing to
the rapid turnover of this enzyme (figure 10) when the in-
ducing hydrocarbons were removed from the lung. (4) In ex-
periments in which the duration of exposure to cigarette smoke
was altered, AHH activity increased with increased duration of
exposure (figure 11) ; with as little as a 30-second exposure, at
24 hours a twofold increase in AHH activity was observed. This
is in agreement with the observations of Miller and Gelboin, in
Gelboin, et al. (CA 7), who utilized hamster embryo cells and
noted that short exposure to benzo (a)anthracene (2 minutes)
resulted in elevations of AHH activity for at least 12 hours. If
the metabolites of polyaromatic hydrocarbons are important
in pulmonary carcinogenesis, the results of these experiments lend
evidence to support the hypothesis that these metabolites would
be formed in increased concentrations in the lungs of smokers,
and thus would lead to increased risk of tumor formation in
smokers. If, on the other hand, the metabolites were noncarcino-
genie, the increase in AHH activity may be looked on as a pro-
tective device against untoward effects on the parent compound
(CA 84).

60


The relationship between pulmonary infection and AHH activ-
ity was investigated by Nettesheim, et al. (CA 16) who found
that at 10 days postiinocuIation of infiuenza virus, AHH activity
mas reduced in mouse lung tissue to 20 percent of control
levels.

Flesher and Sydnor (CA 6) reported the synthesis of 6-
hydroxymethylbenzo (a) pyrene by incubation of benzo (a) pyrene
with rat liver homogenates as a result of enhanced AHH
activity. This metabolite was carcinogenic; it produced sarcomas
in rats when injected subcutaneously, as did injection of benzo-
(a) pyrene and 6-methylbenzo (a) pyrene. No control rats were
utilized. The authors postulated that methylation and/or hy-
droxymethylation may be a key step in the metabolism of
benzo(a)pyrene, and that the products thus formed may be po-
tent carcinogenic agents in vivo. The fact that 100 percent of
the injected rats developed sarcomas, and that no sham treated
or solvent injected rats (controls) were utilized, limit the con-
clusions which may be drawn from this study.

Flaks, et al. (CA 5) demonstrated that the 7-hydroxymethyl-
K&methyl and 12-hydroxymethyl-`7-methyl derivatives of `i',E-
dimethylbenz (a)anthracene showed similar carcinogenic poten-
cies to the parent compound. In testing for the carcinogenicity

1500






1000






500

0      1      2      3      4

   Cigarette Smoke Exposure (hr)

FIGURE b-Effect of cigarette smoke on benzo (a)pyrene-hydroxylase activity
in rat lung. Four rats were placed in a chamber and exposed continuoufdy to
smoke from 5 cigarettes per hour for various time periods. After expo6ure,
the rats were killed and the lungs were examined for benm(a)PYNm?-hY-
droxylase activity. The data are representative of 4-5 experiments (mean
* SE).

SOURCE : Welch, B. If., et aL (CA 36).

61


of these compounds, these investigators utilized the mouse lung
explant experimental model.

Nitrogen dioxide is a known component of cigarette smoke.
Palmer, et al. (CA 18) found no change in AHH activity
of tracheobronchial mucosa of rabbits after exposure to 5, 20, and
50 p.p.m. of NO,.

ORAL CANCER

Introduction

In the United States, oral cancers comprise approximately
2.5 percent of all cancers reported. These include cancer of the
oropharynx, lip, tongue, hard and soft palate, floor of the mouth,
gingiva, alveolar mucosa, and buccal mucosa. The relationships
of cigarette and pipe/cigar smoking to the development of oral
cancer are summarized below:

1. Prospective and retrospective studies have shown an as-
sociation between mortality for oral cancer and tobacco usage in

men and women.

2.000






1.000

Puromycin

FIQURE 9.-Effect of actinomycin and puromycin pretreatment on the induction
of benzo(a)pyre.ne-hydroxylase by cigarette smoke in the rat. Rats were
treated with actinomycin or puromycin and exposed to cigarette smoke for 4
hours. Benzo(a)pyrene-hydroxylase was measured in lung immediately after
exposure. Results represent the mean + SE from 4 rats.

SOURCE : Welch, R. Y., et al. (CA $6).


2. This association has been demonstrated for all different
modes of tobacco usage-cigarette and pipe/cigar smoking, tobacco
nnd snuff chewing, reverse smoking, and "pan" chewing.
3. Several studies have shown that the development of recur-
rent oral cancers has a highly significant correlation with con-
tinued smoking.

4. Tobacco usage may act in concert with alcohol consumption
to increase the risk of development of oral cancer.
5. The association between tobacco use and oral cancer in
both men and women has been demonstrated for Caucasian,
Indian, and Asian populations.

6. Epidemiologic data suggest that premalignant lesions in
the oral cavity (e.g., leukoplakia) are associated with tobacco
usage.

7. Results from experimental studies indicate that cigarette
smoke may contain tumor promoters active in oral carcino-
genesis and is a promoting agent in the hamster cheek pouch.

Epidevniologic Studies

In a st.udy of 483 patients with cancer of the mouth and pharynx
selected from three New York City VA hospitals, Rothman and
Keller (CA 21) found that the relative risks of development of

Days After Exposure

FIQURE l&-Time course for maximum induction of benzo(a)pyrene-hydroxylase
in lung after exposure of rats to cigarette smoke. Rats were exposed to cigarette
smoke from 20 cigarettes (4 hours) and killed at various times after exposure.
The activity of benzo( a)pyrene-hydroxylase was determined at various in-
tervals after exposure. Each point represents the mean -C SE from 3 rata.

SOURCE: Welch, R. M.. et al. (CA JS).

63


Smoke Exposure (minutes)

FIGURE Il.-The relationship between lung benzo (a)pyrene-hydroxylase activity
and the dnration of exposure to cigarette smoke in the rat. Rats were exposed
to cigarette smoke from 30 seconds to 180 minutes and killed 24 hours after
exposure ; the lung benzo( a) pyrene-hydroxylase was measured. Each result
represents the mean z SE from 3 rats.

SOURCE: Welch, R. N., et al. (CA 36).

these cancers were higher for men who consumed either tobacco
or alcohol than for nonsmokers and nondrinkers. When both
tobacco and alcohol consumption were present, dose-response
relationships for combinations of the two were demonstrated
(table 2). The data presented strongly suggest that both inde-
pendent and additive effects of tobacco and alcohol consump-
tion were operative in the development of these oral cancers.
The authors concluded that the increases in the relative risks of
development of these oral cancers produced by smoking and
alcohol consumption were additive and, therefore, independent.

Ramanathan, et al. (CA 20) examined 40'7 medical attendants
and health workers in Malaysia for evidence of oral precancer-
ous lesions. The authors found significant relations between

TABLE 2.-Relative risk* of oral cancer according to level of ex-
        posure to smoking and a&oh.ol

Alcohol         0      1.00      1.62      1.43      2.43
(oz./day)      co.4    1.40      1.6'7      3.18      3.25
            0.4-1.5    1.60      4.36      4.46      8.21
           1.6+     2.33      4.13      9.69      15.6

o Riab are expressed relative to o tick of 1.00 for pemnl who neither amoked nor drank.
SOURCE: Rothm~n. K.. Keller. A. (CA 92).

64


tobacco smoking (P <.05) and mixed habit (smoking, chewing,
and/or drinking) (P <.OOl), and the prevalence of oral pre-
cancerous lesions in MaIay men. Significant differences in the
prevalence of oral precancerous lesions were also observed between
Indian men with smoking, chewing, and mixed habit and those
without these habits. Many oral precancerous lesions were found
among women who used tobacco, but the control group of women
was too small to make statistically significant comparisons.

Lee, et al. (CA 18) retrospectively studied 356 men with
squamous cell carcinoma of the oral cavity, matching 316 of these
patients with controls of similar age and smoking habits. They
concluded that alcohol consumption was significantly correlated
with development of oral cancer. They then took 96 of the
matched pairs who had similar drinking habits and found no
differences in smoking habits.

CANCER OF THE ESOPHAGUS

1. Prospective and retrospective studies have shown a re-
lationship between cigarette smoking and mortality from esoph-
ageal carcinoma in men and women.
2. Dose-response relationships have been demonstrated for this
association.

3. These relationships have been observed in Caucasian, Asian,
and American Indian populations.
4. The effect of cigarette smoking on esophageal cancer mortal-
ity rates has been shown to be independent of and synergistic
with the effect of alcohol consumption.
5. Experimental data show that benzo(a) pyrene can induce
esophageal cancer in mice.

PANCREATIC AND GASTRIC CANCER

1. Data from prospective and retrospective studies of men
and women have demonstrated an association between smoking
and mortality from pancreatic cancer.
2. Dose-response relationships have been shown for this asso-
ciation.

3. No firm relationship between stomach cancer and cigarette
smoking has been established.

Wynder, et al. (CA 40, .41), in a retrospective study of 100
men and 42 women with adenocarcinoma of the pancreas, found
a significantly higher percentage of male cigarette smokers (P

65


<.026), female cigarette smokers (P C.06)) male cigarette and
pipe/cigar smokers (P <.026), and male cigar smokers (P <.025)
in the pancreatic cancer group than in the age, sex, and race-
matched controls. For male cigarette smokers, a dose-response
relationship was demonstrated for numbers of cigarettes consumed
in the pancreatic cancer group (figure 12). The number of cases of
women smokers with pancreatic cancer was too small to draw
statistically significant conclusions with regard to dose-response
relationships. Patients who smoked cigars only had a relative
risk of 3.1 compared to nonsmokers, and this was also statistically
significant (P <.025). (Although the association between
cigarette smoking and pancreatic cancer was significant, it was
not as strong as the association between cigarette smoking and
lung cancer.) Patients who smoked pipes predominantly did not
demonstrate a significantly higher risk of development of pan-
creatic cancer than nonsmokers.

Never
Smoked

11-20        2140

Cigarettes per Day

FIWJRE 12.-Relative risk of pancreatic cancer by number of cigarettes smoked
                       in males.

SOURCE : Wynder, E. L., et al. (CA 41).

66


lvith gastric cancer in Kanagawa prefecture from 1960 to 1961,
be noted no association between smoking habits and gastric can-
cer. However, 67 percent of the cases were diagnosed either by
X-ray or "clinical methods". In 1963, he studied six prefectures;
in 1,524 patients with gastric cancer, there was "no striking
nssociation" between smoking habit and gastric cancer. In 1965,
Hirayama began his prospective study of 265,118 adults. Anal-
ysis of the S-year follow-up data revealed a higher death rate
from gastric carcinoma for males who smoked cigarettes and
drank hot green tea. In addition, the age-standardized death
rate from gastric carcinoma for male smokers was 128 per 100,000
compared to 85 for nonsmokers ; mortality ratios for male
smokers:nonsmokers were 1.51. Differences between female
smokers and nonsmokers were minimal. The author suggested
that, in future studies, a detailed examination of the possible
relationships between cigarette smoking and gastric cancer be
performed.

CANCER OF THE LARYNX

1. The epidemiologic, autopsy, and experimental data which
suggest a strong association between cancer of the larynx and
smoking habits have been reviewed in past editions of this re-
port. No new data have been presented within the past year
which significantly add to our knowledge of the association
between smoking and laryngeal cancer.

CANCER OF THE GENITOURINARY SYSTEM

Introductim

1. The association between cancer of the urinary bladder and
kidney and cigarette smoking has been reviewed in previous
editions of this report. No new epidemiologic data has been
published within the last 12 months which amplifies our knowl-
edge of this association.

2. Data from experimental studies dealing with tryptophan
metabolism have demonstrated that metabolites of tryptophan
can be carcinogenic in the bladders of mice. These metabolites
are found in increased amounts in the urine of patients with
non-occupational bladder carcinomas. Some data show an effect
of cigarette smoking on tryptophan metabolism, while other
data have not shown such an effect.

67


Thomas (CA SO), in a retrospective study on cytologic and
histologic abnormalities of the uterine cervix, reported a signif-
icant association between current smoking habits and the in-
cidence of carcinoma in situ (P <.05), with a relative risk for
smokers being 1.71 (P ~~05). The "adjusted" risk for smokers
was 1.47 times that of the nonsmokers. Intensity and duration
of smoking were not analyzed ; ex-smokers were also not accounted
for. The controls consisted of a hospitalized group of patients
with normal cervical smears and may have contained a higher
percentage of smokers than the population as a whole. Further
epidemiologic studies are needed for full investigation of the
relationship between cigarette smoking and development of car-
cinoma in situ of the uterine cervix, as suggested by this study.

Experimental $tudiea

Humans

Schievelbein, et al. (CA 28) reported no significant differences
in the excretion of various urinary metabolites of tryptophan
between smokers and nonsmokers, nor between patients with
bladder carcinoma (also smokers) and those without this car-
cinoma. Problems in the design of this study limit the conclusions
which may be drawn from the data.

Animals

Wagle and Lee (CA 35) found a 2 percent incidence of
transitional cell bladder tumors in rats whose bladders were im-
planted with- pellets of cigarette smoke condensate. A total of
22 percent of the rats developed squamous metaplasia.

SUMMARY OF RECENT FINDINGS ON THE RELATIONSHIP
         OF SMOKING ANDCANCER

1. Recent epidemiologic evidence confirms the finding that
  cigarette smoking is the major cause of lung cancer for
  both men and women.

2. Current evidence suggests that, even in the presence of a
  possible genetic susceptibility to the development of lung
  cancer, cigarette smoking remains the major cause of lung
   cancer.


3.

4.





5.

6.

7.





8.






9.

10.




11.

1. A

Results from several studies demonstrated a dose-response
relationship between smoking and oat cell carcinoma ; a
major prospective study demonstrated such a relationship
for well-differentiated squamous cell carcinoma, oat cell
carcinoma, and adenocarcinoma.
The current epidemiologic data suggest that the incidence of
lung cancer in women continues to rise. The rising in-
cidence of lung cancer in women correlates well with the
increasing trends in smoking among women.
present data are conflicting with regard to dose-response
relationships for cigar and pipe smokers and the develop
ment of lung cancer; the data are consistent for the fact
that light cigar smokers are at a low risk of developing lung
cancer.

Recent data confirm the synergistic effect of asbestos and
smoking exposure on the risk of developing lung cancer in
both men and women.

Results from experimental studies in hamsters continue
to demonstrate that exposure to benzo(a)pyrene results in
the production of respiratory tract malignancies, especially
squamous cell carcinomas.

Data from experimental studies in animals suggest that
chronic respiratory infections may enhance the carcino-
genicity of components of cigarette smoke, as may altera-
tions in the immune system.

Current evidence suggests that components of cigarette
smoke induce AHH activity in pulmonary macrophages
in humans and in pulmonary parenchymal tissue and em-
bryo cells in animals. The role of AHH in tumorigenesis
and/or as a host defense mechanism against potential car-
cinogens is presently unclear.

Recent epidemiologic data strongly indicate that cigarette
smoking plays an independent role in the development of
oral cancer.

Recent epidemiologic data confirm the association between
smoking and pancreatic cancer.

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30. THOMAS, D. B. An epidemiologic study of carcinoma in situ and
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61


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41. WYNDER, E. L., MABVCBI, K., MARVCEI, N., FORTNER, J. G. Epidemiology
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CANCER SUPPLEMENTAL REFERENCES

Port Z

(Articles which were reviewed but not discussed in the text, providing data
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72-0933. ASAL, N. R, ANDERSON, P. S., JR The etiology of lung cancer in
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62


72-0634. .&EAk KEAN, M., J~ARE~, N. A. Oral exfoliative cytology for
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73-0284. BEDROSSIAN, C. W. M. Coexistent emphysema and bronchogenic
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73-0151. BIBUS, B. Die papillaren Tumoren der Hamwege. (Papillary tumors
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72-1070. CECILIONI, V. A. Lung cancer in a steel city: Its possible relation
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72-1267. C~A~DH~RI, M. R. Primary mixed carcinomas of the bronchus.
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72-0637. CHAWLA, T. N., MATEUR, M. N., MISRA, R. K. Oral environmental
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73-0152. CLEMMESEN, J., NIELSEN, A. Age-adjusted mortality rates for lung
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72-0489. COLE, P., MACMAEON, B. Attributable risk percent in case-control
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72-0935. COUNCIL OF EUROPE. Lung Cancer in Western Europe. Council of
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63


73-6163. DE COBBAL S-A, F. J. Clinica de 10s tumores vesicales. (Clinical
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72-0490. DOLGINTSEV,  V. I. Matematicheskiye metody v epidemiologii
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73-9403. DGNTENWILL, W., ELMENHORST, H., HARK& H.-F., IWKZEH, G.,
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`72-0733. DROCENDIJK, A. C. De vrouw en het roken-longkankervraagstuk.
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73-0446. ESTEVEZ VALDEZ, R. Analieis e information estadistica de 435
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72-0736. FARR, H. W., ARTHUR, K. Epidermoid carcinoma of the mouth and
     pharynx 1969-1964. Journal of Laryngology and Otology 86(3) :
      243-263, March 1972.

72-0941. FERON, V. J., EMME~, P., VOSSENAAR, T. Lower respiratory
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73-0497. GIACOBBE, E., CARUSO, P. L. Cytologic changes in the oral cavity
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     February 1973.

`72-9492. GSELL, 0. R., ABELIN, T. Cigar and pipe smoking in relation to
      lung cancer and excess mortality. Journal of the National Cancer
      Institute 48 (6) : 1795-1803, June 1972.
72-0907. HAMNER, J. E., III. Betel quid inducement of epithelial atypia in
      the buccal mucosa of baboons. Cancer 30(4) : 1001-1005, October
       1972.

72-0714. HAPLPPERT, J. L., ENGEL, J. C. Le role nocif du tabac vu par
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     mental pathology.) Revue de Tuberculose et de Pneumologie'
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72-0638. HEALY, T. M. Carcinoma of the lung: 326 eases. Irish Journal of
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72-0493. JAYANT, K., BALAKRISHNAN, V., SANGIIVI, L. D. A note on the
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64


;2-6494. KANNEB~TEIN, M., Crrunc, J. Pathology of carcinoma of the lung
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i2-64g5. KENNEDY, A. Lung cancer in young adults. British Journal of
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734449. KISSIN, B., I(ALEy, M. hf., Su, W. H., LEBNER, R. Head and
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72-1078. LEMOINE, J. M. Tabac et cancers bronchiques des femmes. (Tobacco
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       1972.

72-0739. MEHTA, F. S., SAHWR, B. E., DREARY, D. K., GUPTA, P. C., PIND
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    epithelial atypia of the palate among Indian reverse smokers.
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73-0985. MEBTA, F. S., SHROFF, B. C., GUPTA, P. C., DAFTARY, D. K. Oral
     leukoplakia in relation to tobacco habits. A ten-year follow-up
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72-0642. MERRICK, D. K., CUR, D. T., PIIYNE, W. S., WOOLNER, L. B.
    Multiple primary cancer of the lung. Geriatrics 27(6) : 71-79,
      June 1972.

72-0740. Mm, A., R~CEEMAURE, J., NADJAR-FOSSE, G., BIENTZ, M. Cancers
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73-0059. MICIETA, I., VAGAC, M., BADAL~K, L., CECEVALOVA, A. O`vaha o
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72-9771. OILAMOTO, T., CHAN, P. C., So, B. T. Effect of tobacco, marihuana
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72-0742. PINDBOBG, J. J., MEHTA, F. S., DAFFAR~, D. K., GIJ~TA, P. C.,
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65


73-0044. PUTNEY, F. J., CHAPMAN, C. E. Carcinoma of the larynx: Analyst
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72-1273. RAMANATHAN, K. Oral carcinoma in the first three decadea of
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73-0630. RAMULU, C., RAJU, M. V. S., VENKATAIUTANAM, G., REDny, C. &
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72-0743. RAMULU, C., REXIDY, C. R. R. M. Carcinoma of the hard palate
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72-1265. REDDY, C. R. R. M., RAMULU, C., RAJU, M. V. S., Rxnnr, P. 0.
     Relation of reverse smoking and other habits to the development
     of stomatitis nicotina. .Indian Journal of Cancer 9(3) : 223-230,
      Sentember 1972.

72-1306. ROEDPETERSEN, B., GUPTA, P. C., PINDBORC, J. J., SINGE, B. As-
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72-0745. SILVERMAN, S., JR., GRIFFITH, M. Smoking characteristics of pa-
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72-9193. SPELL, P. 211. Smoking and laryngeal cancer. Lancet l(7751) : 617-
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72-0746. WAGNER, J. C. Current opiniona on the asbestos cancer problem.
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73-0464. WAPNICK, S., CASTLE, W., NICHOLLE, D., ZANAMWE, L. N. D.,
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73-0634. WEISS, W. Cigarette smoke as a carcinogen. American Review of
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73-0616. WEISS, W., LANCSTON, H. T. Lung cancer-future projection.
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72-0953. WYNDER, E. L., MABUCFII, K. Etiological and preventive aspects of
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Part rz

(Additional articles which were reviewed but not discussed in the text.)
73-0281. ABBEY SMITE, R., NICAM, B. K., THOMPSON, J. M. Influence of
      parental age on survival after resection for lung carcinoma.
     Lancet l(7808) : 843-845, April 21, 1973.
`724727. ABBE, D. W., WILKINS, M. M., KIRSCHNER, G., WESTON, D. L.,
     BROWN, R S., BUXTON, W. D. Self-frustration5 nighttime smoking
     and lung cancer. Psychosomatic Medicine 34 (5) : 395-404, Sep-
       tember-October 1972.

66


72~900. Ano, A., VAINIO, H., HILNNINEN, 0. Enhancement of drug oxlda-
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73-oo11. AWM, B. S., JARAMILU), F. E., SCHLEGEL, J. U., DE~UHEN, T. A.
    The effect of ascorbic acid upon bladder uptake of p-napbtbyla-
    mine metabolites. Proceedings of the Society for Experimental
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72-0901. ALEXANDROV, K., FRAYSSINET, C. The effect of cigarette-smoke
     condensate on the in vitro fixation of benzo(a)pyrene on DNA.
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73-0240. AYES, B. N., SIMS, P., GROVES, P. L. Epoxides of carcinogenic
    polycyclic hydrocarbons are frameshift mutagens. Science 176
     (4030) : 47-49, April 7, 1972.

73-0442. ARCHER, V. E., WAGONE& J. K., LUNDIN, F. E., JR Uranium
    mining and cigarette smoking effects on man. Journal of 00
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   BAUER, F. W., ROBBINS, S. L. An autopsy study of cancer patienta.
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    Hospital. Journal of the American Medical Association 221(13) :
     1471-1474, September 25,1972.

72-0707. BENEDICT, W. F. Early changes in cbromosomal number and strut-
      ture after treatment of fetal hamster cultures with trans-
    forming doses of polycyclic hydrocarbons. Journal of the
     National Cancer Institute 49(2) : 585-589, August 1972.
72-0698. BOCK, F. G., SWAIN, A. P., STEDMAN, R. L. Carcinogenesis assay
     of subfractions of cigarette smoke condensate prepared by sol-
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     National Cancer Institute 49(2) : 477-483, August 1972.
73-6618. BOUCOT, K. R., WEISS, W. Is curable lung cancer detected by
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73-9243. BRIGGS, M. H., BRIGCS, M. Induction by topical corticosteroids of
     skin enzymes metabolizing carcinogenic hydrocarbons. British
     Journal of Dermatology 88(l) : 75-81, January 1973.
72-1069. BBOWN, R. R., FRIED&L, G. H. LEKLEM, J. E. Tryptopban metabo-
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     222, April 1972.

72-1063. BURBANK, F. U.S. Lung cancer death rates begin to rise propor-
     tionately more rapidly for females than for males: A doze
     response effect? Journal of Chronic Diseases 25 (8) : 473-479,
      August 1972.

72-1303. BURTNER, D., GOODMAN, M., MONTCOMERY, W. Elastic cartilaginous
     metaplasia of vocal cord nodules. Annals of Otology, Rhinology
     and Laryngology 81(6) : 844-847, December 1972.
73-0040. CASE% A. E., GRA~LEE, J. F., DOWNEY, E., COPELAND, H. A
     template of serum chemistries in cancer of the lung. Alabama
     Journal of Medical Sciences 9 (4) : 376-382, October 1972.
73-9621. CLEMMESEN, J., Bxx~ggsxov, V. Parallel morbidity age-curves for
     neoplasms of lung and bladder. Biomedicine 19 (5) : 198-199,
      May 20, 1973.

67


73-0401. CROCKER, T. T., O'DONNELL, T. V., NUNES, L. L. Toxicity of
     benzo(a)pyrene and air pollution composite for adult human
     bronchial mucosa in organ culture. Cancer Research 33(l) :
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73-0758. DALE, M. M., EASTY, G. C., TCHAO, R., DESAI, H., ANDJARGnoLI, 116,
     The induction of tumours in the guinea-pig with metbyIcbolan.
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72-1268. DIPAOW, J. A., TAKANO, K., POPESCU, N. C. Quantitation of
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     cloned cell lines. Cancer Research 32(12) : 2686-2695, December
       1972.

73-0583. ESBER, H. J., MENNINGER, F. F., JR., BOCDEN, A. E., MASON, M. M.
     Immunological deficiency associated with cigarette smoke inhala-
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      August 1973.

73-0447. FIGUEROA, W. G., RASZKOWSKI, R., WEISS, W. Lung cancer in
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72-0491. GANGADHARAN, P., PAYMASTER, J. C. Leukoplakia-An epidemiolog-
     ical study of 1504 cases observed at the Tata Memorial Hospital,
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       cember 1971.
73-0252.  GAUDIN, D., GREGG, R. S., YIELDING, K. L. Inhibition of DNA repair
     by cocarcinogens. Biochemical and Biophysical Research Com-
      munications 48 (4) : 945-949, 1972.
73-0022. GULLINO, P. M., GRANTHAM, F. H., L~SON~Y, I., BERCHOFFER, B.
     Mammary tumor regression. III. Uptake and loss of substrates
     by regressing tumors. Journal of the National Cancer Institute
      49 (6) : 1675-1684, December 1972.

73-0288. HENSCKE, U. K., LEFFALL, L. D., Ja., MASON, C. H., REINHOLD,
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      cer 31(4) : 763-768, April 1973.

    HICKS, R. M., WAKEFIELD, J. ST. J., CHOWANIIX, J. Co-carcinogenic
      action of saccarin in the chemical induction of bladder cancer.
      Nature 243(5406) : 347-349, June 8, 1973.
73-0154. KOVI, J., HESHMAT, M. Y. Incidence of cancer in Negroes in
      Washington, D.C., and selected African cities. American Journal
     of Epidemiology 96(6) : 401-413, December 1972.
72-1272. KRAIN, L. S. Cancer incidence. The crossing of the curves for
     stomach and pancreatic cancer. Digestion 6(6) : 356-366, 1972.
73-0534. KRAIN, L. S. Wby is pancreatic cancer incidence up; stomach
     cancer down? Geriatrics 28 (4) : 140-145, April 1973.
73-0986. LANCSTON, H. T. Lung cancer-future projection. Journal of
     Tboracic and Cardiovascular Surgery 63 (3) : 412-415, March
       1972.

73-0418. LASNITZKI, I. Effects of carcinogenic agents on organ cultures.
      Oncology 25(l) : 263-268, 1971.

72-0641. LINDEN, G., DUNN, J. E., JR., HOM, P. H., MANN, M. Effect of
     smoking on the survival of patients with lung cancer. Cancer
      30(2) : 325-328 August 1972.

68


i3-0769. LOUIS, C. J,, BLUNCX, J. M., RICHMOND, L. M. Agarose-gel elec-
    trophoresis of soluble proteins from bronchial mucosa and
     bronchogenic carcinoma. Oncology 27 (4) : 324-335. 1973.
;2-0497. MACDONALD, W. C. Clinical and pathologic features of adeno-
    carcinoma of the gastric cardia. Cancer 29(3) : 724-732, March
      1972.

72-0948, MADEY, J., LACHOWICZ, E., OSSOWSXA, K., SZYMANSXA, D., ZAJACZ-
     XOWSIUL, J. Rak oskrzela wspolistnejacy z gruzlica pluc. (Bron-
     chial carcinoma associated with pulmonary tuberculosis.)
     Gruzlica i Choroby Pluc 40 (4) : 285-296 1972.
73-0625. MANDEL, M. A., DVOVORAK, R., DECO.%%, J. J. Salivary immunoglobu-
     lins in patients with oropharyngeal and bronchopulmonary
     carcinoma. Cancer 31(6) : 1408-1413, June 1973.
    MITELMAN, F., MARK, J., LEVAN, G. Chromosomes of six primary
     sarcomas induced in the Chinese hamster by 7,12-dimethylbenz-
     (a) anthracene. Hereditas `72 (2) : 311-318, 1972.
73-0451. O'DONNELL, T. V., CROCICER, T. T., NUNES, L. L. Maintenance of
    normal, metaplastic and dysplastic states of adult human bron-
    chial mucosa in organ culture. Cancer Research 33 (1) : 78-87,
     January 1973.

73-0775. POUND, A. W., LAWSON, T. A., HORN, L. Increased carcinogenic
     action of dimethylnitroeamine after prior administration of car-
     bon tctrachloride. British Journal of Cancer 27(6) : 451-459,
      June 1973.

72-0920. RANDERIA, J. D. Tobacco induced changes in the bladder buccal
     and vaginal mucosae. Indian Journal of Medical Research 66(S) :
     694-698, May 5,1972.

73-0263. RHIM, J. S., CEO, H. Y., JOCLE~& M. H., HUEBNER, R. J. Com-
     parison of the transforming effect of benzo(a)pyrene in mam-
     malian cell lines in vitro. Journal of the National Cancer Insti-
     tute 48(4) : 949-957, April 1972.

73-0424. RHIM, J. S., HUEBNER, R. J. In vitro transformation assay of
     major fractions of cigarette smoke condensate (CSC) in mam-
     malian cell lines. Proceedings of the Society for Experimental
     Biology and Medicine 142 (3) : 1003-1007, March 1973.
73-0425. RHIM, J. S., HUEBNER, R. J, Transformation of rat embryo cells
     invitro by chemical carcinogens. Cancer Research 33(4) : 695-
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72-1274. ROTH, D., HAYE% R. L., Ross, N. M., GITMAN, L., KISSIN, B.
     Effectiveness of acridine-binding method in screening for oral,
     pharyngeal, and laryngeal cancer. Cancer 29 (6) : 15'79-1583,
      June 1972.

    SMITH, R. A., NIGAM, B. K., THOMPSON, J. M. Influence of parental
     age on survival after resection for lung carcinoma. Lancet
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72-1254. SPENCER, T. A comparison of aryl hydrocarbon and estrogen micro-
     somal hydroxylases of rat liver. Enzymologia 43(5) : 301-310,
      November 30, 1972.

73-0610. THOMAS, W., HOLT, P. G., KEAST, D. Effect of cigarette smoking
     on primary and secondary humoral responses of mice. Nature
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69


78-6277. WIEEEL, F. J., LEUTZ, J. C., GJZLBOIN, H. V. Awl bdmarboa
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     nucleobaees by one-electron oxidation. Journal of the National
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     activity in human oral epithelial cells to cellular maturation:
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      December 1972.

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72-0748. ZAKRZEW~~I, A., DUIWKA-Z~xcazxw SXA, A., SKONIECZNY, J., KON-
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70


CHAPTER3

iv~N-NEOPLASTIC BRONCHOPULMONARY DISEASES

INTRODUCTION ___-__--_-_-_--_-___--~~~~~~~-~~~
EPIDEMIOLOGIC STUDIES

SmokingandCOPD ____ --_-___--_--__-- __________
The Eflects of Smoking on Pulmonary Function in
Patients with COPD _- ____ ---_-___-___--__-__-
The Effects of Smoking on Pulmonary Function in
Healthy Populations _--- ______ --__---_-- ______
The Roles of Smoking and Pollution in the Development
of COPD -____-__-__--__-____----------------
The Relationship Between Cigarette Smoking and
Small Airways Disease ___--____-- _____________
The Interactions Between Cigarette Smoking and the
Genetic Susceptibility to the Development of COPD _
The Effect of Smoking on the Development of Bullous
Disease of the Lungs __--_- _____________-___-__
Smoking and Post-Operative Complications _ _ _ _ - _ _ _
The Influence of Cigarette Smoking on the Develop-
ment of Pulm0n.a~ Disease Associated with Rheu-
matoid Arthritis ___-___-__- ____ -___-- _______--

Occupational Diseases and Smoking
  Byssinosis _ - _ _ _ - _ _ _ _ _ - _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
  Asbestosis  ____ - _______________________ -___-
Chronic Bronchitis and Pulmonary Symptoms in
  Cement and Rubber Industry Workers _ _ _ _

AUTOPSY, STUDIES

The Effect of Smoking on the Prematurity of De-
velopm.entandSeverit~of COPD __- ____ -_- __.__.

Page
75

78

80

80

82

84

87

90

92




92


93
95


95





97

71


Smoking and Mucous Gkmd Abnormalities __ _ _ __ _ _   97
Abnomdities of the Small Airways _ _ 7 _ _ _ _ _ _ _ _ _ _ _ _ _   97

EXPERIMENTAL STUDIES

Studitw in Rummz8 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ - _ _ _ _ _ _ _   99
Studies in Animals _________________ - ____ --_- ____  102

CYTOLOGIC AND HISTOLOGIC STUDIES _ _ _ _ _ _ _ _   104

SUMMARY OF RECENT NON-NEOPLASTIC BRON-
CHOPULMONARY FINDINGS  _ - _ _ _ _ - _ _ - _ _ _ _ _ _ _ _   106

BRONCHOPULMONARY DISEASE REFERENCES _ _   107

BRONCHOPULMONARY DISEASE SUPPLEMENTAL
REFERENCES _________-_______________________   112

List of Fignres

Figure 1.Prevalence of chronic nonspecific respiratory
disease by cigarette smoking habits and traffic exposure _ _
Figure 2.-Relationship between "closing volume" and
agein39smokers ___----________-__________________
Figure S.-Prevalence of abnormal closing volume/vital
capacity ratios in nonsmokers, cigarette smokers, and
ex-smokersbyagedecades ____ - _______ -__-- _________
Figure 4.-Comparison of the prevalence of respiratory
symptoms and pulmonary function abnormalities in male
smokers according to their daily cigarette consumption _
Figure L-Comparison of the prevalence of respiratory
symptoms and pulmonary function abnormalities in fe-
male smokers according to their daily cigarette con-
sumption _-______________________________________-
Figure 6.-The distribution of smoking histories in men
with bronchitis and/or emphysema - _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Figure `(.-Chronic bronchitis in female wool and cotton
textile workers __-- _______________________ -___- ____
Figure &-Chronic bronchitis in male wool and cotton
textile workers _______ - _______________ -__-___- ____
Figure 9.-Effect of smoking on pulmonary ventilation
at different levels of time-weighted dust exposure __ _ _
Figure lO.-Effect of smoking on prevalence of byssinosis
at different time-weighted dust exposure levels _ - _ _ _ _ _ _

82

86

86

87

88


89


93


94


95


96

72


Page

Figure Il.-A frequency distribution curve of the inter-
nal diameters of the small airways in an autopsy
population of nonemphysematous patients with and
without histories of chronic bronchitis  _ _ _ _ _ _ _ _ _ _ _ _ _ _
Figure 12.-Mean clearance curves for normal subjects,
subjects with airway obstruction, and restrictive im-
pairment of the lungs - _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Figure 13.-Mean clearance curves for smokers, ex-
smokers, and nonsmokers in the healthy group and the
group with respiratory impairment _ _ _ - - - _ - _ _ _ _ _ _ _ _ _ _
Figure 14.Effects of aqueous cigarette smoke extract
on initial oxygen uptake, final oxygen uptake, and cell
viability of pulmonary macrophages  _ _ _ _ _ _ _ _ _ - _ _ _ _ _ _

List of Tables

Table l.-Number, percentage, and age-standardized per-
centage of chronic bronchitics among 5,438 cigarette
smoking male volunteers for mass radiography, aged 40
and older, by amount and method of smoking _ _ _ _ _ _ _ _ _ -
Table 2.-Prevalence of chronic nonspecific respiratory
disease grouped by current cigarette categories and traffic
exposure ____________-___________________________
Table 3.-Prevalence (percent) of cough day or night
in both sexes in winter by air pollution index, social
class, cigarette smoking, and history of chest illness
under 2 years of age _____________ -___- ____ _-__ __ __
Table $.-Estimated rates of bullous disease of the lung
per 1,000 men by age, race, and cigarette smoking habits -
Table IX-Estimated rates of bullous disease of the lung
per 1,000 men with no demonstrable odcupational hazard
(class 1) __-________________ -_- ____ __ _________ ____

98

100

101

106

79

83

91


91




92

73


CHAPTER3

NON-NEOPLASTICBRONCHOPULMONARYDISEASES

INTRODUCTION

Chronic obstructive pulmonary disease (COPD) (defined here
as chronic bronchitis and emphysema) accounted for approxi-
mately 25,000 deaths in the United States in 1969. In 1970, in
the U.S., the combined prevalence of chronic bronchitis for mem-
bers of both sexes over age 17 was 29.5 per 1,000 population,
and for emphysema was 9.8 per 1,000 population. In 1970, per-
sons with chronic bronchitis lost, on the average, 1.4 workdays
per year, and those with emphysema lost greater than 5 work-
days per year due to disability from these diseases.

Epidemiologic, autopsy, and experimental data presented in
previous editions of this report (1964, 1967, 1968, 1969, 1971,
1.972, 1973) indicate that cigarette smoking is the primary cause
of chronic bronchitis and emphysema. A summary of that evi-
dence is presented below:

1. Results from numerous prospective studies show a markedly
increased mortality from COPD for male smokers compared to
nonsmokers. There is a limited amount of data dealing with the
relationship between cigarette smoking and COPD mortality in
women.

2. Dose-response relationships between cigarette smoking and
mortality from chronic bronchitis and emphysema were demon-
strated in all studies in which dose-specific mortality rates were
evaluated. Heavy cigarette smokers ran relative risks of mortal-
ity from chronic bronchitis ranging from 3.6 to 21.2 times those
of nonsmokers, and relative risks of mortality from emphysema
ranging from 6.9 to 25.3 times those of nonsmokers.

3. Data from many studies demonstrate that male and female
smokers suffer from symptoms of COPD (including cough, spu-
tum production, and dyspnea) more frequently than do nonsmok-
ers.

76


4. Of the studies in which dose-specific prevalence rates were
examined, strong dose-response relationships between cigarette
smoking and symptoms of COPD were generally demonstrated.
5. The relationship between cigarette smoking and COPD mor-
tality has been demonstrated in the United States, Canada, Great
Britain, and Ireland ; strong associations between cigarette smok-
ing and COPD morbidity have been shown in the United States,
Canada, England, Australia, Finland, Sweden, France, Belgium,
Hungary, and Japan.

6. Epidemiologic evidence from many countries indicates that,
for both sexes, symptomatic and asymptomatic cigarette smok-
ers have greater impairment of pulmonary function than do
nonsmokers.1

7. Previous evidence indicates that cessation of smoking re-
sults in lower death rates from COPD, improved pulmonary func-
tion, and a decrease in the prevalence of pulmonary symptoms.

8. Prospective and cross-sectional analyses of data reveal that
pipe and cigar smokers have higher mortality rates from chronic
bronchitis and emphysema than do nonsmokers, but lower rates
than those of cigarette smokers. Pipe and cigar smokers have a
higher prevalence of respiratory symptoms than do nonsmokers.
The limited data on pulmonary function studies in pipe and cigar
smokers are, thus far, inconclusive.

9. Available data suggest that although air pollution may con-
tribute to the prevalence of symptoms of respiratory disease,
cigarette smoking is far more important in producing respira-
tory disease. Cigarette smoking and air pollution may interact
to produce higher rates of puImonary disease than are seen with
either factor alone.

10. Certain occupational exposures result in an increased inci-
dence of COPD, but the relationship is not as strong as for ciga-
rette smoking. The combination of certain occupational hazards
and cigarette smoking has been observed, in many studies, to
result in additive effects on morbidity from COPD. Exposures
to cotton fiber, asbestos, and coal dust, in particular, appear to
act in concert with cigarette smoking in the development of pul-
monary disease. The role cigarette smoking plays in the develop-
ment of coal workers' pneumoconiosis is unclear at present.

' In these studies, the degree of the relationship between smoking and im-
paired pulmonary function was found to be dependent on the sensitivity of
the particular pulmonary function test utilized to detect pnImonary obstruc-
tion and/or small airways disease, the age, sex, occupation, place of residence,
general state of health, and intensity of the smoking habit of the population
examined.

76


11. A genetically determined protease-deficiency (alpha,-
antitrypsin deficiency), inherited as an autosomal recessive trait,
is found as a homozygous deficiency in approximately 1 in 3,600
people and as a heterozygous deficiency in approximately 5 to 8
percent of the population. Those with the homozygous deficiency
have an increased prevalence of pulmonary emphysema. It is not
clear whether cigarette smoking is an important contributor to
the premature development of emphysema in people with the
homozygous or heterozygous deficiency states. It is also Unknown
whether nonsmoking heterozygotes are at a greater risk of
developing emphysema than nonsmokers or smokers with normal
alpha,-antitrypsin activity.

12. Data from most studies implicate cigarette smoking as an
important factor in increasing the risk of developing post-
operative pulmonary complications.
13. Some data suggest that cigarette smoking may increase the
risk of development of spontaneous pneumothorax.
14. Data from pathologic and autopsy studies have demon-
strated a dose-response effect of cigarette smoking on the severity
of emphysema ; pipe and cigar smokers have degrees of emphy-
sema intermediate between those of nonsmokers and cigarette
smokers.

1.5. Goblet ceI1 density and distention, alveolar septal rupture,
thickened bronchial epithelium, and mucous gland hypertrophy
have been shown at autopsy to be more common in cigarette
smokers than in nonsmokers.

16. Experimental data on humans have demonstrated that
inhalation of cigarette smoke results in acute impairment of cer-
tain parameters of pulmonary function. Overall pulmonary clear-
ance, ciliary function, and aIveolar macrophage function have
been found to be impaired in smokers as compared to nonsmok-
ers. Some recent data suggest that acute heavy cigarette smoking
with deep inhalation may result in increased pulmonary clear-
ance.

17. In animal studies, in vivo and in vitro exposures to whole
cigarette smoke (CWS) and several of its components have re-
suited in impairment in overall pulmonary clearance, ciliary
function, and alveolar macrophage function.
18. Experimental data on humans and animals presented in
the past suggest that cigarette smoke may impair the function of
the pulmonary surfactant system.

Most of the studies reviewed in the last year confirmed the
knowledge of the relationship between cigarette smoking and
hronchopulmonary disease, A listing of these studies appears in a

77


separate section of the Supplemental Bibliography. A number of
studies extended the knowledge of the association between ciga-
rette smoking and bronchopulmonary disease, but several studies
presented data which were either partially or wholly inconsistent
with the known relationships ; these two types of studies are re-
viewed below.

EPIDEMIOLOGIC STUDIES

Smoking and COPD

There have been relatively few studies designed to evaluate the
association between cigarette consumption and the prevalence of
chronic obstructive pulmonary disease (COPD) in elderly popu-
lations. In a random cross-sectional study of 487 men and women
between the ages of 62 and 90, living in Edinburgh and registered
with a practicing physician, Milne and Williamson (BP 45, 46)
reported that over 73 percent of the women had never smoked
compared with 7.9 percent of the men ; 62 percent of the men
were current smokers (71 percent of whom inhaled), while only
18 percent of the women were current smokers (50 percent in-
halers). In both men and women, a higher percentage of smokers
had persistent cough and sputum production than nonsmokers
(P <.OOl for men and P <.Ol for women), but twice the pro-
portion of male smokers had these symptoms than women smok-
ers. A dose-response relationship was demonstrated, since a
higher percentage of heavy smokers had these symptoms than
lighter smokers (P c.01). In men, 12.4 percent of the smokers
had persistent cough, sputum, and a recent chest illness; none of
the nonsmokers had this combination. For men, significant dif-
ferences in histories of wheezing and dyspnea were found be-
tween smokers and nonsmokers. For women, a significant differ-
ence between smokers and nonsmokers was demonstrated only
for wheezing (P <.05). The authors found that the FEV%
(FEV/VC) was below 60 in 32 percent of the men who smoked
compared to 6.7 percent of the nonsmokers (P <.05). For
women, the figures were 9.4 percent and 3.9 percent. This differ-
ence was not statistically significant.

In a cross-sectional study of 300 men and women aged 65 and
over in Glasgow, Scotland, Caird and Akhtar (BP 6) found that
among women chronic bronchitis was reported by 11 percent of
nonsmokers, 13 percent of light smokers, and 50 percent of
heavy smokers. For men, a dose-response relationship was shown
for light and heavy smokers, but the small numbers of non-

78


smokers ( 5 nonsmokers ; 2 with chronic bronchitis) limit the
conclusions which can be drawn from the data.
In a retrospective study of 5,433 men aged 40 and over who
were current smokers, Rimington (BP 55) examined the relation-
ship between the pattern of smoking and the prevalence of
chronic bronchitis. He found that for each level of daily con-
sumption of cigarettes, chronic bronchitis was more prevalent
among those smokers who kept their cigarettes in their mouths
during the entire period of smoking ("droopers") than among
those smokers who removed their cigarettes from their mouths
between puffs (normals) (table 1). For all levels of consumption,
there was a significantly higher prevalence of chronic bronchitis
among "droopers" than among normal smokers (P <.OOl). When
these values were age-standardized (this was necessary because
there was both a higher incidence of bronchitis and a higher
percentage of droopers in men over 60 years of age), there was
still a higher prevalence of chronic bronchitis among the
"droopers" than among the normals, but the statistical signifi-
cance of this difference was not presented, nor could it be calcu-
lated from the data given.

In an analysis of data from Bosnia and Hercegovina in Yugo-
slavia, Zarkovic (BP 73) reported dose-response relationships be-
tween depth of cigarette smoke inhalation and prevalence rates
for chronic bronchitis, pulmonary emphysema, asthma, car pul-
monale, and clinical and laboratory signs of obstructive lung
disease.

TABLE l.-Number, percentage, and age-standardized percentage
of chronic bronchitics among S,4$8 cigarette smoking male
volunteers for mass radiography, aged 40 and older, by amount
and method of smoking

                      Cigarettea per day

                     1-a         IO-19        eo+          All

                  D. N.     D.    N.     D. N.     D. N.
Number of
volunteers ______ 60   681   134 1,839   266 2,568   460 4,978
Number of chronic
bronchitics ______ 22   160 56   552   113   971   191 1,673
Percentage chronic
bronchitics _ _ _ _ _ _  36.6   25.8 41.8 30.0   42.4   37.5 41.5' 33.6*
Age-standardized
percentape of
chronic
bronchitics _ _ _ _ _ _  33.9   26.0 41.1 32.1   44.1   41.1   41.6   35.1

`P <.ool.
D. = "drooDing" cigarette smokera. N. = normal cigarette smokers
%NJRCE: Riminstos. J. (BP 55).

79


Olziihutag, et al. (BP 50) studied the prevalance of chronic
bronchitis in Mongolia and found no association between ciga-
rette smoking and chronic bronchitis in urban women, and a neg-
ative association in rural women. These authors found close asso-
ciations between chronic bronchitis and smoking in men. The
authors pointed out that chronic bronchitis increased in fre-
quency with age.

Sherman, et al. (BP 58) conducted a study in Detroit on 489
working men and women, among whom 459 were employed in
the auto industry. All subjects were referred to one physician for
evaluation for workmen's compensation. The authors concluded
that their data challenged "the traditional view (held) by . . .
much of the medical profession that workers' lung and heart
diseases are largely caused by cigarettes rather than by work-
place poisons." These investigators studied various occupational
exposures within the auto industry and found that both in ex-
posed and unexposed working populations, approximately the
same percentages of cigarette smokers and nonsmokers suffered
from bronchitis, emphysema, and heart disease. Imprecise smok-
ing histories and the absence of adjustment for several potentially
confounding variables limit the conclusions which can be drawn
from these data.

   The Eflects of Smoking on Pulmonury Function
           in Patients with COPD
In a retrospective study of 41 hospitalized cigarette smokers

with a diagnosis of pulmonary emphysema, Lepine and Myre
(BP 37) found dose-response relationships between number of
daily cigarettes smoked and years of dyspnea, years of cough,
and impairment of the maximum expiratory flow rate (MEF).
No dose-response relationships were found for the presence of
car pulmonale by ECG, X-ray evidence of cardiomegaly, impair-
ment of carbon monoxide diffusion, functional residual capacity,
arterial blood gas abnormalities, or the ratio of residual volume
t.o total lung capacity (RV/TLC) .

In a retrospective analysis of pulmonary function tests
(PFTs) of 140 patients with emphysema, chronic bronchitis,
or both, Kass, et al. (BP 31) found no correlation between the
severity of impairment of pulmonary function tests and the
amount or duration of cigarette smoking.

The Effects of Smoking on Pulmonary Function in
       Healthy Populations

Grimes and Hanes (BP 24) studied 1,059 employees of a Iarge
insurance company and found that cigarette smoking was associ-

80


ated with decreases in FVC and FEV, for all age groups in men.
In women, the younger ex-smokers had higher values on pulmo-
nary function testing than the nonsmokers. Higgins and Keller
(BP 26), utilizing data obtained from the Tecumseh Study, did
note differences in FVC, FEV,, FEVJVC, and MEF,,% between
smokers and nonsmokers for both sexes and between smokers of
greater than and less than 20 cigarettes per day. In this study,
smokers of either sex had lower mean FVC, FEV,, FEVJFVC,
MEF 508, average flow during the middle half of expiration
(MMEF 25-i5s), average flow between 0.2 and 1.2 liters of expira-
tion (MMEF 0.2.2L), and peak expiratory flow rate (PEF) than
nonsmokers, and all these values decreased with increasing tobac-
CO consumption.

Krumholz and Hedrick (BP 35) studied pulmonary function in
91 cigarette smoking and 136 nonsmoking "healthy" male execu-
tives, aged 35 to 64. They found significant impairment in the
smokers for VC (P <.Ol), FEV, (P <.OOl), FEV% (P <.OOl),
FEW 25-75~~  (P <.OOl), Raw (airway resistance) (P <.05),
MVV (P <.05), RV/TLC (P <.05), CO diffusion (DXO) (P
<.OOl), and D&O/TLC% (P <.OOl). Mean lung volumes were
the same in the two groups except for RV/TLC. The methods of
selection of patients for this study were not detailed.

Brooks and Waller (BP 2), in a study of 2,703 people attending.
a public health exhibition, found a nonsignificant difference in
peak flow rates between smokers and nonsmokers age 45 and
over; no differences were demonstrated for the younger than 45
age groups. The authors pointed out a number of biases which
limit the conclusions which may be drawn from these data.

Coleman, et al. (BP 11) investigated the maximal oxygen con-
sumption (physical work capacity) of 78 members of the Texas
Tech University faculty and found no difference in this value
between smokers and nonsmokers. However, as the authors
pointed out, the mean age of the smokers was seven years less
than that of the nonsmokers, and the daily activity level of the
smokers was also greater than that of the nonsmokers. The
combination of these two effects may have partially accounted
for the lack of difference in maximal physical work capacity be-.-
tween the smokers and nonsmokers in this study population.

In a cross-sectional study of men and women from the Western
Highlands District and Trobriand Islands in New Guinea, Wool-
cock, et al. (BP 70) found a greater decrease of FVC, FEV,,
and PEF with age in men who smoked compared to nonsmokers
(no P value reported). No such differences were found for women
for FEV, and PEF.

Woolcock, et al. (BP 69) also reported that in this same group

81


of New Guineans smoking was not strongly associated with
cough on a single examination in the Western Highlands Dis-
trict (WHD) population, but was strongly associated in the
Trobriand Islands (TI) population. The authors stated, though,
that the TI population smoked western cigarettes, whereas the
WHD population smoked predominantly home-grown tobacco
rolled in newspaper and smoked as cigars.

The Roles of Smoking and Pollution in the
    Development of COPD

Cigarette smoking is the predominant factor in the develop-
ment of chronic nonspecific respiratory disease (CNRD), but
there have been few prospective studies on the interaction be-
tween air pollution and cigarette consumption as risk factors in
the development of chronic nonspecific respiratory diseases. In
an analysis of the initial data from a prospective study of Bos-
ton policemen, Speizer and Ferris (BP 61) found that a higher
percentage of men in three of four smoking categories who
worked in areas of heavy traffic had chronic nonspecific respira-
tory disease compared with men who worked in the outskirts of
Boston (figure 1) .I In general, for each of the four traffic exposure

*Criteria for diagnosis of CN&D were those established by the British
Medical Research Council Bronchitis Committee (1966).

Nonsmokan

UL

l-24

25+     Ex-smokers

Current Number of Cigarettes Smoked Daily

FKWBE l.-Prevalence of chronic nonspecific respiratory disease by cigarette
           smoking habits and trafIic exposure.

SOURCE

82

Spelzer, F. E., Ferris, B. G., Jr. (BP 6ZJ.


,.stegories, the prevalence of CNRD was greater among ex-
smokers than nonsmokers, and greater among current cigarette
smokers than among either ex-smokers or nonsmokers (table 2).
conversely, the prevalence of CNRD in current smokers appeared
to be related to the number of years of traffic exposure ; those
men with few years of such exposure had approximately the
same incidence as those who worked in the outskirts. In the
analysis of this reIatively homogenous group of men, it appears
that "traffic pollution" and cigarette smoking may be acting in
concert to increase the risk of deveIoping chronic respiratory
disease.

TABLE 2.-?%?vatence of chronii: nonspecijic respiratory disease
grouped by current cigarette categories and trafic exposure

-~                                         In TmUic

     %%E       I-10       11-20       20+
Total No. Men                        3-r

Never smoked ___   46'     11.6      11.1      26.0      16.7

Ex-smoker ______   86      30.3      27.3      19.0      28.6

Current cigarette
smoker _ _ _ _ _ _ _ _  137      49.2      44.1      67.7

Total  _ _ _ _ _ _ _ __ _ _  268      36.1      36.2      39.2

o ????? ?????? utecor~ includes 12 men who I've smoked pipe mnd cigars.
SOURCE: Spcieer. F. E. Feti. B. G.. Jr. (BP 81).

64.8

39.0

These authors also measured pulmonary function in this co-
hort of policemen (BP 62) and found correlations between im-
pairment of FEV, and lifetime cigarette smoking for all the men
(P <.OOl). Statistically significant correlations between im-
pairment of flow volume relationships at 50 and 25 percent lung
volume and current cigarette consumption (P <.05 and <.OOl),
and lifetime cigarette consumption (P <.Ol and <.OOl) were
found for the outskirt station officers, but not for the. traffic
officers, although the heavier smokers among them did demon-
strate impairment of these parameters compared to the non-
smokers and ex-smokers. The data also revealed that the heavier
smokers with the longest exposure to traffic had the greatest
impairment of flow-volume relationships at 50 percent (and 25
percent) vital capacity, again suggesting the synergistic action
of air pollution and cigarette smoking in producing obstructive
pulmonary disease.

33


The Relationship Between Cigarette Smoking and Small
         Airways Disease

The role of small airways disease in the pathogenesis of COPD
has come under close scrutiny in recent years. Results from
several studies indicate that the resistance of airways less than
2 mm. internal diameter contributes little to the total measurable
pulmonary resistance, and that considerable obstruction of these
small airways may be present before changes in the total pul-
monary resistance are recorded (BP 41) . Several techniques have
been developed to detect the presence of small airways disease,
but some of these are technically difficult, expensive, and imprac-
tical for large-scale screening. The measurement of dynamic
compliance was one of the first techniques used to demonstrate
disease of the small airways (BP 71). Patients with small air-
ways disease demonstrate frequency dependent decreases in dy-
namic compliance compared to controls. More recently, the meas-
urement of closing volume (CV) has been used as a technically
easier and less expensive method for the assessment of small air-
ways function. The theoretical basis of these methods in the as-
sessment of small airways disease is described in many recent
publications (BP 3, 4, 5, IO, 20, 23, 25, 28, 34, 36, 40, 41, 42, 43,
63, 66, 71). It is currently unclear whether those subjects with
evidence of small airways disease are particularly susceptible to
the development of clinically identifiable forms of COPD.
McCarthy, et al. (BP 40) measured closing volumes in 112
subjects by the single-breath argon gas bolus method. Closing
volume increased in a linear fashion with respect to age. Of the
66 nonsmokers, no subjects had closing volumes greater or less
than 2 SDS from the mean normal values, whereas 26 of 39
cigarette smokers (7 smokers yere excluded because of grossly
abnormal ventilation distribution as measured by the argon tech.
nique) had closing volumes greater than 2 SDS above the mean
(figure 2). This difference in closing volume was highly signifi-
cant (P <.OOl) and indicated a higher prevalence of small air-
ways disease in the group of smokers. Of 14 smokers with
abnormalities of standard pulmonary function tests, 13 were
symptomatic and all but one had abnormal closing volumes. Of
note was that of 17 asymptomatic smokers, 9 had abnormally
high closing volumes. Although none of the smokers had sought
medical attention, 29 of the 46 smokers had chronic bronchitis,
and had, on the whole, higher closing volumes than the asymp-
tomatic smokers.

In a separate pubhcation, McCarthy and Craig (BP 39) re-
ported that 15 percent of a group of 91 asymptomatic female
smokers in Manitoba had abnormally high closing volumes (CV),

34


60        I       I       I    :-


       Smokers
       Seated

. Symptomatic

0 Asymptomatic

10                          50

30      40

  Age (Yea6

60      70

FIGURE 2.-Relationship between "closing rolume" and age in 39 smokers.
(Thirty-two smokers with normal conventional lung function data and seven
smokers whose data are identified by numbers.) Average relationships 22 SD
between "closing volume" and age in sixty-six nonsmokers are also shown.
Solid circles indicate smokers who, according to the questionnaire used, had
simple chronic bronchitis, and open circles indicate smokers who were as.vmp-
tomatic. Note that in nine asymptomatic smokers the "closing volume" was
above the normal limits.

SOURCE : i\icCartbp, D. S., et al. (BP JO).

in contrast to the `72 percent of 46 male smokers in London
(BP 48) who had abnormally high closing volumes. None of the
female nonsmokers had any CV abnormalities. The authors sug-
gested that differences in pollution exposure of the London and
Manitoba study groups might, in part, account for the differ-
ences in prevalence of the CV abnormalities.

In a study of pulmonary function of subjects voluntarily re-
porting to an emphysema screening center, Buist ,et al. (BP 5)
reported that 6 percent of the nonsmokers, 35 percent of the
current cigarette smokers, and 23 percent of the ex-smokers had
abnormal CV/VC ratios. In each decade from age 20 to 79, more
smokers and ex-smokers had abnormal CV/VC ratios than non-
smokers (figure 3). The daily consumption of cigarettes was re-
lated to CV abnormalities in a dose-response relationship for
men (figure 4). Among the women, those with a daily consump-
tion of less than 10 cigarettes per day had significantly lower

86


n Nonsmqkem (284)

Smokers (524)

0

n=7   7   3    43 61 20     30 91 26     32 126  51    63 143 60     66  65 54     32  11 21    11 3

     <20       20-29        30-39       40-49        !lo-59        60-69         70-79      =a0
                                 Ace (yearn)

F'IOUBE 3.-Prevalence of abnormal closing volume/vital capacity ratios in non-
     smokers, cigarette smokers, and ex-smokers by age decades.

SOUBCl : Buirt, A. S., et at (BP 6).


CV/VC ratios than those smoking more than this amount (P
<.05) ; but overall, no dose-response relationship was demon-
strated (figure 5).

100

SO

60

E
0
2
2


   40









   20









   0

< 10 Cigarettas/Day   n=21
10-20 Cigamttar/Day n=136
2-O Cigarettes/Day n= 175
>40 Cigarettes/Day  n=19

Symptomatic

26.3

FIQIJBE 4.-Comparison of the prevalence of respiratory symptoms and pulmonary
function abnormalities in male smokers according to their daily cigarette
consumption.

cc   -Closing capacity
TLC  -Total lung capacity
cv   --Closing volume
vc   -Vital cepacity
FEvl  --One-second forced expiratory volume

SOUBCE : Buist, A. 9.. et al. (BP 5).

  The Interactions Between Cigarette Smoking and the
  Genetic Susceptibility to the Development of COPD
Mittman, et al. (BP 47, 47, 49) reported on the interaction
between cigarette smoking and the genetic susceptibility to de-
velopment of chronic obstructive pulmonary disease (the alpha,-
antitrypsin deficiency state).  These authors described the

8'7


  100









  a0







E
8   60
k
P







   40









   20









   0

100
m

< 10 Cigarettes/Day  n=19
IO-20 Cigarettes/Day n=75
20-40 Cigarettes/Day "~77
> 40 Cigarettes/Day   n=3

FIMJRE Zi.~omParison of the prevalence of respiratory symptoms and p&
monarY function abnormalities in female smokers according to their daily
cigarette consumption.

CC  -Closing capacity
TLC  -Total lung capacity
cv  -Closing volume
vc   -Vital capacity
FE& --One-second forced expiretory volume

SOURCE : Buid, A. S.. et aL (BP 5).

polymorphic (multiple gene) system of protease inhibition (Pi) by
alphal-antitrypsin (AAT), and listed some of the partial and
severe deficiency states of this enzyme system. In a series of 170
consecutive patients with a diagnosis of COPD admitted to the
City of Hope Medical Center who had no previously known his-
tory of AAT deficiency, 40 patients (24 percent) demonstrated
some type of AAT deficiency. This was a significantly higher

88


  20




  10



2 0
2
8
I3
E
1
>4Q
:
e
E 30
t
E
s
; 20
L



  10




   0 I

0

I      I      I      I      I      I      I     I
15    30     45     50     75     90    105    120

              Pack Years

percentage than was found in a control group of the Norwegian
population, which is known to have a high incidence of this
enzyme deficiency (P <.OOl). The lifetime cigarette consump-
tion of the population of patients with emphysema who had an
intermediate degree of AAT deficiency was significantly less than
those emphysema patients with a normal phenotype (PiMM)
(P <.05) (figure 6), suggesting a possible interaction between
smoking and the genetic abnormality. The data imply that a
greater degree of exposure to tobacco was required to produce

FIOIJEE B.-The distribution of smoking histories in men with bronchitis and/or
emphysema. Patients grouped by phenotype; Pi a patients above, those with
intermediate MT deficiency below. Each bar depicts the fraction of patients
reporting smoking histories in the ranges shown.

SOURCE : Mlttman, C., et aL (BP 48).

89


emphysema in those patients who did not have a genetic predis.
position than in those with the genetic defect. The authors con-
cluded that any degree of AAT deficiency makes an individual
more susceptible to the effects of smoking. The same authors
have also examined 144 people with partial AAT deficiencies
who were apparently healthy and compared them with 100 con-
trols matched for age, sex, and smoking history (BP 48). They
found that 25 of the 62 smokers with partial AAT deficiency
(40 percent) had abnormalities of pulmonary function tests sug-
gestive of obstruction, while 7 of 47 smokers in the control
group (15 percent) demonstrated such abnormalities. This differ-
ence was statistically significant (P c.05).

Hutchison, et al. (BP 27) studied 28 patients with pulmonary
emphysema, 8 of whom were homozygous deficient for alpha,-
antitrypsin. Although the annual consumption of tobacco up to
the age of onset of dyspnea was equal in the deficient and non-
deficient group of patients, total lifetime tobacco consumption
was significantly Iess among the AAT deficient patients than
among the nondeficients (P c.01). AI1 8 AAT deficient patients
were smokers. Although there was no significant difference in the
incidence or age of onset of chronic bronchitis between the two
groups, the AAT deficient group of patients developed exertional
dyspnea 12 years earlier than the nondeficients (P <.OOl). These
data suggest a synergistic effect of cigarette smoking on the
development of pulmonary emphysema in those patients with
homozygous deficiency of alpha,-antitrypsin.

Colley, et al. (BP 12) analyzed a cohort of 3,899 persons born
in the last week of March 1946 in England, Scotland, and Wales
and found that irrespective of a history of lower respiratory
tract illness before the age of two, the smokers had a greater
prevalence of symptoms of winter cough at age 20 than the
nonsmokers (table 3). The authors argued that cigarette smoking,
by age 20, is a far more important factor in the development of
respiratory disease than is a history of lower respiratory tract
illness. The results of this study are suggestive evidence against
the hypothesis of a purely constitutional susceptibility to the
development of respiratory diseases independent of tobacco ex-
posure.

The Effect of Smoking on the Development of BuUous
      Disease 04 the Lungs

Stoloff and Victor (BP 64) reviewed 44,887 outpatient photo-
fluorograms seen in the Philadelphia Central Mass X-ray~Unit
from 1969 to 1970, and found 59 men and one woman with bul-
lous disease of the lung. Smoking information was available on

90


TABLE 3.-Prevalence (percent) of cough o2q.1 or night in both
sexes in winter by air pollution index, social class, cigarette
making, and history of chest illness under two years of age.*
(Figures in parentheses are population.)

                            Air poktion index
HistorY Of                        7-17                18-28
cigarette    Chest illness under        SocisI dell9            Social claes
smoking     2 Years of age     1+2      a-l-4     1+2     a-t4

Never    No chest illness _  4.7 (344)  6.7 (369)  4.7 (277)  6.6 (212)
smoked  One or more chest
       illnesses _ _ _ _ _ _  12.3 (67)  8.3 (108)  8.3 (84) 10.8 (102)

Present  No chest illness _ 11.2 (214) 12.6 (326) 14.1 (192) 16.7 (261)
smoker  One or more chest
       illnesses _____. 16.4 (66) 11.8 (102) 12.3 (73) 22.2 (144)
*Excluding 980 pzmone-that ie. examokem and thwe whose history of cigarette smoking.
social class, air pollution index, cheet illneaa under 2 yearn of age. and history of cough day
or nipht not known.
SOURCE: Cdey, J. IL T.. et IL (BP 12).

51 of the men. There were no nonsmokers among the 51 cases
(P <.OOl). In nonwhite and white men under age 45 and in
nonwhites greater than 45 years old, the rates of this disease
increased for each progressively higher level of daily cigarette
consumption (table 4). When men without known possible or
probable occupational hazards were studied, dose-response rela-
tionships were again demonstrated in the nonwhite population,
inclusive of all age groups (table 5). The absence of dose-
response relations in whites older than 45 may be at least par-
tially explained by the small numbers of cases of bullous disease
of the lung found in whites (19 of the 51 cases). The authors
stated that the data "are consistent with the hypothesis that
cigarette smoke is capable of causing alveolar septal rupture . . ."
and, hence, bullous disease of the lung.

TABLE 4.-Estimated rates of bullous disease of the lung per
1,000 men by age, race, and cigarette smoking habits.

yg2 $x                    Nonsmoker   <1 Pack/Day    1 Pack+/Day
WM
26-44                     0         0          1.0
        ____________________--
46f  _______________________    0        4.6         2.9

NWM
26$                                        9.9
       __________________-----   0         4.3
46+  ___________________-___    0         4.1        13.0

SOURCE: StolofY. I. IA, Victor. S. B. (BP 64).

91


TABLE 5.-Estimated rates of bullous disease of the lung per
1,000 men with no demonstrable occupational huzccrd (c.luss 1).

Nonsmoker      <I. Pack/Dar   1 Pa&+/Day

WM
26-44  ______________________    0         0          0
45+  ___--_-_____-_--_______   0         4.0         2.2
NWM
25-44  ______________________   0         2.0         6.4
45+  __-_-_-_-__-__--_-_____    0         4.6         7.7

Total  _ _ __ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ _    0         6.2         4.9

SOURCE: Stoloff. I. L.. Victor, S. R. (BP 84).

Smoking and Post-Operative Complications

Laselo, et al. (BP 35) studied the incidence of post-operative
puImonary complications in 52 bronchitic and 88 nonbronchitic
patients undergoing elective surgery in London. They found
that a significantly higher percentage of current nonbronchi-
tic smokers (53 percent) developed post-operative pulmonary
complications than nonbronchitic nonsmokers (22 percent) (P
<.02). In patients with no history of chronic bronchitis, there
was a dose-response gradient of post-operative bronchitis and/or
pneumonia from nonsmokers through ex-, light, and heavy smok-
ers. The presence of bronchitis did not seem to influence the
effects of smoking; the bronchitic and nonbronchitic smokers
had an equal incidence of pulmonary complications. Of the six
cases of severe post-operative bronchitis, five occurred in smok-
ers. The authors noted that each of the three patients who de-
veloped severe purulent bronchitis after minor surgery smoked
more than one pack of cigarettes per day.

The Influence of Cigarette

Smoking on the Development of Pulmonary
D&ewe Associated with Rheumatoid Arthritis

Frank, et al. (BP I?) investigated 14 men and 2'7 women
with classical rheumatoid arthritis and evaluated the presence or
absence of pulmonary dysfunction in this group. They reported
the presence of pulmonary function abnormalities in 5'7 percent
of the men and 33 percent of the women. The men with abnormal
pulmonary function tests (spirometry and CO diffusion) had a
higher mean lifetime consumption of cigarettes than men with
normal pulmonary function tests (P c.05) ; however, the mean
age of the abnormal group was 5 years greater than that of the
normal group. The women with abnormal values of pulmonary

92


function tests smoked more than those with normal values (14.44
VS. 9.72 pack years), but the difference was not statistically sig-
nificant. The group of women with abnormal values was also
slightly older than the normal group (by 1.12 years).

Occupational Diseases and Smoking

Byssinosis

Kilburn, et al. (BP 3.2) reported on the prevalence of chronic
bronchitis in wool and cotton mill workers in North Carolina.
These investigators found that in women the combination of
cigarette smoking and cotton dust exposure was associated with
a marked increase in the prevalence of chronic bronchitis (figure
7). Of the nonsmoking nonexposed employees, less than 1 percent
had chronic bronchitis. Cotton dust exposure and cigarette smok-

30 r

25 t     Bronchitis
  u Grade 1
  B  Grade 2

       Grads 3

    20
.-o
.z
e
2
P    15
E
z
ii
0.

10

5

NO.      55    38    40    35    63    21    26    25

Age    <40   so+ <40   40+ <40   40f <40   4Of

Exposure    WOOI      cotton      WOOI      Cotton

Smoking      Nonsmokers            Smokers

FIGURE `i.--Chronic bronchitis in female wool and cotton textile workers.

SOURCE : Kilbum, K. H., et al. (BP 3Z).

93


ing alone were associated with prevalence rates of 7 percent and
13 percent, respectively. Both exposures in combination resulted
in a prevalence rate for chronic bronchitis of !27 percent. For
men, a synergistic effect was demonstrated (figure 8), but it was
not as striking as that for women. The authors suggested that the
differences in prevalence of chronic bronchitis between men and
women, and the differences in the effects of the two noxious
exposures in combination may have been due to the fact that
men were more heavily exposed to both cotton dust and cigarette
smoke than women.

In a cross-sectional survey of 1,140 cotton workers in England,
Fox, et al. (BP 16) found by regression analysis, that for each
level of dust exposure (mg. yrs./m.*) smokers and ex-smokers had
lower FEV, observed/predicted percent than nonsmokers. The
differences in the slopes of these lines were not significant (figure

30

III Grade 1

Bronchitis
O Grade 2

i Grade 3

25

10

5

No.     30 4     47 16 88 36   103 57

Age    <40   40+ <40   40+ <40   40+ c40   40+

Exposure   WOOI       COttOIl      Wool      COttOIl

Smoking      Nonsmokers             Smokers

FIWRE R-Chronic bronchitis in male wool and cotton textile workers.

SOURCE : Kilburn, K. H.. et al. (BP S.9).

94


9). The authors also reported that the percentage of smokers
with byssinosis was higher than that for nonsmokers at each
level of exposure, the slopes of the lines being significantly differ-
ent (P <.OOl) (figure 10).

Time-waightad Dust Maasurement (mg years/m9

  0       10      20      30      40      50       60      70
100         I        I       I        .        1        a       I

`Nonsmokers':
FE&A (observed)
FN, ~ ~exp~~d)%=99~W-O~035XCTWDM): r=-0.08

`Smokers':
;z;:: :;:;zz; %=94*684~083X(lwDM): r=-0.13

FIGUBE Q.-Effect of smoking on pulmonary ventilation ( FEVI) at different levels
            of time-weighted dust exposure.
SOURCE : Fox. A. J., et aL (BP 19).

Chew, et al. (BP 9) examined 112 asbestos workers in Singa-
pore and found only slight differences in mean FEVls between
smokers and nonsmokers (2.73 L and 2.79 L, respectively).

    Chronic Bronchitis and Pulmonary Symptoms
     in Cement and Rubber Industry Workers
In a cross-sectional study of 847 cement workers in Yu~o-
slavia, Kalacic (BP 29, 30) found that nonsmokers had a higher
prevalence of cough, sputum production, exertional dyspnea, and

96


30 1

IS-    Ex-smokers (51)
  ---------

lo-





5-





0         I        I        I        I       L        I       1
  0       10       20       30      40      60      60 70

`Nonsmokers':

lima-weighted Dust Measurement (mg years/ml)

%=1.67+0*23XCTWDM): rz0.27

`Smokers':

$4 ~6.76+0-30X(lWDM):' rc0.25

From IO.-EKe& of smoking on prevalence of byssinosis at diKerent time-
            weighted dust exposure levels.

SOURCE : Fox, A. J.. et al (BP lb).

chronic bronchitis than controls with other occupations. Within
the group of cement workers, cigarette smokers had higher
prevalence rates of cough, sputum production, exertional dyspnea,
wheezing, and chronic bronchitis than nonsmokers regardless
of the number of years of exposure in the cement plants. No
significant differences in FVC or FEV% were observed between
cigarette smoking and nonsmoking cement workers.

Osman, et al. (BP 51) studied 230 rubber industry employees
in Egypt and found a higher prevalence of upper respiratory
tract irritation, acute bronchitis, and chronic bronchitis in
smokers compared to nonsmokers (NS). There was a lower
prevalence of these three conditions among control smokers
compared with smokers exposed to these industrial fumes, thereby
suggesting a synergistic action of cigarette consumption and
exposure to rubber industry fumes.

96


AUTOPSY STUDIES

The Effect of Smoting

on the Prematw-it~ of Development and Severity of COPD

Spain, et al. (BP 60) evaluated the degree of emphysema
in whole lung mounts of 134 victims of accidents, suicide,
homicide, or sudden coronary death autopsied at the office of the
Medical Examiner of Westchester County (86 men and 49
women). Degree of emphysema was graded from 0 to 100. In
men, 3 of 30 nonsmokers had grades of 20 or higher (10 percent),
while 16 of 41 heavy smokers had grades of 20 or higher
(39 percent). This difference was significant (P c.01). The
highest grade which the nonsmokers reached was 20, whereas
several of the heavy smokers reached grades of 50 (precise data
not given). The mean ages of the nonsmokers, light smokers,
and heavy smokers with grades 20 or greater were 66, 62, and 52,
respectively. The mean grade of emphysema in all the heavy
smokers was 14, compared to 11 in the lighter smokers and 8 in
the nonsmokers. Among 21 nonsmoking women, there were no
cases of grade 20 or greater, while in the heavy smokers 5 of
22 cases had grade 20 or greater. The mean age of this group of
smokers was 40. For the women, as in the men, the mean grade
of emphysema rose with the intensity of smoking. The authors
attributed the differences in degrees of emphysema solely to
smoking.

Smoking and Mucous G&d A h.mmatities

In an autopsy series in Glasgow of 149 men and women with
known smoking histories, Scott (BP 57) studied the degree of
mucous  gland hypertrophy using the Reid index and
point-counting technique. He found that the mean Reid index
was significantly greater in smokers than nonsmokers (P <.Ol)
and that fewer smokers had normal Reid indices than non-
smokers (P = .02). Although more smokers had an abnormally
high Reid index compared to nonsmokers, the difference was
not statistically significant. In this autopsy series, the Reid
index was found to be higher in young subjects; also men were
noted to have a significantly higher index than women (P C.05).

A bnmmdities of the 23ma.U Airways

Matsuba and Thurlbeck (BP 44)) in a study of postmortem
lung specimens, found that in patients with chronic bronchitis
without emphysema who died of nonrespiratory causes, there

97


was significant narrowing of small airways compared to pa-
tients without either chronic bronchitis or emphysema, as meas-
ured by the smaller average diameter of the small airways (P
c.001). These patients had an excess of airways with 0.2 to
0.6 mm. internal diameter and a deficit of airways with an
internal diameter of 0.6 to 1.8 mm. (figure 11). In addition,
these workers observed more mucus in the airways of the pa-
tients with chronic bronchitis without emphysema than in those
patients without either disease. The authors concluded that
both small airway narrowing and mucus plugging constitute the
major morphologic Iesions corresponding to the functional ab-
normalities of small airways seen in patients with chronic bron-
ChitiS.

.--,

-. 2

. ..A   -. 6    -.8   -1.0   -1.2   -1.4   -1.6   -1.8   -2.0

Diemeter of Aimsye (mm)

----- No Bmnchitis. No Emphyeeme
- Chronic Bronchitis, No Emphysema

homuz Il.--A frequency distribution curve of the internal diameters of the small
airways in an autopsy population of nonemphysematous patients with and
without histories of chronic bronchitis.

SOURCE: Matsuba, K., Thurlbeck. W. M. (BP 44).

98


EXPERIMENTAL STUDIES

Paterson, et al. (BP 52) measured pulmonary function in a
group of 16 nonsmokers and 10 heavy cigarette smokers before
and after exercise. No significant differences in FVC, FEV,,
MMEFR, and FRC were observed between these two groups be-
fore exercise. However, after exercise, the smokers exhibited a
greater drop in MMEFR, FEV,, and specific airways conductance
than t.he nonsmokers, thus demonstrating that post-exercise air-
ways narrowing was greater in the smokers. The nonsmokers dem-
onstrated a greater improvement in all these parameters meas-
ured after exercise following use of disodium chromoglycate
(an anti-bronchoconstrictive agent) than the smokers. The
authors suggested that the increase in airways resistance in non-
smokers was mostly due to bronchoconstriction; that seen in
smokers was thought to be a combination of bronchoconstriction,
mucosal edema, and accumulation of secretory debris.

Using simultaneous helium bolus and nitrogen dilution tech-
niques on 9 subjects, Linn and Hackney (BP 38) showed that,
with the He method, none of 4 nonsmokers had mean CV/VC
% greater than 16.9, whereas both the current cigarette
smokers and the one ex-smoker had CV/VC% greater than 21.3.
The one pipe smoker had a ratio of 18.9. With the nitrogen
dilution technique, the same pattern of abnormalities of the CV/
VC ratio in this group of subjects was demonstrated. The highest
CV/VC% among the nonsmokers was 17.4, and the lowest
among the current, ex-, and pipe smokers was 18.0.

Reintjes, et al. (BP 54) studied the acute effects of smoking
one cigarette on large airway resistance in a group of 30 young
healthy male volunteers (16 smokers and 15 non and ex-
smokers), and found that immediately after the smoking of one
nonfilter cigarette there was a significant increase in mean air-
way resistance for both smokers and nonsmokers (P <.OOl). The
FEV% did not vary after the smoking of the cigarette in either
group of volunteers.

Da Silva and Hamosh (BP 14) reported on pulmonary func-
tion tests performed on 21 volunteers before and after smoking
one nonfilter cigarette, and found that total airway resistance
(Raw) was significantly increased (P <.OOl and MEF,as
was significantly decreased after smoking (P <.OOl). Other
measurements, including those used to assess small airways func-
tion, showed no significant changes from the control to the post-
smoking states.

Stone, et al. (BP 65) conducted experiments on 19 volunteers,

99


4 of whom had chronic bronchitis. There were 11 cigarette
smokers and 8 nonsmokers. These authors found that the infusion
of isoproterenol increased specific airway conductance (SGaw)
equally in smokers, nonsmokers, and patients with chronic bron-
chitis. Likewise, infusion of propranolol decreased SGaw equally
in all these groups of subjects. Alpha-adrenergic stimulation and
blockade had no effect on SGaw in any of the experimental
groups.

In an experimental study evaluating pulmonary clearance in
79 elderly subjects, Thomson and Pavia (BP 67), utilizing Tcngm.
labeled polysterene particles of 5pm,, found no statistically
significant difference in pulmonary (mucociliary) clearance of
these particles between smokers and nonsmokers with and with-
out evidence of obstructive and restrictive pulmonary disease.
The volume of inhaled particles was controlled in this group of
experiments. There was a slight diminution in mucociliary clear-
ance of the healthy smokers compared to the nonsmokers. The
group of subjects with impaired pulmonary function had higher
clearance rates than the normals, probably owing to the greater
deposition of particles nearer the mouth. Amon,g the subjects
with subnormal pulmonary function, smokers had slower clear-
ance rates from I to 5 hours after inhalation of the particles, but
these differences were not statistically significant (figures 12 and

z
6   40  -
z                              .A\
B                              L yObstructiva (13)
k a.      F  0.37  0.67 0.65 1.00 0.60 1.26  1.99 3.09 2.40  1.92  1.86  3.06
     L               Lr             J

0       1       2       3       4       6       6

Time After Inhalation (hr)

FIQURE B.--Mean clearance curves for normal subjects, subjects with airway
obstruction, and restrictive impairment of the lungs. F=Snedecor's F; the
value required for significance here at the 5 percent level is 3.11.

SOURCE: Thomson, M. L., Pavia, D. (BP 67).

100


13). Camner, et al. (BP 8) reported on clearance rates in 17
young and middle-aged ex-smokers who had stopped smoking for
3 months. These workers noted that mucociliary clearance of 6
c(m. fluorinated ethylene propylene (Teflon 120) particles tagged
with Tcssm. measured at 2 hours post-inhalation had improved
at 3 months post-quitting in 11 of 17 patients. Mean retention
of particles was significantly higher prior to stopping smoking
than at 3 months (P <.05), and also was higher at 1 week post-
cessation compared to 3 months post-cessation (P =.005). In
this study, the volume of inhaled aerosol was not controlled. In
addition, coughing after inhalation of the particles was reported
to be conspicuously absent or rare, whereas in the Thomson
study (BP 67), the effect of coughing during the study was not
discussed.

FIGURE 13.-. Uean clearance curves for smokers, ex-smokers, and nonsmokers in
the healthy group and the group with respiratory impairment. F=Snede~or's
F; the values required for significance at the 5 percent level are 3.19 for the
healthy group and 3.35 for the impaired group.

SOURCE : Thomson, M. L., Pavia, D. (BP 67).

The question of whether the short-term effect of cigarette
smoking on enhancing mucociliary transport is specific to ciga-
rette smoke, or is due to a nonspecific reaction of the tracheo-
bronchial tree, was investigated by Camner, et al, (BP 7) who
found that inhalation of inert carbon particles by 8 normal sub-
jects (including 2 smokers) resulted in similar or enhanced

101


pulmonary clearance rates compared to the control states. These
results suggest that the increased mucociliary transport effected
by short-term exposure to cigarette smoke may be a nonspecific
reaction.

Westergaard and Olsen (BP 68) studied ciliary activity in
biopsy specimens from the larynx and carina in 20 patients and
found that there was no ciliary activity in epithelial cells from
these sites in the entire group of 16 moderate and heavy smokers,
while in 3 nonsmokers and 1 cigar smoker normal ciliary activity
was observed.

Binns and Clark (BP 1) described a new experimental model
for testing the short- and long-term effects of cigarette smoke on
pulmonary physiology. By using male cynomolgus monkeys which
were fitted with a specially designed smoking device, these au-
thors demonstrated marked increases in total pulmonary resist-
ance in animals smoking approximately 12 cigarettes per day,
for 5 days per week. These changes stabilized at about 20 weeks
of exposure and extended through the g-month test period. The
changes in pulmonary resistance were statistically significant
(P <.OOl). After 6 months, no changes in tidal volume, respira-
tory rate, or dynamic compliance were noted. Histologic sections
of Iungs from smoking monkeys showed clumping of pulmonary
alveolar macrophages containing pigmented granules and foamy
cytoplasm. These nonspecific cytologic changes have been observed
in other animals exposed to cigarette smoke.

Previous editions of this report (1972, 1973) have described
experimental evidence concerning the production of emphysema-
tous changes in rat and guinea pig lungs by exposure to nitrogen
dioxide (NOz), one of the gaseous components, of cigarette
smoke. Freeman, et al. (BP 18) described experiments whereby
low (10 to 15 p.p.m.), intermittent doses of NOz administered
over the normal life span of rats resulted in more severe changes
of the pulmonary parenchyma than those previously reported ;
these changes included fibroblastic proliferation, epithelial hy-
pertrophy, loss of cilia in the respiratory bronchioles, fibrosis of
alveolar ducts, destruction of aIveolar wails, and enlargement of
alveolar air spaces. These authors calculated a 29 percent loss of
ventilatory surface in the NO,-exposed rats, occurring in a pan-
lobular distribution. The lungs of the NOz-exposed rats had
greater residual volumes than the controls, and these rats suf-
fered from hypoxemia, hypercarbia, and acidosis, as well as a
compensatory polycythemia. Thus, by administering lower doses
of NO, intermittently, survival of these rats was prolonged (com-
pared with survival of rats receiving continuous NOz), and the

102


development of a full-blown picture of emphysema similar to that
seen in humans was produced. The relative roIe of NO* in the
causation of emphysema in humans is still unknown.

In another series of experiments, Giordano and Morrow (BP
21) studied mucociliary clearance rates in female rats exposed
continuously to low doses of NO* (6 p.p.m.) over a period of 6
weeks. They found a significantly decreased rate of clearance in
rats exposed to NO, than in nonexposed rats (P <.02). In
those animals with a decrease in mucociliary activity, the effect
of NOz was reversible within 7 days following this long-term low
dose exposure.

Goldstein, et al. (BP 22) reported on the effects of low level
NO, exposure on bactericidal activity of the mouse lung. They
first infected mice with radioactively labelled Staphylococcus
aureus and then exposed them to different concentrations of NO,
for 4 hours. The authors then measured pulmonary radioactivity
and bacterial concentrations. They found that at concentrations
of 7, 9.2, and 14.8 p.p.m. NO, the level of radioactivity was
unchanged, but bacterial counts were greater in the NO,-
exposed mice (P <.05), and they concluded that the bacterici-
dal activity of the NO,-exposed animals was significantly less
than that of control animals at these concentrations of NO,. In a
series of experiments where mice were first exposed to 1.0, 2.3,
and 6.6 p.p.m. NO* for 17 hours and then infected with the label-
led Staphylococcus aureus, pulmonary bactericidal activity was
decreased in the mice exposed to the latter two concentrations
of NOz (P <.05 and P <.Ol). In both sets of experiments, the
physical removal rates of bacteria by the pulmonary tree (as
measured by the degree of remaining radioactive label) was not
influenced by NO*. These experiments suggest that the retarda-
tion of pulmonary bactericidal activity was due to dysfunction
of the cellular elements of the pulmonary defense mechanism
(i.e., pulmonary alveolar macrophages [PAMs]) in the NO,-
exposed mice.

Fenters, et al. (BP 15) exposed four monkeys to low dose
NO, (1 p.p.m.) for 16 months and infected these animals with
influenza virus. Three control monkeys were exposed to the virus,
but not to the NO,. The NO,-exposed animals had higher hemag-
glutination-inhibition and serum neutrahzing antibody responses
against the virus than the nonexposed animals. Pathologic ex-
amination of the lungs of these animals demonstrated slight to
moderate emphysema in the NO,-exposed and virus-infected
monkeys, along with thickening of the bronchial and bronchiolar
epithelium, and no such changes in those animals only infected
with virus.

103


Dalhamn (BP 13) conducted experiments on 40 live rata,
exposing them to cigarette smoke of different chemical composi-
tions. The cigarette smoke was analyzed for "tar", nicotine, pH,
acrolein, nitrogen oxides (NO), acetaldehyde, hydrogen cyanide
(HCN), and carbon monoxide (CO). The author found an in-
verse correIation between the number of puffs required to produce
ciliostasis of the tracheobronchial tree and the amount of acro-
Iein, HCN, CO, "tar", and nicotine found in the cigarette smoke.
The data appeared to indicate that the majority of the effect was
caused by the "tar" and acrolein content of the cigarette
smoke.

Gairola and Aleem (BP 19) studied the effect of the water
soluble and insoluble fractions of tobacco smoke on rat liver
mitochondrial function. These investigators found that both
fractions were effective in inducing a decline in energy produc-
tion by the mitochondria, but to differing degrees, thereby
suggesting some difference in their mechanisms of action on
mitochondria.

Snider, et al. (BP 59) exposed rats to 0.1 percent cadmium
chloride solution by `aerosol, and were able to demonstrate cen-
trilobular emphysema in these animals after 10 days. Since
cadmium has been found in cigarette smoke, and smokers and
patients with emphysema have been shown to have elevated tis-
sue levels of cadmium at postmortem, further studies defining
the role of cadmium in the development of pulmonam emphy-
sema in man would be useful. In Snider's experimental pro-
tocol, animals exposed to 1 percent of CdCl, developed a severe
hemorrhagic necrotizing chemical pneumonia, and the lower dose
of CdCl, also elicited a hemorrhagic response, although no evi-
dence of such an inflammatory response was evident 10 days
post-exposure.

CYTOLOGIC AND HISTOLOGIC STUDIES

Experimental evidence indicates that cigarette smoke can im-
pair the function of pulmonary alveolar macrophages (BP 53).
Pulmonary macrophages appear to be the primary defense
against bacterial invasion of the pulmonary parenchyma and
also serve to remove particulate contaminants from inspired
air. In recent experimental work, Powell and Green (BP 53) in-
vestigated the mechanism of action of cigarette smoke on macro-
phage function. By using histochemical staining techniques, these
workers found that the filtered gas phase of cigarette smoke
(FGP) inhibited aldehyde dehydrogenase activity in rabbit pul-

104


monary alveolar macrophages (PAMs). This effect of FGP was
inhibited by prior addition of cysteine to the medium. The loss
of enzyme activity correlated with the loss of macrophage phago-
cytic function (which was also prevented by the prior addition
of cysteine). No other enzyme was inhibited by cigarette smoke
(except for GGPD in those preparations of cells which adhered
to glass). By using crystalline glyceraldehyde 3-phosphate de-
hydrogenase, the authors demonstrated that FGP inhibited ac-
tivity of this enzyme, and the degree of inhibition was directly
related to the period of incubation (most of the inhibition oc-
curring within the first five minutes). This enzyme was not
inhibited by FGP in the presence of cysteine. When enzyme
activity was assayed in cell preparations, glyceraldehyde 3-
phosphate dehydrogenase activity was reduced by FGP. This
inhibition was dose-related to FGP. FGP did not influence GGPD
or LDH activity in the pulmonary alveolar macrophages. These
experiments suggest that FGP inhibited the glycolytic pathway
within the pulmonary alveolar macrophages concurrent with the
impairment of phagocytic activity of these cells. The authors
postulated that FGP may act as a sulfhydryl agent (thereby
explaining the protective effect of cysteine) in the disruption
of the activity of glyceraldehyde 3-phosphate dehydrogenase.
-York, et al. (BP 72) showed that incubation of sheep pul-
monary macrophages with tobacco extract resulted in an initial
stimulation, then inhibition of macrophage oxygen consumption.
When cigarette smoke extract was incubated with the macro-
phages, a continuous decrease in oxygen consumption was ob-
served, proportional to the incubation period and concentration
of smoke extract (figure 14). The enzymatic mechanism of the
inhibition of macrophage respiration was not examined in these
experiments.

Invertase placed in a medium of calf's serum results in en-
hanced pinocytosis by sucrose-laden mouse peritoneal macro-
phages (monocytes). Schwartz, et al. (BP 56)) utilizing this
test system, reported that nicotine inhibited invertase-induced
pinocytosis by sucrose-laden mouse peritoneal monocytes by 29
and 18 percent, depending on the concentration of nicotine added
to the medium. The contribution of this type of pinocytosis to
the bactericidal activity of these monocytes is unclear at present.

105


0.2 0.k    0.6 0.8 1.0

      Smoke Extract, ml

1.2 1.4

Frarrrre 14,-E&& of aqueous cigarette smoke extract on initial oxygen uptake,
   final oxygen uptake, and cell viability of pulmonary macrophages.

SOURCE : York. 0. K., et al. (BP 7s).

SUMMARY OF RECRNT. NON-NEOPLASTIC
  tiRONCHOPULMONARY FINDINGS

1. Results from epidemiologic studies on elderly populations
demonstrate an increased prevalence of respiratory symp
toms and impairment of pulmonary function among smokers
of both sexes compared to nonsmokers.
2. Data from several recent studies indicate that standard pul-
monary function tests and physical work capacity are impaired
in apparent.ly healthy smokers compared to nonsmokers.
3. Recent epidemiologic data suggest that smokers who retain
their cigarettes in their mouths continuously while smoking
("droopers") have a higher prevalence of chronic bronchitis
than those smokers who remove the cigarette from their
mouths between puffs.

4. A recent epidemiologic study confirms the observation that
cigarette smoke and air pollution act synergistically in the
development of symptoms of respiratory disease.
5. Results from several recent studies indicate that cigarette
smokers have a higher prevalence of functional abnormali-
ties of the small airways than do nonsmokers.

106


6. Results from a recent study suggest that although a history of
lower respiratory disease as an infant is related to the preva-
lence of cough at age 20, cigarette smoking is a far more
important factor in the development of cough in young
adulthood.

7. Data from a major retrospective study indicate that cigarette
smoking is related to the development of bullous disease of
the lung.

8. Experimental studies in animals have shown that exposure to
nitrogen dioxide, a constituent of the vapor phase of cigarette
smoke, results in emphysema-like changes in t.he pulmonary
parenchyma, diminished mucociliary clearance, and impair-
ment of bactericidal activity of alveolar macrophages.
9. Data from experimental studies have demonstrated that the
filtered gas phase of tobacco smoke may effect changes in
pulmonary alveolar macrophage metabolism through inhibition
of the glycolytic pathway ; cigarette smoke may also impair
oxygen consumption and pinocytic activity of pulmonary
alveolar macrophages.

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   August 1973.

73. ZARKO~IC, G. Etiology of non-specific chronic respiratory illness and
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BRONCHOPUIMONARY DISEASE SUPPLEMENTAL
           REFERENCES

Pa&I

(Articles which were reviewed but not discussed in the text, providing data
confirming we&established relationships between smoking and bronchopul-
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72-1082. ANDERSON, J. A., DUNNILL, M. S., RYDER, R. C. Dependence of the
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72-0648. BRINKMAN, G. L., BLOCK, D. L., CUESS, C. Effects of bronchitis
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112


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74-0069. FERRIS, B. G., Jr., RANADIVE, M. V., PETERS, J. M., MURPHY,
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72-1108. FEUEREISL, R., KIZZHIYANE& I., REIL, I., KUEXK, A., FELKEL, K.
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73-0296. FOX, A. J., TOMBLEXJN, J. B. I,., WATT, A., WILKIE, A. G. A sur-
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73-0643. FRAPPIER-DAYIGNON, L., S~.-Pn!znt~& J. Etude de l'effet combine de
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73-0807. Ga~oc, I., NUNN, A. J. Peak expiratory flow in normal subjects.
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113


72-1260. HAENSZEL, W., HOUGEN, A. Prevalence of respiratory symptom8 h
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72-1089. HOTTEMANN, U., OSWALD, P., LODE, H., HUCKAUF, H. Uber dcl,
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73-0054. H~~TTEMANN, U., SCHOREN, K. P. Cronisch obstruktive Lungenerk.
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73-0475. IMnus, H. R., SUH, M. W. Byssinosis. A study of 10,133 textile
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73-0413. IRAVANI, J. Effects of cigarette smoke on the ciliated respiratory
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72-0760. JAIN, B. L., ABRAHAM, E., KOKAN, A. R. A study of ventilatory
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73-0301. JEDRYCHOWSKI, W. Badania epidemiologiczne wplywu warunkow
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73-0478. KIBELSTIS, J. A. Diffusing capacity in bituminous coal miners.
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73-0303. KOSTREWSKI, J. Chronic non-specific lung disease in Krakow. Sante
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73-0166. KOZAREVIC, D., ROBERTS, A., PIRC, B. Prevalence of chronic obstru?-
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73-0168. KURIK, A., FEUEREISL, R., GALLAS, J., KAVAN, F., FELKEL, H,
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73-0041. KUBO, R., ONO, M. Kitsuen no koto poripu ni oyobosu eikyo ni
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114


73-0068. Luz, T. P., BUSTAMANTE, H. T. DE, SZKL~, M., STROZENBERC, A.
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72-1284. MATAUR, K. C., MISRA, S. N. Incidence of pulmonary diseases
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73-0486. MERCHANT, J. A., LUMSDEN, J. C., KILBURN, K. H., O'FALLON,.
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72-0772. ROBBINS, W. T. Bronchial eplthelium in cigarette-smoking college
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72-1057. SAKAKURA, Y., PROCTOR, D. F. The effect of various conditions on
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115


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73-0316. WALTON, M. Industrial ammonia gassing. British Journal of In-
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72-0663. WYSOCKI, M. Testy spirometryczne T&T i FEV%-wlaseiwosci i
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Part II

(Additional articles which were reviewed but not discussed in the text.)
    AILSBY, R. L., GHADIALLY, F. N. Atypical cilia in human bron-
     chial mucosa. Journal of Pathology 109 (1) : 75-78, January 1973.
73-0047. ALBERT, R. E., LIPPMANN, M., PETERSON, H. T., JR., BERGER, J.,
     SANBORN, K., BOHNING, D. Bronchial deposition and clearance
     of aerosols. Archives of Internal Medicine 131(l) : 115-127,
     January 1973.

72-0647. ASTIN, T. W. Reversibility of airways obstruction in chronic bron-
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73-0157. CARILLI, A. D., KOTZEN, L. M., FISCHER, M. J. The chest roent-
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   DAVIDSON, F. F., GLAZIER, J. B., MURRAY, J. F. The components of
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    and in patients with pneumonia and obstructive lung disease.
     American Journal of Medicine 52: 754-762, 1972.
73-0583. ESBER, H. J., MENNINGER, F. F., JR., BOGDEN, A. E., MASON, M. M.
    Immunological deficiency associated with cigarette smoke inhala-
    tion by mice. Primary and secondary hemagglutinin response.
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73-0128. EVANS, M. J., CABRU, L. J., STEPHENS, R. J., FREEMAN, G. Cell
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    to NO,. American Journal of Pathology 70(2) : 199-208, Feb-
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73-0129. EVANS, M. J., CABRAL, L. J., STEPHENS, R. J., FREEMAN, G. Re-
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       1973.

73-0474. HIRST, R. N., JR., PERRY, H. M., JR., CRUZ, M. G., PIERCE, J. A.
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116


720614. HO, W., BENTON, M., FURST, A. The clearance of benzo(a) pyrene
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73-0810. HOLT, P. G., KZAST, D. Acute effects of cigarette smoke on mUrine
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73-0254. HOLT, P. G., KEAST, D. Cigarette smoke inhalation: Effects on
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73-0411. HOLT, P. G., KEAST, D. The effect of tobacco smoke on protein
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   ICHIOKA, M. Model experiments on absorbability of the airway
     mucous membrane of SOI and NO1 gases. Bulletin of the Tokyo
     Medical and Dental University 19 : 361-375,1972.
72-1046. IRAVANI, J. Flimmeraktivitat im Respirationstrakt nach chronischer
     Zigarettenrauchexposition. (Ciliary activity in the respiratory
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73-0415. JONES, R., BOLDUC, P., REID, L. Goblet cell glycoprotein and tra-
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    methyloxadiazole. British Journal of Experimental Pathology
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73-0476. KANNIZR, R. E., KLAUBER, M. R., SATANABE, S., RENZETTI, A. .D.,
    JR., BIGLEX, A. Pathologic patterns of chronic obstructive pul-
     monary disease in patients with normal and deficient levels of
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73-0346. KOSMIDER, S., FELUS, E., WYSACKI, J. Ocena niektdrych h wyynu-
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     Polski Tygodnik Lekarski 28(2) : 47-50, January 8, 1973.
72-1240. LEWIS, A. J., NICHOLLS, P. J. Effect of inhaled cigarette smoke
     on content, release and breakdown of histamine in guinea-pig
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73-0646. LEWIS, C. I., MCGEADY, J. C., TONG, A. S., SCHULTZ, F. J., SPEARS,
     A. W. Cigarette smoke tracers: Gas chromatographic analysis
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     108(2) : 367-370, August 1973.

72-0590. LEWIS, C. I., MCGEADY, J. C., WAGNER, J. R., SCHULTZ, F. J.,
     SPEARS, A. W. Dichlorbenzophenone as `a nonradioactive tracer
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       tember 1972.

72-0766. MCFADDEN, E. R., JR., LINDEN, D. A. A reduction in maximum mid-
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       June 1972.

MACKLEM, P. J., DESPAS, P. J., LEROUX, M. Site of airway obstruc-
tion in asthma. Chest 63(4, Supplement) : 28S, April 1973.

117


73-0306. MARTIN, R. R. Altered morphology and increased acid hydrolq-
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       1973.

   MITCHELL, C. A., ZUSKIN, E., BOUHUYS, A. The effect of cigarette.
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72-1286. OSCHERWITZ, M., EDLAVITCH, S. A., BAKER, T. It., JARBOE, T. Differ-.
    ences in pulmonary functions in various racial groups. American
    Journal of Epidemiology 96 (6) : 319-327, November 1972.   -'
73-0423. PARKINSON, D. R., STEPHENS, R. J. Morphological surface chan&
    in the terminal bronchiolar region of NO:-exposed rat lung.
     Environmental Research 6( 1) : 37-61, March 1973.
71-1180. RYLANDER, R. Free lung cell studies in cigarette smoke inhalation'
    experiments. Scandinavian Journal of Respiratory Diseases
     62 (2) : 121-1231971.

7866. SIMONSSON, B. G. Clinical and physiological studies on chronic
   bronchitis. I. Clinical description of the patient material. Acta
   Allergologica 20 (4) : 267-300,1966.

73-0313. STEEBINCS, J. H., JR. Two observed associations between respira-
    tory allergies and hypertension in nonsmokers. American Journal
     of Epidemiology 97(l) : 4-16, January 1973.
73-0497. STOLOFF, I. L. Bullous lung disease in short order cooks. Journal
    of Occupational Medicine 16 (3) : 202-203, March 1973.
73-0781. TASAKIN, D. P., LEVY, S. E., THOMPSON, J. II., SIMMONS, D. II.,
    GORDON, B. M. Pulmonary effects of chronic nicotine adminis-
    tration in young and old Fischer-344 rats. Proceedings of the
    Western Pharmacological Society 18 : 209-214, 1973.
73-0610. THOMAS, W., HOLT, P. G,, KEAST, D. Effect of cigarette smoking on
    primary and secondary humoral responses of mice. Nature 243
     (6404) : 240-241, May 26,1973.

THURLBECK, W. M. Small airways disease. Human pathology 4(2) :
160-152, June 1973,

73-0434. VASSALM, C. L., DOMM, B. M., POE, R. H., DUNCOMBE, M. L.,
    GEE, J. B. L. NOz effects on alveolar macrophage phagocytosis
     and metabolism. Archives of Environmental Health 26(6) : 27Q-
     274, May 1973.

73-0662. WARR, G. A., MARTIN, R. R. Response of human pulmonary macro-
    phage to migration inhibition factor. American Review of Res-
    piratory Disease 108 (2) : 371-373, August 1973.

118


INDEX

Abnormalities                Autopsy stud&
in ~~IJCOUS glands, in smokers vs. non-  emphysema development and smoking, 97
smokers, 97              mucous gland abnormalities and smoking,
jn small airways,  in smokers vs. non-    97

smokers, 97.98
Acrolcin

Smdll airway abnormatitics and smoking,
97.98

effect on respiratory tract, in rats, 104
Adipose tissue

effect of nicotine, in rats, 13
AHH activity

see Aryl hydrocarbon hydroxylase activity
Air pollution
and smoking, in COPD development,
82,83
and smoking, in lung cancer development,
45,46
Airways, large
effect of smoking one nonfilter cigarette,
99
Airways, small
abnormalities, in smokers vs. nonsmokers,
autopsy studies, 9798
effect of smoking one nonftlter cigarette,
99

Alcohol consumption
and smoking, in oral cancer etiology,
53-55

Alveolar macrophages
effect of cigarette smoke, 50
Angina pectoris

carbon monoxide exposure and, 11 ,12
coffee drinking, smoking, and, 8
smoking and, 8
Antitrypsin deficiency
and smoking, in COPD etiology, 87-90
Arteriosclerosis obliterans (ASO)
see Vascular disease, peripheral
Arthritis, rheumatoid
pulmonary function abnormalities. smok-
ing, and, 92,93

Aryl hydrocarbon hydroxylase activity
role in lung cancer development, 49-52
Asbestos exposure
synergistic effect with smoking in lung
-cancer development, 41-43 -      -

Asbestosis
in smokers vs. nonsmokers, asbestos work-
ers in Singapore, 95
Atherosclerosis, peripheral
see Vascular disease, peripheral
Atherosclerotic brain infarction (ALU)
see Vascular disease, peripheral

Bcnzo(a)pyrene
and air pollution, in lung cancer develop-
ment, 45,46
role in respiratory tract carcinoginesis, in
animals, 46,47
Bladder cancer
see Cenitourinary cancer
Blood cholesterol
effect of smoking, 17,18
Blood coagulation
effect of smoking, 18,lY
Blood lipids levels
effect of smoking, 17
Blood pressure

effect of CO exposure, 11 ,I 2
effect of nicotine, 13
effect of smoking. 17
          . . -,

Boston Collaborative Drug Surveillance Pro-
gram

role of coffee &inking and smoking in
myocardial infarction, 8
Bronchial eoithelium

. .

changes after nitrogen dioxide exposure,
in animals, 102,103
effect of filtered gas-phase cigarette
smoke, in rabbits, 104,105
Bronchitis
post-operative, incidence in smokers vs.
nonsmokers, 92
prevalence in cement and rubber industry
workers, smokers vs. nonsmokers, 95,96
prevalence in the elderly, smokers vs. non-
smokers, 7879
prevalence in male smokers by smoking
patterns, 79
prevalence in rubber industry workers,
smokers vs. nonsmokers, 96
prevalence in urban vs. rural population in
Mongolia, 80
prevalence in U.S., statistics, 75
prevalence in wool and cotton textile
workers in North Carolina, 93

119


and small airway abnormalities, in smokers
vs. nonsmokers, 97,98           disease, peripheral, Cerebrovascular
                               sease

and smoking, effect on pulmonary func-  relationship of smoking to, 3-19
tion, 80

summary of previous findings on refation-  summary of previous findings, 3,4
                     summary of recent findings, 19
ship to smoking, 75-78           Cardiovascular system

Bronchopulmonary diseases, non-neoplastic
see ufso Bronchitis, Emphysema
air pollution and smoking in etiology of,
82,83
antitrypsin deficiency and smoking in eti-
ology of. 87-90
closing volume abnormalities, in smokers
vs. nonsmokers, 84-87
history of respiratory diseases and smok-
ing in etiology of, 90
incidence in autoworkers, 80
occupational exposure and smoking, 80
prevalence in Boston policemen, smokers
vs. nonsmokers, 82,83
prevalence in the elderly, smokers vs. non-
smokers, 78
prevalence in urban vs. rural population, in
Mongolia, 80
reference listings, 107-l 18
small airways disease, pulmonary function,
and, 84-87
small airways disease, smoking, and, 84-87
summary of recent fmdings, 106, 107
Bullous disease

incidence in men by age, race, and smok-
ing habit, 90-92
Byssinosis
dust exposure and smoking in etiology of,
94-96

Cadmium

in emphysema etiology, in animals, 104
Cancer
see also Specific site, e.g., Lung cancer
summary of recent fmdings on relation-
ship to smoking, 58.59
Carbon monoxide
coronary heart disease and, lo-12
effects on cardiovascular system, 10-l 2
from freeway traffic, effect on myocardial
work capacity and angina, 11
Carboxyhemoglobin levels
coronary heart disease and, lo-12,19
Carcinogenesis
experimental. 46,47
mechanism of action, in lung cancer induc-
tion, in animals, 46,47
Carcinogens
in cigarette smoke condensate, 47
role in tumor induction in animals, 46,47
Cardiovascular diseases
see also Coronary heart disease, Vascular

effect of carbon monoxide exposure, lo-13
effect of nicotine. 13
Catecholamine leveis
effect of nicotine, in rats, 13
Cerebrovascular disease (CVD)
epidemiologic studies, 16,17
incidence in longshoremen, 17
incidence in men, Framingham study, 17
incidence in women, smokers vs. non-
smokers, 16.17
oral contraceptives and smoking in etiok
ogy of, 16,17
Cervical cancer

see Genitourinary cancer
CHD

see Coronary heart disease
Cholesterol levels
effect of smoking, 17
Chronic bronchitis
see Bronchitis

Chronic obstructive pulmonary diseases
see Bronchopulmonary diseases, non-
neoplastic, Bronchitis, Emphysema
Cigar smoking
relationship to lung cancer, 39.40
Cigarettes
filter vs. nonfdter, in reducing lung cancer
risk, 40,4 1

Cigarette consumption
see Smoking
Cigarette smoke
see Smoke, cigarette
Ciliary activity

effect of nitrogen dioxide, in rats, 103
effect of smoking, 101,102
Closing-volume abnormalities
as indicator of small airways disease, in
smokers vs. nonsmokers, 84-87
co
see Carbon monoxide
Coffee drinking
angina pectoris, smoking, and, 8
myocardial infarction, smoking, and, 8
Contraceptives, oral
incidence of stroke and, in women smo-
kers vs. nonsmokers, 16,17
CQPD
see Bronchopulmonary diseases, non-
neoplastic

Coronary Drug Project Research Group
epidemiologic study of smoking and CHD.
46

Coronary heart diseases
see also Angina pectoris, myocardial in-
  farction

120


associated risk factors and smoking, 17
autopsy studies, 4
carbon monoxide and. 1 O-1 2
epidemiologic studies, 4
incidence in men under 60, in New South
Wales, 6
incidence in men with and without ventri-
cular premature beats, 4-6
incidence in middle-aged men from various
countries, 6
incidence in a tribal population, New
Guinea, 9
incidence in smokers vs. nonsmokers,
Peoples Gas Co. Study, 6,7
incidence in smokers vs. nonsmokers,
Stockholm Prospective Study, 6
incidence in women, smokers vs. non-
smokers, 9,lO
nicotine and, 13
pathophysiology of, effect of carbon mon-
oxide exposure, 10
summary of relationship to smoking,
3,4,19

Cotton dust exposure
see. Dust exposure
Cough

workers, smokers vs. nonsmokers, 95.96
CVD
see Cerebrovascular disease, 16
Cytologic studies
effect of air pollution and smoking, 90,Y 1
prevalence in cement and rubber industry

Enzymes

effect of cigarette smoke, in rabbit lungs.
104,105

and macrophage function, in rabbit lungs,
104,105

Epidemiological studies
COPD and smoking, 78-80
lung cancer and smoking, 37
oral cancer and smoking, 53
pancreatic cancer and smoking, 57
Esophageal cancer
summary of previous findings on relation-
ship to smoking, 55
Exercise performance
effect of carbon monoxide exposure,
11,12

and pulmonary function, smokers vs. non-
smokers, 99

Filters

as a factor in reducing lung cancer risk,
40,41

Framingham Study

  14-16
Free fatty acids (plasma)
epidemiologic study of CHD, CVD, inter-



effect of nicotine, in rats, 13
mittent claudication, and smoking,

macrophage function and smoking,
104.105

Gastric cancer

                      mortality rates in Japanese smokers vs.
                        nonsmokers, 56,57
Dust exposure                 tea drinking and smoking in etiology of,
and smoking as risk factors in bronchitis    56,57
development, 93,94            summary of previous findings on relation-
and smoking, as risk factors in byssinosis   ship to smoking, 55
development, 94-96              Genetics
                     role of antitrypsin deficiency and smoking
                       in COPD development, 87-90

and smoking, role in lung cancer develop-
ment, 37

Elderly

prevalence rates for COPD in smokers vs.
nonsmokers, 78
Emphysema
antitrypsin deficiency and smoking in eti-
ology of, 87-90
cadmium exposure in etiology of, in ani-
mals, 104
premature development and smoking,
autopsy studies, 97
prevalence rates in U.S., 75
pulmonary function studies and, 80
summary of previous fmdings on rektion-
ship to smoking, 75-78

Genitourinary cancer
cigarette smoke condensate as cause, in
animals, 58
excretion of tryptophan in smokers vs.
nonsmokers with, 58
incidence in smokers vs. nonsmokers, 58
summary of previous findings on relation-
ship to smoking, 5 7

Heart rate

effect of CO exposure, 11.12
effect of nicotine, 13

121


Heart work capacity
effect of CO exposure, 10-l 2
effect of nicotine, 13
Histological studies
lung cancer and smoking, 38
macrophage function and, 104,105
Hypercholesterolemia
incidence in Belgium military men, 17,18
Hypertension

incidence in male Israeli civil servants, 18

Immune system

response to benzo(a)pyrene-induced lung
tumors, 48,49

Intermittent claudication
smoking as a major risk factor, 14-l 6

Laryngeal cancer

summary of previous findings on relation-
ship to smoking, 57
Lung cancer
asbestos exposure and smoking as risk fac-
tors, 41-43
epidemiologic studies, 37,38
experimental studies, 43-52
genetics and smoking as risk factors, 37
histopathologic studies in smokers vs. non-
smokers, 38,39
immunologic response to benzo(a)pyrene-
induced tumor, in animals, 48,49
incidence in cigar and/or pipe smokers vs.
nonsmokers, 39,40
incidence in smokers vs. nonsmokers, in
India, 37.38
incidence in women smokers vs. non-
smokers, 39,40
mortality rates from lung cancer for men,
43
particle deposition in bronchi and site of,
44,45
Philadelphia Pulmonary Neoplasm Re-
search project histopathologic study, 38
risk reduction with filter vs. nonfilter ciga-
rettes, 40,41
role of aryl hydrocarbon hydroxylase acti-
vity and polyammatic hydrocarbons in
development of, 49-52
role of pulmonary infections and smoking
in etiology of, 47,48
sex ratio statistic, 40
Xenon-133 washout technique for detec-
tion of, 43,44
summary of previous findings on relation-
ship to smoking, 35-37
Lung function

sfe Pulmonary function

Menopause

and cardiovascular disease, in women smo.
kers vs. nomsmokers, 10.19
Mitochondria

effect of tobacco smoke, in rat liver, 104
Mortality
from CHD, age as a factor, 6
from CHD. in middle-aged men in seven
countries, 6
from CHD, in smokers vs. nonsmokers, 3-6
from CHD, in swivors of myocardial in-
farction, smokers vs. nonsmokers, 4-6
Mucociliary transport
effect of smoking, 101,102
Mucous gland
abnormalities, in smokers vs. nonsmokers,
97

Myocardial infarction
coffee drinking, smoking and, 8
incidence in men with and without vent+
cular premature beats, 45
incidence in pre- vs. postmenopausal we
men, 10
prevalence in current vs. ex-smokers, 8
recurrency in smokers vs. nonsmokers, in
Buenos Aires, 9

and smoking in India, 8

Nicotine

coronary heart disease and, 13,lP
effect on adipose tissue, in rats, 13
effect on peritoneal macrophages, in mice,
105

effect on pinocytosis, in mouse peritoneal
macrophages, 105
effect on respiratory tract in rats, 104
Nitrogen dioxide
effect on AHH activity, 52
effect on bactericidal activity, in mouse
lung, 103
effect on lung physiology, in monkeys,
  103
effect on pulmonary physiology, in ani-
mals, 102-103
Nitrosamines
role in respiratory tract carcinogenesis, in
animals, 47

Occupational diseases
asbestosis, in asbestos workers, in Smga-
pore, 95
bronchitis, in cement and rubber industry
workers, 95,96
bronchitis and respiratory tract irritation,
in rubber industry workers, 96
bronchitis, in wool and cotton textile
workers, 93,94

122


byssinosis,  in cotton and wool textile
workers, 93,94
COPD, in auto workers, 80
smoking and, 93-96
Occupational hazards
air pollution exposure in Boston police-
men, 82,83
asbestos exposure and smoking as factors
in lung cancer development, 4143
rubber industry fumes and smoking, 96
textile dust exposure and smoking, 93-96
Oral cancer
alcohol consumption and smoking in etiol-
ogy of, 53-55
epidemiologic studies, 53-55
summary of previous findings on relation-
ship to smoking, 5 2.5 3

Pancreatic cancer
incidence in cigar/pipe and cigarette smo-
kers vs. nonsmokers, 55,56
relative risk in men by number of cigar-
ettes smoked, 55
summary of previous findings on relation-
ship to smoking, 55
Particulate matter
and lung cancer development, 44,45
Peoples Gas Company Study
epidemiologic study of smoking and CHD,
697

Peritoneal macrophages
effect of nicotine, in mice, 105
Peripheral vascular disease
see Vascular disease, peripheral
Philadelphia Pulmonary Neoplasm Research
Project
lung cancer histopathologic studies and,
  38
Pinocytosis
effect of nicotine, in mouse peritoneal ma-
crophages, 105
Pipe smoking
relationship to lung cancer, 39,40
Polyaromatic hydrocarbons
role in lung cancer development, 49-52
Postoperative complications
incidence in bronchitic and nonbronchitic
smokers vs. nonsmokers, 92
Pulmonary bactericidal activity
effect of nitrogen dioxide, in mouse lungs,
  103

Pulmonary clearance
effect of nitrogen dioxide, in rats, 103
effect of smoking, 101,102
in smokers, ex-smokers, and nonsmokers
with and without pulmonary disease,
100,101

Pulmonary function
abnormalities, and rheumatoid arthritis in

smokers vs. nonsmokers, 92.93
of Boston policemen, smokers vs. non-
smokers, 82,83
before and after smoking one non-filter
cigarette, 99
effect of cigarette smoke, in monkeys, 102
effect of dust exposure and smoking, 95
effect of exercise performance and smok-
ing, 99

effect of isoproterenol in smokers, non-
smokers and bronchitics, 99,100
effect of nitrogen dioxide, in animals,
102,103

effects of smoking, in healthy populations,
80.81
effects of smoking, in patients with COPD,
  80
of insurance company employees, smokers
vs. nonsmokers, 80.8 1
of male executives, smokers vs. non-
smokers, 81
of male and female smokers, in New
Guinea, 81,82
of pipe and cigarette smokers, exsmokers,
and nonsmokers, 99
small airways disease, smoking, and, 84-87
of smokers vs. nonsmokers, 80-82
Pulmonary infections
and smoking, role in lung cancer develop:
ment, 47,48

Pulmonary macrophagcs
effect of cigarette smoke, in rabbits,
104,105

effect of cigarette smoke extract, in sheep
lungs, 105

Pulmonary physiology
new animal model for testing of, 102

Renal cancer

see Genitourinary cancer
Respiratory symptoms
see also Cough

Respiratory symptoms
effect of air pollution and smoking, PO,91
prevalence in cement and rubber industry
workers, smokers vs. nonsmokers, 95,96
Respiratory tract
carcinogenesis induction in animals, 46,47
irritation, prevalence in rubber industry
workers, smokers vs. nonsmokers, 96

Seven Countries Study
epidemiologic study of smoking and CHD,
  6
Sex ratio
in mortality rates from lung cancer, 40,46

123


Small airways disease
see Airways, small
Smoke, cigarette
effect on lung AHH-activity, 50,5 1
effect on pulmonary macrophage func-
tion, in rabbits, 104

effect on pulmonary physiology, in ani-
mals, 102

effect on respiratory tract, in rats, 104
extract, effect on pulmonary macro-
phages, in sheep lungs, 105
Smoke condensate, cigarette
as cause of bladder turn ors, in rats, 5 8
role in respiratory tract carcinogenesis, in
animals, 47
Smoke, tobacco
effect on mitochondrial function, in rat
liver. 104

Smoking

and air pollution, effect on pulmonary
function and COPD prevalence. 82.83
and asbestos exposure, as factors in lung
cancer development, 41-43
association with other risk factors in CHD.
6,7,17
bronchitis prevalence rates and, 79
and CHD, age as a factor, 6
and CHD, in women, 9,lO
and coffee drinking, in myocardial infarc-
tion etiology, 8

effect on platelet function, 18,19
as the major risk factor in intermittent
claudication, 14-16
as a major risk factor in peripheral vascular
disease, 14-16
trends for U.S. men, for years 1955, 1966,
and 1970,40
vasoconstrictive effects in normal subjects,
16

Smoking characteristics
bronchitis prevalence rates in men and, 79
COPD prevalence rates in Yugoslavia and,
79

Stockholm Prospective Study
epidemiologic study of smoking and CHD,
  6

Stomach cancer
see Gastric cancer
Stroke

see Cerebrovascular disease
Sudden death

incidence in men with and without ventri-
cular premature beats, 5
incidence in women, smokers vs. non-
smokers, 9,19

smoking as a risk factor, 4-6.19

Surgery

complications following, in smokers vs.
nonsmokers, 92

Tecumseh Study
lung function differences in smokers and
nonsmokers, 8 1
Thromboangiitis obliterans (TAO)
see Vascular diseases, peripheral
Thrombosis

smoking and, 18.19
Traffic

effect on air pollution in Boston, 82,83

Urinary bladder cancer
see Genitourinary cancer
Uterine cancer
see Cenitourinary cancer

Vascular disease, peripheral
see also Intermittent claudication
epidemiologic studies, 14-l 6
experimental studies, 16
smoking in etiology of, 14-16

Women

CHD incidence in, 9,lO
lung cancer incidence in. 39,40
mortality rates, in smokers vs. non-
smokers, 9,lO
mortality rates from lung cancer and
asbestos exposure, 42,43
mortality rates from lung cancer, statisti-
cal sex ratio, 40,45
myocardial infarction in pre- vs. post-
menopausal, 10
secular trends of lung cancer development
in, 40
sudden death rates in, 9,lO
trends in cancer incidence rates for selec-
ted sites in, 41.42

Xenon-l 33

washout technique for detection of lung
cancer, 43,44

r?r U.S. GOVERNMENT PRINTING OFFICE: 1975 0-650-614

124