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

           Public Health Service
    Health Services and Mental Health Administration


Th e

Health Consequences
of Smoking

January 1973

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


  For sale by the Sqwintendent of Documents
U.S. Government. Printing Office, Washington. D.C. 20102
Priw $1.85 domestic postpaid or $1.60 GPO Rookstow
        Stock Number 17'2&00064


Preface

This report is the seventh in a series issued by the Public Health
Service reviewing and assessing the scientific evidence linking ciga-
rette smoking to disease and premature deat.11. The current report
reiterates, strengthens, and extends the findings in earlier reports
that cigarette smoking is a major health problem in the United
States.

The evidence has broadened dramatically in recent years. A Public
Hea1t.h Service assessment of evidence available in 1050 was largely
focused on the relationship of cigarette smoking and lung cancer.
The first formal report on this subject in 1964 found that cigarette
smoking was not, only a major cause of lung cancer and chronic
bronchitis, but was associat.ed with illness and death from chronic
hronchopulmonary disease, cardiovascular disease, and other diseases.
The 1973 report confirms all these relationships and adds new
evidence in other areas as well. The evidence in the chapter on preg-
nancy strongly indicates a causal relationship between cigarette
smoking during pregnancy and lower infant, birth weight. and a strong,
probably causal, association between cigarette smoking and higher late
fetal and neonatal mortality. Also reported is the convergence of other
evidence which suggests that, cigarette smoking during pregnancy
interacts with other risk factors to increase the risk of an unfavorable
outcome of pregnancy for certain women more than others.
For the first time in this series of reports, a separate chapter is
(lcroted to pipe and cigar smoking and the health hazards involved.
lt~clnded is an assessment of the health implications of the new small
+ars which look like cigarettes.

41 final chapter, new to the reports. concerns cigarette smoking and
"starcise performance. A review of a number of fitness tests comparing
>tliokers to nonsmokers indicates that cigarette smoking imp,airs exer-
"in performance for many types of athletic events and activit.ies in-
l'Olving maximal work rapacity.
The interrelationships of smoking and health are no less complex
tc)cl:iy than they were reported to be in the 1964 report. But, since
(ll:lt;irne we have greatlv broadened our knowledge and understanding
`If +he problem. The curient report svmbolizes this progress.

. . .
111


Table of Contents

PREFACE___-_~-_______-___-~~~---~-~~_-~--~_~__---~__

TABLE OF CONTENTS.. _ - - _ _ _ _ - _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ -

PREPARATION OF THE REPORT AND ACKNOWL-

EDGMENTS______-_-___-__-__--______--____________

Chapter 1. Cardiovascular Diseases- _ _ _ _ - _ - _ _ _ _ _ _ _ - _ _ __ _ _ _

Chapter 2. Nonneoplastic Bronchopulmonary Diseases- _ _ _ _ _ _
Chapters. Cancer--------..-- ____-______ - -______________
Chapterk Pregnancy----___________________________----
Chapter 5. Peptic Ulcer Disease-------- ____ --_- ____ ----_-
Chapter 6. Pipe and Cigar Smoking--_----_-_--_-----_----
Chapter 7. Exercise Performance-----_-------------- _____ -
l~DEX_______-__--------------------------------------

Page
. . .
111

V

vii

. . .
xln


33


65


99


153


167


239


251


Preparation of the Repot-t
and Acknowledgments

"Smoking and Health. Report of the Advisory Committee to the
Surgeon General of the Public Health Service," subsequently referred
to as the "Surgeon General's Report,`? was published in 1964. The
National Clearinghouse for Smoking and Health, established in 1965,
has the responsibility for the continuous monitoring, 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, the
following three reviews of the medical literature on the health conse-
quences of smoking, which had come to the attention of the Clearing-
house since the original "Surgeon General's Report," were sent to
the Congress :

1. "The Health Consequences of Smoking, ,4 Public Health Service
Review : 1967" (submitted July 1967).

2. "The Health Consequences of Smoking, 1968 Supplement to the
1967 PHS Review" (submit,ted 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 t,his period, a comprehensive review of all of the medi'-
~1 literature available to the Clearinghouse relating 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 Smoking, ,4 Report of the Surgeon
General: 1971," submitted to the Congress in January of 1971. Sub-
wqnently, a review of the medical literature in the field, which had
r"ll~e to the attention of the Clearinghouse since the publication of the
1~1 report, was published as? "The Health Consequences of Smoking,
-1 Report of the Surgeon General: 1972," submitted in January of
I!,??.

vii


Every report published since the original "Surgeon General's Re-
port" has contained a review of the medical literature relevant to the
association between smoking and cardiovascular disease, nonneoplastic
bronchopulmonary disease, and cancer. Several of the reports in-
cluded reviews of the relationship between smoking and peptic ulcer
disease (1967,1971,1972) and cigarette smoking and pregnancy (1967,
1969, 1971, 1972). Other topics relating to the use of tobacco have
received special emphasis in single reports :

1. Tobacco Amblyopia (1971 Report).

2. Allergy (1972 Report).

3. Public Exposure to Air Pollution From Tobacco Smoke (1972
Report).

4. Harmful Constituents of Cigarette Smoke (1972 Report).

5. Noncancerous Oral Disease (1969 Report).

The present document, "The Health Consequences of Smoking:
1973," includes reviews of the relationships between smoking and
cardiovascular disease, broachopulmonary disease, cancer, and peptic
ulcer disease which are based upon medical liter&ture which has
become available to the Clearinghouse since the publication of the
1972 report. It also includes special reviews of the health consequences
of pipe and cigar smoking and of the relationship between cigarette
smoking and the outcomes of pregnancy. The material in these two
latter chaptersreflects a comprehensive review of the pertinent world
medical literature which has come to the attention of the Clearing-
house since the publication of the original "Surgeon General's Re-
port," including material which has be&me available since the 1972
report. The final chapter in t.his year's report is a review of the rela-
tionship between. smoking and exercise performance, an area not
covered previously in any report.
With the exception of "Chapter 4, Pregnancy," each chapter is orga-
nized in a: similar fashion. The introduction to each chapter is a sum-
mary of t.he work reviewed in previous reports. The summary of each
chapter encompasses only the work which has most recently become
available to the Clearinghouse. The pregnancy chapter is organized
into separate sections according to several different dutcomes of preg-
nancy. Each section includes a brief review of previously reported
work and contains its own separate summary, in place of an.overaIl
summary for the entire chapter.

Viii


The preparation of this report was accomplished in the following
fashion :

1. The continuous monitoring and compilation of the medical liter-
ature on the health consequences of smoking was accomplished
through several mechanisms.
(a) An inform&on science corporation is on contract to extract
  articles on smoking and health from the medical literature
  of the world. This organization provides a semimonthly ac-
  cessions list with abstracts and copies of the various articles.
   Translations are called for as needed. Articles are classified
  according to subject and filed by a series of code words and
   phrases.

(6) The Kational Library of Medicine, through the Medlars
system, sends the National Clearinghouse for Smoking and
Health a monthly listing of articles in the smoking and
health area. These are reviewed, and articles not identified
by the information science corporation are ordered.
(c) Staff members review current medical literature and identify
pertinent articles.

2. The first drafts of the individual chapters were sent to reviewers
for criticism and comment with respect to the articles reviewed,
articles not included, and conclusions. The drafts were then re-
vised until they met wit.h the general approval of the reviewers.
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, the Surgeon General, and by
additional experts both within and outside of the Public Health
c ervice.
$

Acknowledgments

`l%e Sational Clearinghouse for Smoking and Healt.h, Daniel Horn.
1%. I)., Director, was respousible for the preparation of this report.
~~rllica'l Staff D' lrector .for the report was Elvin E. Adams, M.D.,
~~ssist:mt AIedical Staff Director was H. Stephen Williams, 3s.D. con-
Sillting editors were Daniel P. Asnes. M.D., David G. Cook. M.D., and
*`Otlll EI. Holbrook, M.D.

`I%? professional staff has had the assistance and aclvice of a number
`If (`~prrts ill the scientific aucl technical fields, both in ant1 outside the

ix


Government. Their contributions are gratefully acknowledged. Special
thanks are due the following :

ANDERSON, WILLIAM H., M.D.-Chief, Pulmonary Section, School of Medicine,
University of Louisville, Louisville, Ky.
AUERBACH, OSCAR, M.D.-Senior Medical Investigator, Veteraus Administration
Hospital, East Orange, N.J.

AYRES, STEPHEN M., M.D.-Director,  Cardiopulmonary LaboratorS, Saint
Vincent's Hospital and Medical Center of New York, New York, N.Y.
BOCK, FRED G., Ph. D.-Director, Orchard Park Laboratories, Roswell Park
Memorial Institute, Orchard Park, N.Y.
BOREN, HOLLIS G., M.D.-Medical Investigator, Veterans Administration Hos-
pital, Tampa, Fla.

BOUTWELL, ROSWELL K., M.D.-Professor of Oncology, McArdle Laboratory for
Cancer Research, University of Wisconsin, Madison, Wis.
BROSS, IBWIN, M.D.-Director of Biostatistics, Roswell Park Memorial Institute,
Buffalo, S.Y.

COOPER, TIIEODOBE, M.D.-Director, National Heart and Lung Institute, National
Institutes of Health, Bethesda, Md.

EPSTEIN, FREDERICK H., M.D.-Director and Professor of Epidemiology, School
of Public Health, University of Michigan, Ann Arbor, Mich.
FALK, HANS L., Ph. D.-Associate Director for Program, National Institute of
Environmental Health Sciences, Research Triangle Park, N.C.
FERRIS, BENJAMIN G., Jr., M.D.-Professor of Environmental Health and Safety,
School of Public Health, Harvard University, Boston, Mass.
FRAZIER, TODD M.-Assistant Director, Harvard Center for Community Health
anif Medical Care, School of Public Health, Harvard University, Boston, Mass.
E'RESTON, JAXES, M.D.-Associate Professor of Medicine, Head, Division of
Gastroenterology. University of Utah Medical School, Salt Lake City, Utah.
GOLDSLUTH, JOHN R., M.D.-Head, &vironmental Epidemiology- Unit, Bureau of
Occupational Health and Environmental Epidemiology, California State De-
partment of Public Health, Berkeley, Calif.
GORI, GIO BATTA, M.D.-Associate Scientific Dix%ctor for Program, Division of
Cancer Cause and Prevention, National Cancer Institute, Bethesda, Md.
HIGOINS. 1.4~ T. T., M.D.-Professor of Epidemiology, School of Public Health,
University of Michigan, Ann Arbor, Mich..
HOFFMAN?, DIETBICH, Ph. D.-Chief, Division of Environmental Carcinogenesis.
American Health Foundation, New York, N.Y.
KELLEK, ANDREW Z., D.Y.D.-Chief, Research in Geographic Epidemiology, Vet-
erans Administration Central Office, Washington, D.C.
KIRSSER, JOSEPH B., M.D., Ph. D.-Chief of Staff and Deputy Dean for Medical
Affairs, The Pritzker School of Medicine, University of Chicago Hospitals and
Clinics, Chicago, Ill.

KOLBYE, ALBERT C., Jr., M.D. J.D.-Deputy Director, Bureau of Foods, Food and
Drug Administration. U.S. Department of Health, Education, and Welfare,
Washington, D.C.

KR~UAOIZ, RIUIARD A., M.D.-Medical Director, Institute of Respiratory Dis-
eases, Ketteriug aledical (`enter, Kettering, Ohio.
LILIEKFELD, ABR~HA~~, M.D.-Professor and Chairman, Department 0P Epidem-
iology, School of Hygiene and Public Health, The Johns Hopkins University,
Baltimore, Md.

M\Ic.~.E.\s, Ross, JI.D.iProfessor of Medicine, Bowman Gras School of Medicine,
Wake Forest University, Winston-Salem, N.C.

x


~loMmr.~K, GABDNEX C., M.D.-Chief, Arteriosclerotic Disease Branch, National
Heart and Lung Institute, Sational Institutes of Health, Bethesda, Md.
,\IACMAHON, BRIAN, M.D.-Professor of Epidemiology, School of Public Health,
Harvard University, Boston, Mass.
NEPEB, MABY B., M.S.-Assistant Professor of Epidemiology, The Johns Hopkins
University, Baltimore, Md.
JIITCHELL, R~~EB S., M.D.-Chief of Staff, Veterans Administration Hospital,
Denver, Colo.
MIUBPHY, EDMOND A., M.D., SC. D.-Associate Professor of Medicine and Bio-
statistics, The Johns Hopkins Hospital, Baltimore, Md.
SETTESHEIM, PAUL, M.D.-Group Leader, Respiratory Carcinogenesis, Biology
Division, Oak Ridge Sational Laboratory, Oak Ridge, Term.
PAFFENBABOER, RALPH S., Jr., M.D.-Chief Epidemiology Section. Bureau Of
Adult Health and Chronic Diseases, California State Department of Public
Health, Berkeley. Calif.

P~EBSON, WILLL~X F., M.D.--Chairman, Department of Obstetrics and Gyne-
cology, Washington Hospital Center, Washington, D.C.
F'ETTY, THOMAS I,., M.D.-Associate Professor of Medicine and Head, Division of
Pulmonary Diseases, University of Colorado Medical Center, Denver, Cola.
RALL, DAVID P.. M.D.-Director, Sational Institute of Environmental Health
Sciences, Research Triangle Park, N.C.
RAUBCHEIL, FRANK J., M.D.-Director, National Cancer Institute, Sational Insti-
tutes of Health, Bethesda, Md.

REINKK, WILLIAM A. Ph. D.-Professor, Department of International Health, The
Johns Hopkins University. Baltimore, Md.
REXZEXTI, ATTILIO D., Jr., M.D.-Professor of Medicine, Pulmonary Disease
Division, University of Utah Medical Center. Salt Lake City, Utah.
ROBINS, MoBToN-Chief of Study, Design, and Analysis Staff, Regional Medical
Programs Service, Health Services and Mental Health Administration, Rock-
ville, Md.
SWFI~TTI, UMBEBTO. M.D.-Associate Scientific Director for Carcinogenesis,
Division of Cancer Cause and Prevention, National Cancer Institute, National
Institutes of Health, Bethesda, Md.
SOtruMAN, LEONARD M., M.D.-Professor and Head, Division of Epidemiology,
School of Public Health, University of Minnesota, Minneapolis, Minn.
StttSIKIN, MICHAEL B., M.D.-Professor of Community Medicine and Oncology
and Coordinator, Regional Medical Program, University of California at San
Blego, La Jolla, Calif.
sTp-\~~LER, JEREMIAH, M.D.-Professor and Chairman, Department of Community
Health and Preventive Medicine, Northwestern University, Chicago, Ill.
\`AS DUIJREN, BENJAMIN L., M.D.-Professor of Environmental Medicine, Insti-
tute of Environmental Medicine, New York University Medical Center, New
York, N.Y.
n'rKoKa, EBXEST L., M.D.-President, American Health Foundation, New York,
S.P.

The following additional staff members of the National Clearinghouse for
stlloking and Health contributed to the preparation of this report: Richard H.
-i*bacher, Marjorie L. Brigham, Emil Corwin. Lillian Davis, Gertrude P. Herrin,
k'Il)frt S. Hutchings, Jennie 31. Jennings, Sancy S. Johnston, Dan Semzer,
`*il(lrcd Ritchie, James A. Robertson, Donald R. Shopland, and Kathleen H.
smith.

xi


CHAPTER 1

Cardiovascular Diseases


Contents

Page

Introduction_---__-_--------------~---------------------
Coronary Heart Disease
Epidemiological Studies

3

Smoking and Certain Risk Factors- _ _ _ _ _ _ _ _ _ _ _ __ _ _
BloodLipids_-__-____--_--___________-_______---
Electrocardiogram_----.- ____ ---__--_ _-__ - -___---
Experimental Studies

4
11
12

   CigaretteSmoke---------- _____ -__- ___________-_    13
    Nicotine-.. _______ -_-- _____ ---_---- _-_- ---- __--__    15
    CarbonMonoxide_--_---___---------------------    17
   Smoking and Thrombosis-- _ _ _ - _ - - _ _ _ _ _ _ _ _ _ _ _ _ _ _ - -    19
Cerebrovascular Disease------- ______ --_----__-__----- ____    19
PeripheralVascular Disease-..-- ______ ---_---_--_-__--- ____    19
Summary of Recent Cardiovascular Findings------....-------    23
References ______ -----_-__-_- ______ -_-_- _____ --_-----___    24

List of Figures

Figure I.-Age-adjusted incidence rates of CHD by body
weight and cigarette smoking (white males) ____ __ _ _ __ _ _- - -
Figure 2.-Age-adjusted incidence rates of CHD comparing
farmers who smoke cigarettes with nonsmoking farmers- - - -
Figure 3.Atandardized mortality ratios for arteriosclerotic
heart disease for males and females by age at initiation of
rigarette smoking (Prospective study 1966-1970) - - - - - - - - -
l%ure 4.-The effect of cigarette smoke inhalation on the ven-
tricular fibrillation threshold (VFT) of normal dogs and dogs
\rith experimentally produced acute myocardial infarction
`~?lII)-..-__________---____-_-_--__----_--F_----_------
l$ure 5.-Eff ec s
           t of smoking five consecutive cigarettes on
Pkrla nicotine concentration-------_-- -_-_---------- ---
piFXre 6.-Relative risk of developing arteriosclerosis oblit-
(`rans (ASO) for males by amount of cigarettes smoked- - -
l'%Wre 7.-Relative risk of developing arteriosclerosis oblit-
prws (ASO) for females by amount of cigarettes smoked---

6

7

8

14


16

20


21




1


Introduction

In the United States, coronary heart disease (CHD) is the leading
cause of death and is the largest contributor to excess deaths among
cigarette smokers. The following is a brief summary of the major
relationship between smoking and cardiovascular diseases as outlined
in previous reports of the health consequences of smoking (62, 63,
l;& 65,66,67).
Many prospective and retrospective epidemiological studies have
identified cigarette smoking, elevated serum cholesterol, and high
blood pressure as major risk factors for t,he development of coronary
heart disease. Cigarette smoking acts independently of and synergis-
tically with the other CHD risk factors to greatly increase the risk of
developing coronary heart disease, The risk of developing CHD for
pipe and cigar smokers is much less than it is for cigarette smokers,
but more than it is for nonsmokers. In the United States, cigarette
smoking can be considered the major cause of car pulmonale since it is
the most important cause of chronic nonneoplast.ic bronchopulmonary
disease.

dutopsy studies have demonstrated that aortic and coronary athero-
sclerosis are more common and severe, and myocardial arteriole wall
thickness is greate.r, in cigarette smokers t,han in nonsmokers.
Those who stop smoking cigarettes experience a decrea.sed risk of
d&h from coronary heart disease compared to that of continuing
smokers.

Experimental studies in humans and animals suggest that cigarette
sllloking may contribute to the development of CHD through the
:l(`tion of several independent ok complementary mechanisms : The
folmation of significant levels of carboxyhemoglobin, the release of
"@cholamines, inadequate myocardial oxygenation which may result
from a number of mechanisms, and an increase in platelet adhesiveness
\vllich may contribute to acute thrombus formation. There is evidence
th;lt cigarette smoking may accelerate the pathophysiological changes
"f I'reexisting coronary heart, disease and therefore contributes to
*II&n death from CHD.
liecently published epidemiological, autopsy, and experimental in-
"`%ations have added to the understanding of the association be-
t'\-& smoking and cardiovascular diseases.
   495-028 O-73-2

3


Coronary Heart Disease

Epidemio2ogicaZ Studies

SXOKING AND CERTAIN RISK FACTORS

A prospective epidemiological study of the factors associated with
cardiovascular diseases was conclucted among the 4,847 white and 2,434
black men and women of Evans County, Ga. ($8). The investigation
was initiated with a private census and preliminary examinations
beginning in 1960. Followup examinations were conducted after 7
years. Cassel (23) reported that high blood pressure, elevated serum
cholesterol, and cigarette smoking were major risk factors for the
development of coronary heart disease. Increased body weight, an
elevated hematocrit, and ECG abnormalities were additional fact,ors
that were associated with elevated CHD rates. A significant finding of
this study was the very low prevalence and incidence of coronary heart
disease (myocardial infarction and angina pectoris) in black men. The
age-adjusted prevalence rates among black men were only half those of
white men. The study showed that blacks were affected by the various
risk factors for CHD in a similar fashion to whites but at a lower level
of disease. This appeared to be true for any level of any risk factor or
any combination of risk factors. Greater physical activity of blacks as
compared to whites appeared to account for part of the observed dif-
ference in rates.

In this study, subjects were classified on the basis of their smoking
history at enrollment and both current smokers and exsmokers were
considered smokers. Both black and white male smokers had a higher


incidence of CHD than did nonsmokers, but white males had a higher
incidence than blacks whether they were smokers or not. The age-
adjusted incidence rate for white nonsmokers was 52.7 per thousand
compared to 9.8 per thousand for black nonsmokers. White smokers
had an incidence of 101, whereas the rate in black smokers was only
3G. The prevalence of CHD increased with the number of cigarettes
smoked per day in both groups.

The combined effect of body weight and cigarette smoking on t.he
incidence of CHD was also examined (~3;). The "Quetelet index" 1
\yas used to determine relative weight. The risk of developing CHD
did not change with increases in relative we.ight among nonsmokers,
but smokers experienced a substantial risk of developing CHD with
increases in weight (fig. 1).
The relabionship of smoking to occupat,ion and CHD was examined
I 1-i). Farmers who performed sustained physical activity had lower
Mes of CHD than nonfarmers. Figure 2 shows that, while smoking
inc*reased the risk of CHD in bot.h farmers and nonfarmers, farmers
ha.d lower rates than nonfarmers whether or not they smoked.

          weight
' W?telet index= -
     height ,x1oo'


Figure 1 .-Age-adjusted incidence rates of CHD by ' body weight and 1 cigarette
     smoking (white males).

160 ,                                                  1

Nonsmoker

140

' Smoker

    120 -

    110 -

    100 -

     90 -

' Rate  80  -
m'ales lP&  70  -


     60.

     50-

     40.

     30 -

     20 -

     10 -

      0
' Distribution
by weight

80

Lower third
(lean)

Number            90    183     99    161     127    119

Cases              5    15     3    14     16     9


1 Smokers excluding ex-smokers.
`67 months follow-up period.
I Based on Quetelet index.

SOURCE: Heyden, S., et al. (26).

6


Figure 2.-Age-adjusted incidence rates of CHD comparing farmers who smoke
    cigarettes with nonsmoking farmers.

Farmers

   100
Rate
per
1,000
males
   50

0

Cases . . . . (8)   (9)
        Nonsmokers

Nonfarmers El
  158.2

(11) (39)
Smokers and
Ex-smokers

SOURCE Cassei. J. C., et al. (18.

Hirayama (27) reported 5-year followup data on smoking in &a-
tion to death rates from a large prospective epidemiological study of
%,118 men and women in Japan. This investigation was the first of
its kind to be conducted in an Asian population. During the followup
Period, 11,858 deaths occurred during 1,269,382 person years of obser-
Wion. Male and female cigarette smokers experienced higher mor-
tnlitv rates from arteriosclerotic heart disease than did nonsmokers.
.\nlong cigarette smokers, the mortality ratios for arteriosclerotic heart
~hise were 1.56 (P<O.oOl) for men and 1.44 (P<O.O5) for women.
I)~s+response relationships were found for both men and women as
tlh\`asured by the number of cigarettes smoked per day and age at initia-
t ion of smoking (fig. 3).


figure 3.-Standardized mortality ratios for arteriosclerotic heart disease for
     males and females by age at initiation of cigarette smoking (Prospec-
      tive study 1966-1970).

     1.50

Mortality
ratio

     1.00

0.50

     0.00
       Age at start   Non-
       of smoking smoker


SOURCE Hirayama, 1. (27).

34      20-24    <20

Gordon, et al. (%`Z! 57)) in a further analysis of the Framingham
data, considered both by univariate and multivariate analysis the rela-
tion of certain key characteristics to the development of coronary heart
disease. The characteristics were : High blood pressure, elevated serum
cholesterol, cigaret,te smoking, left ventricular hypertrophy diagnosed
by electrocardiogram, and glucose int.olerance. Cigarette smoking
emerged as one of the important risk factors for the development of
coronary heart disease. There was a strong association between ciga-
rette smoking and CHD other t,han angina pectoris, particularly
among young male and female smokers. The relative role of cigarette
smoking as a risk factor was emphasized by multivariate analysis.
Cigarette smoking was not. as strongly related to CHD in women as it
was in men. This ma\- have been in part due TV the fact that there are
fewer heavy smokers among women? and women tend to inhale smoke
less than men.

Kapan. et al. (31) reported preliminary findings from the Honolulu
Heart Study. The effect of migration on dietary pat.terns and the inci-
dence of cardiovascular diseases in a cohort of men of Japanese ances-
try born between 1900 and 1919, who were residents of Oahu in 1965,
was examined in this prospective study. During the 2 years of fol-
lowup, 101 men developed CHD in t.he population of 8,006 men ini-


tially examined. A significant relat,ionship to CHD was found for the
following risk factors: Cigarette smoking, elevated systolic and dia-
stolic blood pressure, increased serum cholesterol, triglycerides or uric
acid, and various measures of obesity.

using data from the International Cooperative Study on Cmdio-
vascular Epidemiology, Keys, et al. (34) calculate the probabilities
for men aged 40 to 59 to develop coronary heart disease in 5 years.
The authors noted "* * * that the relative CHD risk of different
men within a given population is well predicted from the results of
the multivariate analysis of the experience of men in other far-distant
populations differing in socioeconomic circumstances, language, and
ethnic background." Although the CHD incidence rate of European
men was about half that of the Americans, the fact still remained
that investigation of the four variables (cigarette smoking, age,
systolic blood pressure, and cholesterol) was sufficient to identify
men whose likelihood of dying of CHD or having a definite myo-
cardial infarction within 5 years was greatly above the average.
Punsar (61) reported IO-year follo:vup data on the cohort of men
in Finland who were part of t,he seven-country study of coronary heart
&sea+ confirming that c.igarette smoking was a major risk factor for
CHD. The authors reported a 1.`7-fold increase in CHD mortality
among cigarette smokers. They estimated that 1,700 excess CHD
deaths occur each year among cigarette smoking men in Finland.
Kozarevic, et al. (38) reported the results of the initial prevalence
survey and the e-year incidence data from the Yugoslavian study
of cardiovascular disease. A total of 11,121 men between the
Wes of 35 and 62 were examined in the towns of Tuzla and Remetinec.
(`iiteria for the diagnosis of CHD were based on objective electro-
"ardiographic findings of myocardial infarction, left bundle branch
IJock, or sudden death. A very low prevalence of myocardial infarc-
tion was initially found, and only 36 new cases of CHD developed
`)~r t.lle 2-year period. The subjects who developed CHD smoked
I`iLmrMes at about the same level as the total study population. The
~`llrl~ml average incidence rate of acute coronary heart disease was
:Iimut 1.6 per 1,000 among both the smokers and nonsmokers. The CHD
irli+&e rates found in this Yugoslavian study are appreciably below
"lo found in the United States.
(`olnstock (16) examined the association between water hardness,
V"ri~lls other environmental factors including cigarette smoking, and
"bill from CHD. A total of 189 deaths from CHD occurred in the
I"Wlntion of Washington County, Md.. in the 3-year period follow-
"`ca C(`INIS in 1963 For each case, two c*ontrols were randomly selected
fr'c'ltl the census list's and matched for race, sex, and year of birt,h. The
r""ltiv~ risk of CHD for all smokers was 1.5 compared to nonsmokers
' 1'<(~.1,5). Th' ' 1s relative risk among cigarette smokers WRS dose-

9


related ; persons smoking more than two packs a day had the highest
risk of CHD. No significant association was found between CHD and
water hardness.

Casciu, et al. (I$?), reported the prevalence of cardiovascular disease
among 4,668 miners on Sardinia. Smoking and drinking habits, blood
pressure, and heart rates were recorded. Smokers had higher rates
of CHD than nonsmokers, and a dose-response was noted with the
number of c.igarettes smoked per day. The prevalence of myocardial in-
farction was 0.9 percent for nonsmokers, 1.62 percent for smokers
of 10 or less cigarettes, 2.34 percent for smokers of 11 to 20 cigarettes,
9.9 percent for smokers of 20 or more cigarettes a day, and 1.42 percent
for cigar or pipe smokers. When cigarette smokers were grouped by
alcohol consumption, no significant difference was found in the prev-
alence of myocardial infarction between drinkers and nondrinkers

Kornitzer, et al. (36, 36, 37) examined the prevalence of CHD in
566 male bank employees aged 40 to 59 in Brussels. They determined
an individual's smoking history, blood lipids, ECG, peak flow rates,
relative weight, skinfold thickness, and blood pressure. The preva-
lence of possible CHD as determined by ECG and CHD history was
7.1 percent in nonsmokers, 11.6 percent in cigarette smokers who in-
haled, 6.9 percent in cigarette smokers who did not inhale, 10.6 percent
in smokers of pipes and cigars, and 15.5 percent in the ex-smokers.
Among the various risk factors examined, the strongest association
was found for elevations in the serum cholesterol and the other blood
lipids examined. Weaker associations were found for increased rela-
tive weight, high blood pressure, and tobacco use.

Agnese, et al. (2) examined 265 patients in Italy aged 20 to 65 years
who had myocardial ischemia. Patients were matched with an eq,ual
number of controls by age. A number of risk factors for CHD were
measured in both groups. Cigarette smoking and elevated serum
cholesterol were identified as major risk factors for CHD, particularly
for individuals under the age of 50.

Boudik (20) found the prevalence of myocardial infarction to be
significantly (P<O.OOl) higher in cigarette smokers than in non-
smokers in a population of 8.292 Czechoslovakian men between the ages
of 52 and 67.

Starch, et al. (GO). Estandia Cano, et al. (17)) and Jakuszewska
(30)) in studies in Germany, Mexico, and Poland of CHD in individ-
uals under the age of 10, reported that cigarette smoking was the
dominant factor in the development of CHI) in these patients.
Golovchiner (;?I) found cigarette smoking to be a significant factor
in the development of myocardial infarction-in a study of 530 patients
with CHD in Leningrad hospitals.

10


Three studies without control groups from New Zealand (69),
Sq)al (47), and India (58) reviewed the prevalence of various risk
factors, including cigarette smoking in populations with documented
(`IID.

BLOOD LIPIDS

In lnost of the follo\ving studies where the effect of cigarette smok-
111~ 011 blood lipids was examined, there was no control for dietary
facstors that may independently affect serum lipid levels. Schwartz,
rt al. (56) examined serum lipids in relation to smoking habits and
h~latire weight in 7,972 male employees of the Parisian civil Service
in the city of Paris. Cigarette smoking was associated with a slight
bet significant (P <O.OOl) increase in serum cholesterol. The authors
f~~llnd a positive correlation between increased relative weight and
WIII~ cholesterol levels, and a negative correlation between rela-
tive weight and smoking habits. These factors would operate in such a
ray as to reduce the apparent effect of cigarette smoking on the
cholesterol levels. After controlling for relative weight, however, the
irlrestigaton found a significant (P <O.OOl) positive relat.ionship be-
tiveen smoking and serum cholesterol.
111 a study of various factors in relation to the mean serum choles-
r(`rol. Pincherle (@) examined the following parameters : blood pres-
Rw. height, weight, and skinfold thickness, X-ray findings of the
rhrst and abdomen, the electrocardiogram, and smoking history ;
l".`H)u British business executives between the ages of 25 and 65 were
p~rnuined. d significant association was found between elevated serum
"licllesterol, obesity, elevated systolic blood pressure, inadequate exer-
"I*`. radiographic evidence of arterial calcification of the iliac arteries,
~lll (Wain other factors. The increase observed in mean serum choles-
`~1 Gth increasing number of cigarettes smoked was not stabistically
Wlti f&~t.
lhsi~ (53) studied the distribution of serum lipids in 324 Nor-
Wi:hl military recruits Cigarette smokers had a small but insignifi-
"`irlt increase in serum &glycerides. No elevation was found for serum
r}~olt5terol. Th e subjects were young, and most smokers had only
"`k'bktYl for a fern years.

llllrlley and Enslein (11) investigated changes in clinical laboratory
t-ts as r&t ec 1 t o aging and smoking in a S-year study of 502 healthy
"~1~' veterans It \vas found that five variables were needed to predict
aK"sr~`bd changes in those over 50. These were: fasting blood glu-

11


case, e-hour post-glucose blood sugar, total serum protein, hemoglobin,
and cholesterol esters. No significant differences in the laboratory data
between smoking and nonsmoking subgroups were found.

Vlaicu, et al. (70) examined the interaction of cigarette smoking
with blood pressure and serum lipids in 100 patients with angina pec-
toris who were between the ages of 40 and 59. Half the patients were
smokers using more than 25 cigarettes a day. The smokers had lower
serum lipids and lower blood pressure than the 50 nonsmoking pa-
tients with angina pectoris.

Miturzynska-Stryjeeka, et al. (@`) found that cigarette smoking
immediately following a fatty meal did not significantly alter the
serum free fatty acid, esterified fatty acid, cholesterol, or plasma tur-
bidity levels over control values.

Ciampolini, et al. (16) examined the effects of cigarette smoking
on blood lipid values in 10 healthy volunteers between the ages of 20
and 40. Cigarette smoking resulted in a prompt rise in free fatty acids
and a delayed rise in serum triglycerides.
The relationship between cigarette smoking and changes in various
serum lipid levels has not been clearly determined. Studies in this area
continue to present conflicting results.

ELECTROCARDIOGRAM

Wysokinski (76') examined the effect of smoking on certain param-
eters of cardiovascular function in 100 healthy nonsmokers and 106
healthy smokers who were military recruits 19 to 2.5 years of age in
Poland. Significant prolongation of the QRS interval (P<O.OOl) , flat-
tening of the T wave, and ST segment depression following exercise
were seen more frequently in the smokers than in the nonsmokers.

Van Buchem, et al. (69) examined the occurrence and significance
of extrasystoles and conduction disorders in 760 healthy Dutch men
between the ages of 40 and 67 who were followed for 7 years. The pres-
ence of extrasystoles was not correlated with cigarette smoking or ele-
vated serum cholesterol and was not associated with the development
of CHD over the Y-year period.

Kattus, et al. (33) tested 314 healthy males 23 to 82 years of age for
ischemic ST segment depression on the ECG during or after submaxi-
mal exercise. The abnormal ST segment depression identified in 30
subjects was correlated significantly with elevated serum cholesterol,
abnormal rest)ing ECG, and a history of cardiac symptoms but not
wit.h smoking, high blood pressure, physical inactivity, or family his-
tory of coronary disease.

12


Van Buchem, et al. (68) found no significant association between
+arette smoking and ischemic ST segment depression on ECG in 120
apparently healthy men who demonstrated this abnormality among a
population of `760 men 50 to 70 years of age.

Experimental Xtudi.438

CIGARETTE SJ~OKE

Studies in Man

Summers, et al. (61) examined the effect of cigarette smoking on
csrtliac lactate metabolism in 15 patients with severe angina pectoris
nho had at least 75 percent obstruction in each of two or three major
c'oronary vessels. All patients had been long-term cigarette smokers.
Cigarette smoking produced increases in heart rate, systolic aortic
pressure, the systolic ejection period per minute, and the tension-time
index per minute, but lactate production was not induced by smoking
in any patient who did not also have lactate production in the control
state. In three patients with lactate abnormalities prior to smoking,
inhalation of cigarette smoke sustained and slightly aggravated this
Wtdition.

Studies in Animals

The effect of Inhalation of cigarette smoke on ventricular fibrillation
threshold (VF'I') in normal dogs and dogs v&h experimentally pro-
lll~d acute myocardial infarction was studied by Bellet,, et al. (6) . .
llongrel dogs weighing 25 to 30 kilograms were anesthetized with
>O(liurn pentobarbital, and respiration was maintained using a Harvard
V~`l~tilator attached to an endotracheal tube. In one group the electrical
iInl)ulses used to precipitate ventricular fibrillation were delivered
tllrough the chest wall, and in another group the impulses were deliv-
`~4 directly to the heart through electrodes implanted in the myo-
Qrcliurn. The experimental group of dogs were exposed to the smoke
`)f three cigarettes over a IO-minute period. Each cigarette contained
:`lWosimately 2 mg. of nicotine. With acute myocardial infarction, the
"VT was significantly (P<O.OOl) decreased, but in both the normal
"11ti lllvocardial infarction groups cigarette smoking resulted in a de-
i'rt';lse'in VFT that averaged 30 to 40 percent of the control value
! !iK. 4). These findings are of interest in view of the increased inci-
`lPI1~(> of sudden death observed among coronarv patients who are
`l";lVY cigarette smokers (65).                  Y

13


Figure 4.The effect of cigarette smoke inhalation on the ventricular fibrillation
     threshold (VFT) of normal dogs and dogs with experimentally pro.
     duced acute myocardial infarction (Ahll).

0.8 r

0.6 t   t
       o ?
      o ??

=.
`* %. smoking (normal)
     . . . . . . . - . . . . . . . *I-.-

                0    15   30   45   60   75   90
                 Time in minutes following
                   cigarette smoking
SOURCE: Bellet, S.. et al. (6).

The effects of passively inhaled cigarette smoke on several measure
of cardiovascular function in treadmill-exercised dogs were examined
by Reece and Ball (52). The experimental dogs were trained on the
treadmill for approximately 1 year before exposure to cigarette smoke
began. Each dog was passively exposed to the smoke of 36 cigarettas
over a 3-hour period 5 days a lveek in a 2.2 m.3 chamber ventilated at
the rate of seven exchanges per hour. The dogs were exposed to this
cigarette smoke and were continued on their exercise program for an
additional year. Exposure to cigarette smoke was associated with
cadiac enlargement, ST segment depression, and an increase in post-
exercise serum lactate concentrations.

14


Studies in Man

Isaac and Rand (98) have recently described a method for the assay
If plasma nicotine. An alkali flame ionization detector was used with a
!a.+liquid chromatograph. The test is sensitive to 1 ng./ml. of nicotine
In a 2.5 ml. sample ; 30 minutes elapsed between end of one cigarette
md start of next. Blood samples were taken before smoking and at 5,
10, and 30 minutes after the last puff of each cigarette. Plasma nicotine
lrvels increased rapidly during cigarette smoking (fig. 5). The post-
making decay curve consisted of two components: an initial rapid
I)hase which may be due to the uptake of nicotine from the blood by
various tissues, and a slower phase which may represent metabolism
:md excretion of nicotine. Some accumulation of plasma. nicotine 00
rarred during a day of smoking, but the background level never ap-
proached the peaks attained during and immediately following active
L8igarette smoking. The rate of elimination was rapid enough to prevent
:Iny appreciable accumulation of nicotine from 1 day to the next. The
dWelopment of sensitive tests of plasma nicotine levels will allow a
greater understanding of various dynamics of smoking. Inhalation
Patterns can be objectively measured, and the role of nicotine in
habituation to cigarettes can be evaluated.

15


Figure 5.-Effects of smoking five consecutive cigarettes on plasma rhOtin@
       concentration.

60

50

Plasma
nicotine   40
(w/ml.)

30

20

10

         0
Smoking period  .  .  .  .

0

1

2        3

Time (hours)

4       5

SOURCE: Isaac, P. F., Rand, M. J. (28).

Studies in Animals

The effect. of nicotine on regional blood flow in the canine heart w&s
exan1ine.d by Mathes and Rival (42). The effects of nicotine were
examined in normal hearts and after partial coronary artery occlusion.
I-rider normal circumstances, as well as after infusion of nicotine in
normal hearts, the subendocardial portion of the myocardium had II
!I..`-percent greater capillary flow than the subepicardial fraction.
Partial ligation of the coronary arteries resulted in a 22.Cpercent
reduction in left ventricular blood flow ; however, the subendocardial
portion remained X.6 percent higher than in the epicardium. After

16


coicnary artery ligation, an infusion of nicot.ine resulted in a signifi-
cast (P<O.OOl) reduction in the capillary flow of the inner portion of
the myocardium relative to the outer part.

Bhagat, et al. (7) examined the effect of cigarette smoking on the
cardiovascular system of dogs, various pharmacological agents; e.g.,
tyramine hydrochloride, propranolol, and chlorisondamine. were used
tn modify the evoked response to tobacco smoke in order to clarify the
nlrchanisms producing the observed effects. The authors concluded that
the more important actions of nicotine include a stimulation of sympa-
thet.ic ganglia and t.he adrenal medulla and the release of catec.hola-
rnines from sympathetic nerve endings and chromaffin tissue.
Bing, Hellberg, and associates (8. ., 95) st~atlied t.he microcirculation
of the left atrium of anesthetized cats by direct visualization using
hiih-speed c.inematopraphg. Nicotine injCctions produced a slight but
insignificant increase in red cell velocity in the capillary circulation
during both systole and diastole.
The effects of nicot.ine on t.he biosyilthesis of various lipid fractions
in the aorta of dogs \\eere studied by Kupke (.@) . After nicotine admin-
istration, significant reduction occurred in the formation of free ("C) -
strrols, while elevated levels of unesterified fatt.y acids were formed in
the media and intima of these in vitro specimens. The author sugested
that nicotine may impair oxidative enzyme systems possibly by damag-
ing the mitochondrial structures, thereby leading to lipid accumulation
ill the aorta.
SchieveIbein and Eberhardt (.54) reviewed the cardiovascular
actions of nicotine and smoking.

CARBOX MONOXIDE

Studies in Man

Sumerous articles have recently been published on the various effects
of carbon monoxide on man and animals and are of particular interest
l*cause of the relatively high levels of carbon monoxide found in the
rllain and sidestream smoke of cigarettes. Only those articles are dis-
"l~%d here which contain data on t.he cardiovascular effects of carbon
`Ii()t\oxide.
.\ronow and Rokaw (,I) examined the effects of smoking-induced
"arl~xyhemoglobin levels on angina pectoris in 10 patients with CHD.
`l'htl time to the onset of angina after smoking a nonnicotine cigarette
`V:IS measured- Each patient had smoked more than a pack of ciga-
r"ttrs a dav f;r at least 1~ yeat*s and had a classical history of ~xel'-
tir)lMl tlyq~lle:~. Snl()kiJip nonnicotine cigarettes failed to twdt in an
"l(Ution of the blood prrsslll.e, or the heart, rate : however, t,here was a

17


significant (P <O.Ol) increase in COHb levels to about 8 percent. Tb
resulted in a significant decrease in exercise performance compared b
the nonsmoking state (P<O.Ol) . This confirms that carbon monoxide
can compromise oxygen delivery independently of the effect of nicotine,

Maximal oxygen consumption under conditions of carbon monoxide
intoxication were studied in human volunteers by several authors (4,
71, 72). COHb levels of 15 or 20 percent resulted in a proportionah
reduction in maximal 0, consumption. The volunteers responded to the
decrease in oxygen-carrying capacity of the blood with a tachycardia
and relative hyperventilation during moderate exercise. Carbon man.
oxide produces a limitation of an individual's maximal oxygen con.
sumption by decreasing the availability of oxygen supplied under con.
ditions of increased oxygen demand.

Heistad and Wheeler (24) reported that the hypoxia induced bI
carbon monoxide inhalation caused an inhibition of reflex vasocon.
strictor responses despite the presence of normal arterial oxygq
tension.

Studies in Animals

The effects of carbon monoxide on coronary hemodynamics and left
-ventricular function in six unanest,hetized dogs were studied by Adarm
et al. (I). The animals reacted to a B-percent carboxyhemoglobin level
with a 14-percent increase in coronary blood flow. Twenty percent
COHb resulted in a 57-percent increase in coronary flow and slight
increases in heart rate and stroke volume.

Birnstingl, e,t al. (9) exposed young adult rabbits to 400 p.p.m. CO
for periods that varied from 6 to 14 hours. The mean COHb level after
a series of 22 exposures was 17 percent. A qualitative increase in plate-,
let stickiness, as measured by the bead-column method, developed dur.
ing the N-hour period following CO exposure. The aut,hors observed
that this (`* * * provides a possible mechanism for intimal deposition
and a further link in the association b&Teen habitual smoking and
peripheral vascular disease." Astrup (5) found the cholesterol level in
the aorta of rabbits exposed to a low level of carbon monoxide for 10
weeks to be, on the average, 2.5 times higher than in the control rabbits
Both the experimental and control groups were maintained on a high-
cholesterol diet.

Gibbons and Mitropoulos (20) reported that CO inhibited cho.
lesterol biosynthesis with accumulation of lanosterol and 24;25-dihy
drolanosterol in an in vitro system of rat liver homogenates exposed
to a go-percent. CO atmosphere. It was felt that CO may have ia.
fluenced an early st,ep in the oxidntive elimination of the l-la-methyl
group of lanosterol.

18


SMOKING AND THROMBOSIS

Previous reports of the Surgeon General on smoking and health
(6.5',63,64 65,66) have reviewed the effects of smoking on thrombosis.
Recent reviews and studies have not, thus far yielded a unifying con-
cept of the effect of smoking on thrombosis (,$,18,19,32, ~$5).

Cerebrovascular Disease

Paffenbarger and Wing (46) examined several precursors of non-
fatal stroke in 102 patients with this disease in a population of 10,327
men who had attended Harvard University between the years of
1916 and 1940 and also returned a self-administered questionnaire in
1966. Examination of university medical records of these former
students revealed four characteristics present in youth that predis-
l'osed those individuals who were more likely to experience a nonfatal
stroke in later life. These factors were: cigarette smoking, elevated
Mood pressure, increased weight for height, and short body stature.
Ihe age and interval-adjusted incidence rates per 1,000 were 10.1 for
uonsmokers, 15.3 for smokers of one to nine cigarettes, and 17.9 for
smokers of 10 or more cigarettes a day. The relative morbidity ratios
for the four factors cited above increased from 1.1 for patients with
()nly one risk factor to 1.7 for those with any two risk factors, and to
X3 for patients with any tl1re.e. or four risk factors.
hfiyazaki (44) studied blood flow in the internal carotid artery
rlsiug ultra sound techniques. Internal carotid blood flow was ex-
:ihed under a variety of experimental conditions. Inhalation of
$arette smoke in three individuals aged 27, 67, and 69 resulted in an
illcreased blood flow due to decre.ased vascular resistance. This effect
`itsted for 10 to 20 minutes following smoking.

Peripheral Vascular Disease

The association betxveen cigarette smoking and arteriosclerosis
f)t)literans (ASO) was invest,igated by JTeiss (7,Y). Patients were con-
>i'l~cl to have AS0 if both the dorsalis pedis and posterior tibia1
!"I~w were absent in one lower extremity and the examining physician
`Il:l(l~ :I diagnosis of XSO. Patients we.re asked the age of init,iation
`If sMiing; the daily number of cigarettes smoked: the amounts
.`liC)k~~d at ages 30. 50, and 70; the age at which they stopped smoking;
  455--028 O-73-~

19


and, for males, whether they smoked cigars or a pipe, A total of 214
male cases, 206 male controls, 390 female cases, and 913 female controls
were studied. The control group was composed of patients with
peripheral vascular problems other than aSO but who had dorsalis
pedis pulses present on initial examination. In each age and sex group,
cigarette smoking was more prevalent among cases than controls. In
both sexes, risks were high for smokers of less than one pack a day,
and increased with the amount smoked (figs. 6 and 7). It was esti.
mated that 70 percent of nondiabetic AS0 in the United States is
related to the use of cigarettes. Diabetes mellitus is a major risk factor
for the development of AS0 ; however, cigarette smoking appeared to
act independently of diabetes.

Figure 6 .-Relative risk of developing arteriosclerosis obliterans (ASO) for males
     by amount of cigarettes smoked.

15.0









10.0

Cases

18         21         33         69

Controls          53         15        26         37

Amount
smoked

Non-
smoker

1 pack
day

SOURCE: Weiss, N. S. (73).

20


Figure 7 .-Relative risk of developing arteriosclerosis obliterans (ASO) for
     females by amount of cigarettes smoked.

1            Fernal&               15.6

cases
Controls
Amount
smoked

79          50          60          41
429          83          69         33
NOW                    1 pack
smoker                 day

SOURCE: Weiss, N. S. (731.

Preuss, et al. (-50) examined the relationship between several factors
including cigarette smoking, blood pressure, weight, and history of
diabetes and the development of occlusive disease of the peripheral
arteries in a population of 300 patients in Germany. Group I consisted
of 150 patients with a mean age of 59 years who had intermittent
claudication. Most of these patients were ambulatory. The 150 patients
in group II had a mean age of 60 years and had far advanced periph-
eral arteriosclerosis with ischemic pain at rest or evidence of gangrene.
There was no control group of patients free of vascular disease. There
Wre few nonsmokers in either group of patients, but. the group with

21


the more severe disease had a higher average daily consumption of
cigarettes t'han did group I.

The influence of cigarette smoking on late occlusion of aortofemoral
bypass grafts was examined by Wray, et al. (75). A series of 100
patients who had aortic reconstruction for aneurysmal or aurtoiliac
occlusive disease between 1965 and 1968 were studied. Of the patients
who had bypass grafts for occlusive disease, 30 patients smoked ciga-
rettes and 16 did not. Late occlusions from thrombosis occurred in nine
patients, each of whom was smoking more than a pack of cigarettes a
day at, the time the thrombosis occurred (P<O.5). The authors re~oxn-
mend cessation of cigarette smoking to all patients undergoing vascu-
lar reconstruction.

Schmauss and Arlt (55): Wilbert (7.4), and Kradjian, et al. (39)
reported a greater than 93 percent prevalence of cigarette smoking in
three separate se+s of patients wit.h severe peripheral vascular
disease.

Isacsson (%9) performed venous occlusion plethysmography in 684
men aged 55 in Malmii, Sweden. In addition to a detailed smoking
history, a number of other factors were studied, including blood pres-
sure, pulse, height, weight, ECG, heart volume, and blood lipids. The
plethysmograms were taken on bot.h legs simultaneously with the
patient in the recumbent position. Measurements were taken at rest and
during reactive hyperemia produced by obstructing arterial inflow to
the legs for 3 minutes with a blood pressure cuff applied to the thigh,
Smokers had a significantly lower mean flow capacity (MFC) than did
nonsmokers. The MFC in the legs was reduced in direct proportion to
the amount of tobacco consumed per day regardless of the mode
of smoking. The MFC was significantly lower with inhalation
(P<O.OOl) and wit.h increasing amount smoked (P<O.OOl).

Matsubara and Sano (42) studied the effect of cigarette smoking on
human precapillary sphincters of the leg using a pressure plethysmo-
graph applied to the calf. Precapillary sphincter tone was e&mated
using the capillary filtration coefficient, which is the product of "funC-
tionai capillary service area"and the filtration constant of the capillary
wall. Four healthy male subjects were tested. All were regular smokeIs
of cigarettes who had not smoked for the previous 24 hours. `TVhen
cigarette smoke was inhaled deeply `at 30-second intervals over a 12- to
15-minute period. there was a 19-percent decrease in the capillary
filtrat.ion coefficient. indicating closure of precapillary sphincters.
Cigarette smoking also resulted in a 31-percent decrease in calf blood
flow3 indicating some degree of constriction of the arterioles in the leg.
The pressure volume curves of the venous system were not affected by
cigarette smoking.

Heistad and Wheeler (24) examined the effect of carbon monoxide
on vascular resistance and reflex vasoconstriction in the forearms of 12

22


healthy men 19 to 23 years old. After control measurements were taken,
the subjects were exposed to enough carbon monoxide to produce car-
boxyhemoglobin levels of 18 to 20 or 25 percent. Carbon monoxide did
not cause a change in alveolar PO, or PCO,. The arterial oxygen satu-
ration was less than 75 percent, but t,his decrease did not result in
altered resting arterial pressure nor was there much evidence of
sympathetic stimulation. Carbon monoxide hypoxia did result in a
significant decrease in vascular resistance in t.he resting forearm
(P<O.O5). Carbon monoxide exposure aalso resulted in a significant
depression of the vasoconstrictor responses of the forearm following
the application of negat.ive pressure to the lower body (P <O.OOl) and
of ice on the forehead. It appears that the hypoxia induced by carbon
monoxide causes an inhibition of reflex of vasconstrictor responses
despite the presence of normal arterial oxygen tension.

Summary of Recent Cardiovascular Findings

In addition to the summary presented in the introduction to this
chapter based on previous reports of the health consequences of smok-
illg, the following statements are made to emphasize the recent develop-
ments in the field :

1. Recently conducted epidemiological st,udies from several coun-
tries continue to confirm that cigarette smoking is one of the major
risk factors contributing to the development of coronary heart
disease.

2. Epidemiological evidence suggests that black men in the rural
South respond to the same risk factors for coronary heart disease,
including cigarette smoking, as white men do but apparently at
lower disease rates, which appears to be in part due to differences
in physical activity.

3. Data from several epidemiological and experimental studies sug-
gest that cigarette smoking is a major risk factor in the develop-
ment of peripheral vascular disease. This may in part be due to the
decreased blood flow in arterioles and capillaries associated with
cigarette smoking. Smoking may complicate the surgical inter-
vention in this disease by contributing to late occlusion of the
treated vessel.

4. A laboratory test has been developed which accurately measures
flicotine levels in blood. This test will be useful in understanding
nicotine metabolism and can be used as an objective measure of
%Yarette smoke inhalation.

23


Cardiovascular References

  (1) ADAMB, J. D., Earcesox, H. II., SIVNE, H. L. The effects of carbon monoxide
     on coronary hemodynamics and left ventricular function in the conscious
-<
`!`d     dog. In: Proceedings of the 1st Annual Conference on Environmental
     Toxicology, September 9-11, 1970. Aerospace Medical Research Labora-
      tory, Wright-Patterson Air Force Base, Ohio, AMRLTR-70-102, Decem-
      ber 1970, pp. 107-110.

(3) AGNES& G., CANEPA, `R., LA ROCCA, M. Eta e valore di alcuni indici per la

P       discrlminazione fra soggetti normali ed ischemici. (Age and value of
      several indices for discrimination in normal and ischemic subjects.)
       Giornale dl Iglene e Medicina Preventiva ll(3) : 140-151, July-S&em-
        ber 1970.

(3) ABONOW, W. S., RQKAW, S. N. Carrboxyhemoglobin caused by smoking non-
   nicotine cigarettes Effects in angina pectorls. Circulation 44 (5) : 7S2-
___ _ 788LN~v~G-wr 1971.

c4) AIITHES, F. r>An epidemiologic survey of hospital&d cases of venous
     thrombosis and pulmonary embolism in young women. Mllbank Memorial
   Fund Quarterly 5O( 1, Part 2) : 233-243, January 1972.
(5) ASTRUP, P. Riiknlng mh koronarsjilkdom (11) : Karbeskadigende virknlng
    af CO og hypoxi. (Smoking and coronary disease (11) : Vascular damag-
    ing effect of CO and hypoxia.) Ukartidningen 67(3) : 44-49, Jan. 14,197O.
(6) BELLET, S., DEGUZMAN, N. T., KOSTIS, J. B., ROMAN, L., FLEIECHMANN, D.
     The effect of inhalation of cigarette smoke on ventricular flbrlllation
    threshold in normal dogs and dogs with acute myocardial infarction.
    American Heart Journal 83 ( 1) : 67-76 January 1972.
(7) BHAQAT, B. RUEHL, A., RAO, P., RANA, `M. W., HUOHES, M. J. Effect of
     cigarette smoke on the cardiovascular system in dogs. Proceedings of the
     Society for Experimental Biology and Medicine 137(3) : 989972, July
     1971.

(8) Br~o, R. J., WAYLARD, H., RICKART, A., HELLBERO, K. Studies on the coronary
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24


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25


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26


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27


(63)

(64)

(65)

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28


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29


CHAPTER 2

       Nonneoplastic
Bronchopulmonaw Diseases


Page
35

Introduction____________________________----------------
Epidemiological Studies

COPD Mortality and n4orbidity--- -- ________ __-_- ______
  Filter Cigarettes---------------------------------
Pulmonary FuncGon----------------------------_
Occupational Hazards

   Byssinosis----------- _____-__--__--__-__________
   Exposure to Asbestos-_--------------------------
   Exposure to Coal Dust'---------------------------
   Miscellaneous Exposures-------_-----~-----------
Air Pollution..-_- _______ -------______--___-___ _______
.iutopsyStudies ____ ~_----------~-_-_-- __-___-_______-__-
Experimental and Histopathological Studies
Histopathological Studies-------------------------~----
Pulmonary Function ___________ --------------_- ____ --
Pulmonary Clearance__--_----------------------------
Phagocytosis _________ -----_---_-_-_----- ~~~~-~~-~~~~
Bacterial and Mycological Stu.dies----------------------
The Surjactant System_-___-_-_-----------__--___- __-_
*;llmmary of Recent Nonneoplast'ic Bronchopulmonary Find-
ings-_---_________--------------~~-----~-------------
Kf e erences _______________ -__----------------- __________

36
37
38

39
41
41
43
44
45

48
50
51
53
54
55

55
56

List of Figures

FiWre 1 .-Age-st.andardized percentage of chronic sputum
I)rcduction in males by amount smoked and type of
+!arette- _ _ __ _ ___ _ ___ ___ _ ___ _ _ _ _ ___ _ ___ _ __ _ __ _ __ _ - ---
I&re 2.-Age-standardized percentage distribution of whole
Iung sections of males with moderate to far-advanced emphy-
<ema (score 3-g) by smoking category- _ - _ - _ _ _ _ __ - - - - - ----
%lre S.-Prevalence of emphysema in adult males at autopsy
`?srnoking categor\-Mm ________ ~---..---__~ ------ ~----~~~

38




47


48

33


List of Tables

Page

Table l.-Percent prevalence of byssinosis for men by index of
severity and smoking habits (numbers in parenthesis indicate
number of cases in exposure risk group) _ - _ _ _ _ _ - _ _ - - _ - - _ _
Table 2.-Degrees of emphysema in current smokers and in
nonsmokers according to age groups- _ - _ - - _ _ - _ _ - _ _ - - _ _ - _ _

40


46

34


Introduction

The term chronic obstruct,ive bronchopulmonary disease (COPD) )
as used within this report, refers to chronic bronchitis and pulmonary
emphysema. The following is a brief summary of the major relation-
ships between smoking and nonneoplastic bronchopulmonary disease
which have been presented in previous reports of the hea1t.h conse-
quences of smoking (91, *9$. 93,94,95,%).

Epidemiological and clinical studies have established cigarette
smoking as the most important cause of COPD in the United States.
Cigarette smokers have higher death rates from pulmonary em-
physema and chronic bronchitis and more frequently have impaired
pulmonary function and symptoms of pulmonary disease than non-
smokers. Respiratory infections are more prevalent and more severe
among cigarette smokers, particularly heavy smokers, than among
nonsmokers. Cigarette smokers appear to develop postoperative pul-
monary complications more frequently than nonsmokers. The risk
of developing or dying from COPD among pipe or cigar smokers is
higher than that of nonsmokers, but it is clearly lower than that
among cigarette smokers. Ex-smokers have lower death rates from
COPD than do continuing smokers. Cessation of smoking is associated
with improved ventilatory  function and decreased pulmonary
symptom prevalence. Young cigarette smokers of high school age
have impaired ventilatorg function compared to nonsmoking peers.

For most of the United States population, cigarette smoking is a
much greater factor in the development of COPD than air pollution
or occupational exposure. Cigarette smoking may, however? act con-
jointly with atmospheric pollution or occupational exposure to pro-
duce greater mortality and morbidity from COPD than would occur
from on0 exposure factor alone.

A genetic error, homozygous alpha,-antitrypsin deficiency, present
in approximately 1 in 3,600 people in the United States, has been as-
sociated with the early development of severe panacinar emphysema.
Available evidence does not permit a firm conclusion about the nature
of the interaction between smoking and this condition.
Autopsy studies have demonstrated that smokers who die of diseases
other than COPD have histologic changes characteristic of COPD
more frequently than do nonsmokers.

                                                    35
405-028 %73---4


Experiments in both animals and humans have demonstrated that
the inhalation of cigarette smoke is associated with acute and chronic
changes in vent,ilatory function and pulmonary histology. Cigarette
smoking exerts an adverse e.flect on the pulmonary clearance mec.h-
anisms including ciliary and macrophage funct,ion.
The effect of cigarette smoking on nonneoplastic bronchopulmonaq
disease has been examined in detail in a number of recently published
epidemiological. pathological, and experimental studies.

COPD Xortality and Morbidity

Reid (70) reported that age-adjusted mortalit,y rates from chronic
nonspecific lung disease (ICD 502, 526, 527) among British citizens
varied with migration patttarns. British males living in the United
Kingdom had a death rate of 125 per 100,000. whereas migrants to the
IJnited States experienced a mortality rate of only 24 per 100,000,
which is similar to the mortality rate from chronic nonspecific lung
disease found in the T-3. population. The possibility that this varia-
tion was due to significant differences in diagnostic criteria was in
part ruled out by the finding that. standardized morbidity surveys
of bot.h populations demonstrated differences in morbidity rat,es that
were similar to the observed differences in mortality rates. The prev-
alence of respiratory symptoms increased in proportion to the num-
ber of cigarettes smoked per day. Cigarette smoking and air pollu-
tion were identified as the major factors contributing to the real excess
in bronchitis morbidity experienced by the British in the United
Kingdom.


Romania. Both areas were free of air pollution. The prevalence of
chronic bronchitis was higher in t,he mountains than in the. lowlands,
and although a definite association between chronic bronchitis and
smoking was found in both areas, smoking pat.terns could not com-
pletely account for the, difierences observed.

Several papers have been recently published (24, 2.5. X. J7.5.5. 100)
comparing respiratory symptoms. such as cough and sputum produc-
tion, among smokers and nonsmokers in different populations. In each
study. respiratory symptoms and disease were more common among
cigarette smokers than nonsmokers. Most of these studies (24, n)C, 37,
100) demonstrated a dose-response relationship be.t.ween smoking and
symptoms for the amount smoked as measured by the number of ciga-
rettes smoked per (lay, the lifetime number of cigarettes, or the degree
of inhalation.

The sl)ont,ane.ous development of a pneumothorax with the resultant
collapse of a lung is often produced by rupture of nn en~l~l~,vsematous
bleb on t.he 1)Ieural surface. Fonrnirr and Zivy (,`I) reviewed 81 cases
of spontaneous pneumothorax. The smoking habits of these patients
were cornp:JJwl with those. of matched controls. Spontancons pnemlo-
thorax after the, age of "5, was strongly associated with cigarette
smoking. Zivy (101) further characterized -IO of these cases.

FILTER CIGARETTES

The effect of smoking plain and filtered cigarettes on the. prevalence
of sputum production was examined by Rimington (71). A total of
10,414 volunteers aged -0) and older were studied by questionnaire and
chest X-ray. Of this group, 3,&G smoked filter cigarettes and 2.393
smoked nonfilter cigarettes. The rate of persistent daily SpUtLJJll pro-
duction was 31.9 peivent in filter cigarette smokers and 37.2 per-
cent in smokers of nonfilter cigarettes. The. difference is significant
(P<O.OOl). Although there was an increase in sput.um production
with the amount smoked in both groups, t.he difference between filter
and nonfilter smokers was maint,ained irrespective of the amount
smoked (fig. 1). The author observed, `While there is 110 doubt that
smokers of any t.ype of cigarette are liable to develop chronic bronchi-
tic symptoms such as persistent phlegm, it seems likely t.hat t,hose
plain cigarette smokers who are unable to stop smoking cigaret&s
~0u1d suffer less if the.y smoked filter brands of comparable size."

The eflect of smoking modified cigarettes on respiratory symptoms
and ventilatory capacity was examined by Freedman, et al. (22). Six
hundred men between the ages of 25 and 54 ~vho smoked at least 10
cigarettes a day and had symptoms of chronic bronchitis were divided
iJlt0 three equal g1.011ps matched by age, pulmonary function. cigarette
consumpt.ion, and cough frequency. The individuals were ljrovided

37


Figure l.-Age-standardized percentage of chronic sputum production in males
     by amount smoked and type of cigarette.

60

0 Filter cigarette smokers
_a Non.filter cigarette smokers

47.2
r7 / I

41.6 r/n

Number of

19.7

-

volunteers   4,976
Number with
sputum      836
          1 Non-

382  259   1,095  878   1,568 1,256

97   75    304  304    571  513
<lO       lo-19      >19

        smokers cigarettes/day cigarettes/day cigarettes/day
1 Includes ex.smokers and non-cigarette smokers.
SOURCE: Rimington, J. (71).

with test cigarettes "A"' " B," or "C." *411 t,he test cigarettes contained
1.65 mg. of nicotine. "A" delivered 22 mg. of tar, and "B" and "C"
17 mg. of tar. In addition. "C" had approximately a 50 percent reduc-
tion in the vapor phase constituents. Those provided with cigarette "C"
increased the average number of cigarettes smoked by about 10 per-
cent, There consumption eventually leveled off. 14fter 4 months, men
smoking cigarette "(1" began to have lower average cough frequency
scores than t,he others. Significant changes did not, OCCUI' in sputum
production or pulmonary function. The authors observed that, "* * *
modification of the composition of cigarettes and their filters can re-
duce smokers' cough, an important and early symptom of bronchitis."

PULMONARY FKTNCTION

Results of studies of pulmonary function and smoking from several
countries, including India (65) ' Turkey (2)) Germany (7,34,38), and
Great Britian (4.1) indicate that cigarette smokers have diminished
average pulmonary function compared to nonsmokers. The various
measures of pulmonary function used included vital capacity, expira-
tory reserve volume. residual volume. residual functional capacity,
maximum voluntary ventilation, forced expiratory volume in I second!
and peak cxpiratorg flow rate.


Other studies in which both pulmonary function and respiratory
symptoms are c0nsidere.d (27, .N. 36: -/. .a
               `3 -9. 69) have again confirmed
that smoking is associated with an increase in pulmonary symptoms
and a decrease in pulmonary function.
Rx-smokers experience a decrease in t.he prevalence of respiratory
symptoms and an improvement in pulmonary function compared to
continuing smokers. These effects have been noted in several recent
studies (36, flw? 43).
Ulmer (87) conducted a survey of respiratory symptoms in a ran-
dom sample of 2>-1-13 individuals between the ages of 10 and 70 years in
I>uisburg, Germany. The prevalence of c.hronic bronchitis as measured
Iq cough and/or sputum produc,tion in the morning or throughout the
day increased with advancing age and with increasing cigarette con-
sumption ( P < 0.001).

Latime,r, et al. (JR) st,udied the ventilatory patterns and pulmonary
complications of 46 patients following elective upper abdominal sur-
gery. Factors that favored the development of postoperative macro-
iit&ctasis included smoking, obesity. and prolonged anest.hesia.
Teculescu and Stanescu (84) examined several measures of pulmo-
nary func.tion in 44 asymptomatic young men bet,ween the ages of 18
and 29 in Romania. So significant differences were found between the
smokers and nonsmokers. This may have been due to t.he selection of
:Isymptomatic subjects for examination and relatively insensitive meas-
ures of early airway obstruct,ion.

Occupationa Wa.saro?s

BYSSINOSIS

Ryssinosis is a respiratory disease found in cotton, flax, and hemp
\vorkers. The earliest manifestations of t'his disease are shortness of
breath, cough, and chest tightness. Initially, symptoms occur only
QIWI reexposure to cott,on dust at, the beginning of the work week.
In more advanced form, byssinosis is associated with permanent and
`lecasionally severe airway obstruction, which mav force the \vorker
to change his occupation 731). Abnormalities i11 &monary function
tc'stS reflect the severity of tile symptoms; however, chest films Of
`Qnkers with bvssinosis reveal 110 characteristic findings. McKerrow
            Y
~(1 Schilling (54) first suggested t.hat. bvssinosis ma,y occur more
il'qurntly among smokerti than noiismokrrs. &\-era1 relatively recent
`trldies hare clarified the relationship between smoking and byssinosis.
l~C)l~liuys, et al. (8) found 61 cases of byssinosis in 214 male workers
`I1 the carding and spinning rooms of a cotton mill. The prevalence of

39


byssinosis symptons was higher among cigarette smokers than in
nonsmokers (P<O.OZ) .

Szymczykiewicz, et, al. (8.2) found a higher prevalence of chronic
nonspecific pulmonary symptoms among smokers than nonsmokers
in a study of 3J6'7 cotton mill workers in Poland.

An examination of 500 cotton textile workers by Schrag and Gullett
(75) disclosed 63 individuals with byssinosis; 57 percent (36 workers)
of those with bvssinosis smoked more than a pack of cigarettes a day,
whereas only 34 percent (152 workers) of those without. by&no&s
smoked this amount (P<O.OOl) .

Merc.hant., et al. (C58) conducted a study of byssinosis in a yanl
mill in North Carolina: 25 employees with byssinosis were identified
in a population of 441 workers. A scale of 0 to 3 (based on 9 weighted
questions concerning cough, breathlessness, and chest tightness on
Monday mornings) was used to indicate the degree of severity of
byssinosis among the working population. The effect, of cigarette
smoking on this byssinosis index is apparent (table 1). Among the
employees with high exposure to cotton dust, no nonsmokers had a
byssinosis index rating orer 1, but nearly 18 percent of those currently
smoking had ratings of 2 or 3. The effect of smoking alone on the
byssinosis index is significant (P<O.Ol). Also, the interaction `between
current smoking and current. exposure-risk on the byssinosis index is
highly significant (P<O.O05). Women in this study were exposed to
lower levels of respirable cotton dust, and among them no age, smok-
ing, or exposure-risk effects were demonstrated. Smoking among
males also had a significant effect on the bronchitis index (P<O.O02).
Spiromet,ry results on 134 males and 100 females were categorized by
sex, age. and smoking history. -1mong men, the greatest impairment

TABLE l.-Percent prevalence of byssinosis for men by index of severi.ty
and smoking h.abits (numbers in parentheses indicate number of caSeS
in exposure-risk group)

                  Percentage of subject
Index rating  ~~ ---- _____------- __--
(see text)     Never smoked  Curren~ts~mokers    Ex-smokers
            m                      (21)

Total.---~~---.-~~..~~-     100         100         100

Source: Merchant, J. A., et al. (68)

40


\vas observed among the smokers who worked in the high exposure-
risk areas. The mean FEY 1 for 66 men in this category was only 76
percent of predicted, and their FVC was 90 percent of predicted.
Sonsmoking men in both the high- and low-exposure areas had better
pulmonary function than their smoking coworkers.

EXPOSCRE TO ASBESTOS

Langlands, et al. ($5) surveyed respiratory symptoms, pulmonary
function, and radiological findings among 252 asbestos insulat,ion
workers in Belfast, Ireland. Respiratory symptoms of cough, sputum
production, and wheezing were ~nr~c*h rno~~ frtqu(wt in smokers. Of the
tests for pulmonary function, the peak flow rate and forced expiratory
volume at 1 second were most impaired in cigarette smokers. Although
little difference was reported in the S-ray- findings of smokers and
nonsmokers, smokers of more than 25 cigarettes a day had a go-percent
reduction in pulmonary function as measured by these tests.
Lung funct.ion and ~~ulrnona~~ symptoms in 1,015 chrrsotile asbestos
mine and mill workers in Quebec were studied by Becklake, et al. (6)
and McDonald, et al. (S.?) . -in analysis of respiratory symptoms indi-
cated that. shortness of breath was more closely related to dust ex-
posure than to smoking. However, cough, wheezing, and sputum
production were much more frequent in smokers than nonsmokers.
Pulmonary function was hssessed by measuring lung volumes, flow
rates, and diffusing capacity. The best pulmonary function was found
in nonsmokers with low dust, exposure while smokers wit.11 high dust
exposure had lower pulmonary function values.

In a survey of 201 asbestos workers, Regan, et al. (67) investigated
the relative power of 16 clinical, radiological, and pulmonary function
variables including smoking for diffcrentiatinp between asbest,osis and
chronic obstructive airway disease. Cigarette smoking was not a char-
acteristic that, could be used to separate these conditions.

EXPOSCRE TO COAL DUST

The spectrum of pulmonary reactions to coal dust was reviewed in
a volume edited by Key, et al. (No). Hunter (33) noted that coal miners
who smoked experienced a higher prevalence of respiratory symptoms
(col;gh, sputum p reduction, breathlessness, and wheezing) and de-
veloped them earlier than nonsmoking miners. Their pulmonary func-
tion tests also t,ended to show greater impairment than those of
*lonsmokers. Lainhart, and Morgan ($4) reported that' coal miners
llad an increase in persistent productive cough with increasing years
of exposure to coal dust. This effect was magnified by cigarette smok-
iV independent of age or wars of underground ~vork In an autopsy

41


study, Naeye (62) observed more right ventricular hypertrophy and a
hig1le.r emphysema intlcx in smoking miners than in nonsmoking min-
ers. In commenting on the et.iolopy of pulmonary re.act,ions in coal min.
crs. T,ee (+@I) felt that snloking in coal miners probably facilitated the
development of bronchitis and emphysema, rather than participating
in the genesis of the characteristic lesion of coal workers! pneumo.
coniosis.

The prevalence of chronic bronchitis in 3,012 ex-coal miners and
9,361 nonminers of sinlilar age and social class was examined by Lowe
and Khosla (51). All were employed at the time of the investigation
in two steel works in South Wales. The es-miners had substantially
more chronic bronchitis and more impaired ventilatory capacit.y than
t,he nonminers irrespective of age and smoking habits. The prevalence
of chronic bronchitis was 24.9 percent in smoking ex-miners and 12.0
percent in nonsmoking ex-miners. The prevalence was 18.6 percent and
7.7 percent in smoking and nonsmoking nonminers, respectively. In
this study, smoking appeared to be a more important factor for the
development of chronic bronchitis than coal mining or age.
Haber, et al. (20) studied cigarette smoking, dust inhalation, and
sputum production as factors in the etiology of chronic bronchitis
among 479 coal miners and 166 farmers in Hungary. In both the
miners and the farmers. there was a significantly higher proportion
of chronic bronchitis cases among smokers than among nonsmokers,
and the proportion of bronchitics increased with the number of
cigarettes smoked. Cigarette smoking was found to be a more im-
portant factor in the etiology of bronchitis than dust inhalation.
Lapp. et' al. (46) examined changes in several measures of ventila-
tory capacity in 93 coal miners and $2 nonminers before and after
a work shift. Follo\vinp the shift. small but significant decrease,s in
vent.ilat0r.v capacity owurr~d anion g the nline.rs (P<O.O:i). while
significant increases in veutilatory capacity occurred among the non-
miners (P<().O;i). I)ccrenses in pulmonary function tests were related
to the dust exposure of the nliners: howc~\-er. the greatest decreases
in pulmonary flinction occ~*rirretl aniong the smokers.
Senton. et al. (76) exaniined several measures of ~mlnionary func-
tion in 214 coal \vorkers who had radiologic evidence of CWP with
lung opacities that r;inged in size from Icss than I.3 mm. to 3 mm. in
diameter. They found no significant diflcrence in pulmonary function
between the lOti snloliels and 112 nonsmokers \vith coal lvorkers
pne~lnlocnniosis. Similar resl1lts were rcportcd by I,yons. et al. (52).
H.vperinflation of the lungs in coal miners was st uditd by Morgan.
et al. ((;I). Residual \olur~ws, total lung capacities. and chest X-rays
of 1.4-5.i working I'ennsylv;~nia coal miners were csainined. The rcla-
t ionship bet wcen radiograpl~ic evidence of coal workers' lmeumoconi-
osis anal lung \-olun~es was investigated. The residual volume in-

42


creased with radiographic category, obstruction to air flow, and
cigarette smoking. Each of these factors had a separate and additive
effect that resulted in an increased residual volume.

Ulmer (86) examined a random sample of t)he working population
in the Ruhr area of West GermanJ. Measurements were made of the
total lung capacity, airway resistance, and arterial oxygen satura-
tion. All coal miners had larger total lung capacities than workers
wit,hout dust exposure. Smokers had significantly larger volumes than
nonsmokers (PCO.05).

Lapp! et al. ($7) examined pulmonary hemodynamics in 47 asymp-
t,omatic coal miners. They were divided into t.wo groups depending
upon the absence or presence of airway obstruction. Pulmonar?; hyper-
tension was more frequent in the group with obstruction. Thr group
of 23 men (mean age 51 years) without airway obstruction. had an
average cigarette consumption of 17 pack-years per miner. whereas
the group of 21 men (mean age 56 Sears) with airway obstruction
averaged 31 pack-Fears per miner.

From t.he work of several investigators it can be concluded that,
cigarette smoking is an important factor in the development of re-
spiratory disease other than pneumoconiosis, among coal miners (a9.
MO, 46, ~$7~ 51, 61, 86). There is no consensus in recent publications on
what role cigarette smoking may play in the development of coal
workers' pneumoconiosis (40, 61, 76).

MISCELLANEOUS EXPOSURE~~

The effect of cigarette smoking on pulmonary function in jet fighter
pilots and crew- members was r~xamine(l by Ijrowning (I,). -It. high
altitudes, loo-percent oxygen is delivered under low pressure to the
aircrew members in order to maintain adequate blood oxygen levels.
The vital capacity was acutely conlpromised in flight on the loo-per-
cent oxygen mixture. This was cspccially t.rue under high G (gravity)
condit,ions. Smokers had a significant, inflight, VO~UIIW loss that, was
three and one-half times that noted among the nonsmokers untlc~
these conditions (P<O.OFi). Recovery of normal vital capacit.y follow-
ing flight was also delayed in the smokers.

Gregory (28) reviewed 840 casrs of chonic bronchitis that, occurred
among the employees of the Shr&ld steclworks in England. Smoking
NLY associated with a high prt~valrnce of chronic bronchitis, but of
part,icular interest. was the etfcct of cigarette smoking on disability.
The interval between th<b onset of chronic bronchit.is and disabilit,y
from t.his diseas(l was significantly less (P<W2) for those smoking
more than 20 cigarettes a day than for nonsmokers and for those
smoking less than this amount ( P<o.o~).

Ratawi (5) examined the prtlvalencc of several diseases including

43


respiratory illnesses in 4,643 employees in Egypt, comprising a 5.3
percent sample of 92,000 employees in 17 major industries. Respira-
tory illnesses occurred more frequently in all segments of the cotton
industry, as well as leather, printinlg, and glass industries; 40 percent
of all employees were smokers, and they experienced higher rates of
respiratory symptoms and illnesses than nonsmokers. Smokers with
occupational exposure to dust were particularly affected.

The effect of cigarette smoking and occupational exposure to dust
on the prevalence of chronic bronchitis was examined by Golli ($3')
in Romania. There were 2,942 individuals examined of whom 142 were
employed in dusty occupations. Chronic bronchitis was present in 24.6
percent of the 457 smokers and 4.4 percent of the 2,343 nonsmokers
(P<O.OOl). Increasing age, cilgarette smoking, and occupational ex-
posure to dust each independently contributed to an increased prev-
alence of chronic bronchitis.

Recent studies in metal casting, plaster, coke, baking, agricultural,
and chemical industries have documented a higher incidence of respir-
atory symptoms and/or diminished pulmonary function among ciga-
rette smoking workers than nonsmoking workers (&,64,89,97,99).

Reichel and Elmer (68,88) examined the effect of air pollution on
the prevalence of respiratory disease among 8,162 men and women in
West Germany. The three areas chosen for study had widely different
atmospheric levels of sulphur oxides and particulate matter. The fre-
quencies of cough and sputum production were the same within the
nonsmoking groups in all three areas. No differences were found in
pulmonary function or arterial blood gases between subjects of the
three districts. Smokers in each are,a had a higher prevalence of res-
piratory symptoms than nonsmokers. The authors concluded, "There
is no doubt that the influence of air pollution is less important than
that of age, sex, and smoking habits."

Tsunet.oshi, et al. (85) examined the prevalence of chronic bron-
chitis in Osaka, Japan. The independent contributions of age, smoking
habits, and air pollution were e.xaminkd. In male cigarette smokers
using more than a pack a day, chronic bronchitis was three to four
times more prevalent than in nonsmokers. In female smokers using
half a pack or more a day, chronic bronchitis was five to six times
more prevalent than in nonsmokers. The standardized prevalence of
chronic bronchit.is increased with the degree of air pollution, particu-
larly sulphur dioxide pollution, but not with increasing levels of
suspended particulate matter.

44


The Federal ,1viation Administ,ration, I)epartment of Transporta-
tion, and the Sational Inst.it.ute for Occupational Safety and Healt,h
jointly conducted a study of the lrvels of c.ertain combustion byprod-
ucts of tobacco on milit.ary and civilian ;tir(araft. I~roduced by pas-
sengers' smoking and also askecl the 1)assenprrs for their subjective
reaction to tobacco smoke (XI). I,e\-els of carbon mo~~ositle, particu-
late, matter, polycyclic hyclrocai~l~ona~ ammonia. and ozone were meas-
ured on 20 military and eight domestic flipht.s. On all aircraft the
measured level of each substanw was 11rw11 ion-PI. thall r~c~co~l~mr~~ltlt~d
ofcnpational and en\.i~r~nnlcntnl air quality stantlards. This was prob-
ably the result of the efficient \-cntilntioll systcnrs wcluirrd on all air-
waft (20 exchanges of cabin air each IIoiIr).
More than 60 lwrcent of the ~mk5~~1Ip1s rrporttd that tlwy w'rc
IJothered by tobacco smoke ant1 su,qystcd tllat corrt,cti\-1% act ion such
as segregation of smokcars and nonsmoktbrs 1~ taktlll. 3101~ tllan 70 per-
rent. of t.he nonsmokers who had a history of respiratory conditions
we annoyed bv tobacco s~nolct~. `1'11~1 disconlfort attributetl to tobacco
Sllloke in spite of the etlicient wnt ilation srstchni might haw wflwtcd
crowded seat.ing conditions or tlrying of the respiratory membranes
\rhich results from the very low humidity found on most aircraft..

Autopsy Studies

dnerbach, et al. (4) studied the relationship b&Keen age', smoking
habits, and emphysematous changes in \I-hole lung sections obtained at
aatopsv from 1,448 males and X88 fenlales. ,\ total of 7.324 sections
1 IIm. ;,hick were graded on a scale of 0 to 9 according to the severity of
(`mphvsema. So distinction was matlc betwwn centrilobular and pan-
lob&r emphysema. Tile IIwII were clwssifietl t)y ape, tyl)r of smoking
`pipe, cigar, or c,igarettr). and amount of cigarcttc smoking. Smoking
habits were ascertained bv interviews with relatives. Within each of
the six smoking catrporieL+ the nwan degree of emphysema increased
aith age. Adju&ing the data for age rc\-paled that. the I~P:I~ dcprw of
"~Qhvsema was lowest, among 1m11 who
Pipe or cigar smokcrj, and highest   never smokctl, was higher in
                             anIon g rrg111n I' ciga rettc snlokers.
-1 dose-rwponsc rc~lationship was found for the number of cigarett.es
smoked per day alIt1 the se\-eritv of c~ml~hyma. Table 2 and figure 2
stKnv these r~rlationshil~s.
Fingerland. et al. (29) investigatrd the prevalence of various patho-
logical contlitions including rI111~lIyse1Im and cllronic bronchitis in an
aLitol)sy population conlprisinp alI lwrsons owr thtx apcl of 20 who
"alllp to autops)- OYCI- R 2-yw1~ lwriotl at thcb Institute of I':~tlrologicaI
-\llatomv in (`z~~choslo\.aI;i;l : 76.7 Iiiulvs iIIl(l .i7:`, f<`Illill(`S \vel'(' inclutl~d

45


in the study. Smoking histories mere obtained from patients before
death, medical records, or relatives. The smokers were divided into
three groups based upon the number of cigarettes smoked during their
lifetime J 26 percent of the male nonsmokers showed some evidence of
emphysema, whereas 70 percent. of male smokers of more than 500,00r~
lifetime cigarettes showed these changes (fig. 3). Similar relationships
were demonstrated for chronic bronchitis.

TABLE 2.-Degrees of emphysema in current 1 smokers and in nonsmokers
           accordi,ng to age groups

Age group and degree of
emphrsems (see text)

Subjects   Current       Packages smoked per day
who never  pipe or ---
smoked    cigar    <M    yi to 1     1 to 2    >2
regularly

-

<60:
  oto0.75--- -._-_-_   53     18     12      3      2       0
  1 to1.75_-- -.-____    2      11      4      9     24       5
  2to2.75--- -._.___    0      1      2     17    130      56
  3to3.75-_- -.--__ -    0      1      5     12     50      38
  4 to 4.75---__-----    0      0      0      4      8       7
  5 to 6.75----------    0      0      0      0      4       5
  7to9.00- __-.----_    0      0      0      0      3       1
    Totals---.._----   55     31     23     45     221     112

  Mean-.----..--_--     . 10    .83    1. 29    2. 37    2. 56    2. 86
  SD---w ____ ----__    .04    .13    .26    .16    .07     .lO

                                                         -
60 to 69:
   0 to 0.75----------   35     17      4      0      0       0
   1 to 1.75---mm-----    1      8       1      0      4       1
  2 to 2.75--------..    2      3      4      5     37      23
   3 to 3.75--_----_..    2      2      2      9     42      24
   4 to 4.75_--m-_m---    0      0      1      3     11       9
  5 to 6.75--_--_-._.    0      0      0      1      8       1
   7 to 9.00--_----.._    0      0      0      1      5       4

    Totalsmm..F.--mm_    40     30      12     19    107      62

   Mean---.__----_--     .39    .95    1. 90    3. 59    3. 39    3. 37
   SD---mm...--mm.m_     13     .16    .34    .35     .l.i     .20

70 or older:
  0 to 0.7.5mmm---  ~~.   68     21      2      0      0       0
   1 to 1.7.5mm_--mm...    4     28     10      8      2       2
   2 to 2.75--m--__._.    -
        ;      22      13     23     40       9
  3 to 3.75-------_-_          8      5     10     38      18
  4 to 4.75----------    0      2      1      7     11       7
   5 to 6.75-_._--mmm.    0      1      0      2      9       3
   7 to 9.00.-----.--.    0      0      0      1     12       5

    Totalsm--_...---   81     82     31     51     112      44

   hlean~.---~~~-----      50
  SD-----m_.------m   :39    1. 66    2. 15    2. 98    3. 68     3. 91
                             11      17     20     17     .27

1 Subjects who smoked regularly up to time of terminal illness.
Source: Auerbach, O., et al. (1).

46


Figure 2. -Age-standardized percentage distribution of whole lung sections of
     males with moderate to far-advanced emphysema (score 3-9) by
     smoking category.

   Number 6
     of    Never
    cases   smoked
       regularly
SOURCE: Auerbach, 0.. et al. (4).

14
Pipe
or
cigars

   64         323
   Cigarette smokers
<l pack/day   >l pack/day

Mitchell, et al. (6'0) conducted a study to determine the accuracy
of the recorded cause of death on deat.h certificates of adults; 578
autopsies were performed on patients 40 years of age and older at two
large hospitals in Colorado. In addition, 409 patienk with COPD were
enrolled in an emphysema registry. A autopsies were performed on the
56 patients who died during the st.udy period. Death certificates were
obtained from the State Health Department, and t,he recorded cause
of death was compared with the autopsy findings. In 211 of the 634
autopsies performed, the cause of death was found to be COP11 ; how-
ever, in only 160 of these cases (76 percent) was COPI) listed as the
cause of death on the death certificate; 3 ljercent, of death certificates
incorrectly listed emphvsema as a cause of death when this was not
supported bv autopsy e;,idence. The authors concluded their study by
suggesting ;* * * that national statist,& which arc based on non-
autopsv confirmed diagnoses. might, understate tlraths f ram chronic
bronchitis and `e.mphysema.' "

47


Figure 3 .-Prevalence of emphysema in adult males at autopsy by smokina
      category.

50




40




30




20




10




0

58.90

48.62

Number autopsies 145       164       236       60       109
Number w/
  emphysema 38        66       139       42        53

Non-    Number cigarettes smoked during life   ii-
smokers  <200,000 200,000-500,000 >500,000 smoh

SOURCE: Fingerland, A., et al. (19).

Experimental and Histopathological Studies

Nistopatholoyical Studies

Studies in Man

Xaeye and Dellinger (63) esamined the small pulmonary art,eries
of 126 male cigarette smokers and 67 nonsmokers for quantitative
changes in collagen, elastic tissue, and circularly and longitudinallp
oriented smooth muscle. Thq fount1 a progressive increase in collagen

40


;,a(1 longitudinally oriented smooth muscle fibers and a progressive
,]rcrease in circularly oriented muscle fibers with age. These changes
\rere more advanced at each age in smokers than in nonsmokers
IP<O.Ol).
Sobonya and Kleinerman (78) quantified t,he smooth muscle and
~~nrcous glands in the bronchi of 13 male cigarette smokers and 11 male
rlonsmokers from Ohio who were 18 to 46 years old and had died of
nonrespiratory causes. The smokers averaged 24 pack-years of ex-
posure. Although the smokers had a Iiistory of more respiratory
symptoms and colds than the nonsmokers. no tliffercncc was found in
the percentages of smoot,h muscle or bronchial glands bet,ween smokers
and nonsmokers. Five of t,he 13 smokers showed evidence of squamous
netaplasia.
Ellefsen and Tos (17) determined the goblet cell density in tracheal
biopsies from 50 pat,ie.nts 1vit.h respiratory symptoms or disease. Goblet
wll density inweased with symptoms of tracheobronchitis and history
of exposure to dust. A slight increase was also noted in mean goblet
Tell density with increasing consumption of cigarettes from 136 in
symptomatic nonsmokers to 15-I in smokers of more than a pack a day.

Sudies in A\nimals

Syzganov, et al. (81) exposed 55 dogs to cigarette smoke inhaled
through tracheostomas for periods of up to a. year or longer. An addi-
tional 15 dogs served as nonsmoking controls. The smoking animals
developed bronchitis, bronchopneumonia, interst,it.ial pneumonia, and
hyperplasia of the, bronchial epithelium. Later histologic changes in-
cluded squamous metaplasia and papilloma formation not found in
controls.

The effect of sulphur dioxide (SO,) and cigarette smoke on the
a~ous glands of rats and the bronchial glands of lambs was studied
by Mamdesley-Thomas, et al. (57). There was a slight increase in the
goblet cell count of rats with the inhalation of SO, and cigarette smoke.
Exposure of lambs to cigarette smoke inhaled through a tracheostoma
resulted in hypertrophy of the bronchial glands.
Jones, et al. (&?) found that the addition of phenylmethyloxadiazole
(NO) to tobacco protects rats against some of the adverse effects of
exposure to cigarette smoke. Two groups of 13 Sprague-Dawley rats
ore exposed to 25 cigarettes a (lay. 4 days a week for 6 weeks. The
:`reUp exposed to cigarettes containing 1'310 showed less immediate
ctistrrss after esposurc and had a lower tmchtal goblet ccl1 count, less
tlnckening of the traclwal epitheIium, antI fewer cells in mitosis than
those exposed to the regular cigarettes.
The response of the rat lung to low levels of nitrogen dioxide (SO,),
i1 (!cnst,ituent, of cigarcttc smoke. was studied bv Strplwns. Evans. and

49


their associates (18, 80). Young male rat.s mere continuously exposed
to X0, at concentrations of 2 p.p.m. and 17 p.p.m. for 1 year. Animals
mere sacrificed after a short exposure and also at regular intervals Over
the 12-month period. ,1t the level of 17 p.p.m., destructive changes
occurred in the respiratory epitheliurli within 4 hours. These changes
included cell hypertrophy. loss of cilia. and increased mitotic, activity.
After 24 hours of exposure at this level some repair began. but cuboidal
cells replaced the normal respiratory epithclium. At 2 p.p.m. the acute
damage was less severe, and complete recovery occurred over a period
of several weeks.

Sherwin, et. al. (77) studied the effect of low doses of SO, on the
alveolar ~111 cells of the guinea pig. They founcl that continuous
exposure of 2 1~p.m. SO, produced a significant. increase (P<O.O5) in
the lactate dehydrogenase (I,I)EI ) index of the lower lobes of the lung.
suggesting that, the ultrathin type 1 (LT)Il positive) alveolar wall cells
were beinp replaced by relatively thick type :! cells resulting in a
physiologically sipnificant blood-gas barrier.

Ingram and O'Cain (3) studied dynamic compliance in nine smok-
ers and nine nonsmokers under the age of 30 who were in good health.
Both groups were identical with respect to airway resistances. lung
volumes. maximal expiratory fiow rates, and static compliance values.
Dynamic compliance fell more rapidly in the sniokcrs than in the non-
smokers above a frequenq- of 40 breaths a minute. `I'lw tlitYercncc was
statistically significant (P<O.OOOl). Isoproterenol produced no sig-
nificant increase in dynamic compliance in either the smokers or the
nonsmokers. In sis of the smokers who stoplw(l s111okinp. the dynamic
complianw CIII'VCS gr:~d~lnll~- :~~~~~IY~:I~~IL~YI tllcx \-illtles of the nonsmokers
over an H-week period. (`liaiipcs over tliis relatively loilg ~wriotl of time
indicate that the decrease in tlynarnic conll)li;~n(~c~ obscr\-cd in s~nokers
was more likely caused 1)~ inflamnlatory c*hanps or SOIW ot lwr mecha-
nism rather than miiscular cwiistriction in tlw I~t~oncliiolrs. Thr authors
concluded that peripheral :lil'\\-;ly :~l)l~ol~~n:~litic~s are rep~larl~ present
in yoiuig as)-mptomat ic smokers.

50


with increases in cigarette smoking. Es-cigarette smokers tended to
have results similar. to those of nonsmokers. The authors found that
the mebrxne component, did not show any consistent change wit 11 in-
cwased current cigar&te smoking. n-lIr~wa the volume of blood in the
lung capillaries decreased markedly with increased cigarette consump-
tion, and slightly with age. The \-alue of this vascular component in
alale 1~oIm1101wrs WIS 7.FG. This tlecreased to 49.1 in males who smoked
25 or more cigarettes a day (I'<O.Ol). The figures for won~en were
77.2 and 50.7 for nonsmokers and smokers. respect.irely (1'<0.05).

Acetaldeh~de is fou~id in cigarette s~fiokc~ and is a known ciliatoxic
agent,. The single-breath retention of acctnldrlr~de vapor b- the respi-
ratory tract of human subjects was measured by Egle (I(;) who found
a direct relat.ionship between the volume inhaled and the percent taken
up. Up to 90 percent of the inhaled acetaldehytie was removed in a
single breath.

Stanescu (79) studied the single-breath oxygen test, in 38 male
smokers and 68 male ~Io~IsmOkers who were in excellent, health. -4 sig-
nificant, difference (P<O.OOl ) in t.he slope of the nitrogen gradient
between smokers and nonsmokers was found.
Teculescu (8.1) performed single-breath determinations of total lung
capacity in 89 males aged 19 through 67 \\-ho had normal chest, X-rays
and no history of respiratory disease. So significant. differences \vere
found with age or smoking habits.

Studies in Man

`rracheobronchial clearance rates were studied in nine pairs of mono-
zygotic ant1 nine pairs of djzygotic twins bv (`aniner. (4 al. (Is). A test
~osol of radioactively taggc(l tcHon 1xI&1es 6 to 7 microns in diam-
Wr was inhaled and `external measurements of radioactivity in t.he
Il111gs were made. The (alearance patterns within pairs of monozygotic
t&s were similar? more so than clearance patterns within pairs of
`(izYgotic tjvins, indicating that tl.aclleobroIlcllial clearance rates may
to &1e extcllt. be constitutiollalIv determined. Onlv one individual had
`wl a I~egular cigarette smoker.
( `:II~cI. alld I'hilipson (I(/) also studied tracheobronchial clearance
,`I S"loking-discoI,daIlt twins. using the same techniques as in the pre-
`j~s study : 10 pairs of Jllonozygotic. twins cliscordant with r~parll to
' `E:lNtcl snlokjIlg IT(`I'~~ studied. ,111 the smokers had usd 10 to 20
"l:`:lWttes a dav f(~l. 111()1'(~ tll:lIl "0 J-CRI'S. `~r~aclleobt~oliclii:~~ clearance
"W. 011 the, a~leragc. sjpific:~~~tly `( 1'<0.02) SloweI~ in the snlokers
   ~!I<L(l2fi o--;:j-. ~~ .r,                                        51


t,han in the nonsmokers. Although the basic rate of mucociliary trans.
port may be constitutionally determined, it is evident that cigarette.
smoking decreases the etrecctiveness of this physiologic mechanism.

The regional deposition of inhaled aerosols in man was studied by
Lippmann, et al. (SO), who used a monodisperse ferric oxide aerosol
tapgcd with a radioisotope. Partic.les were deposited in the pharynx,
trachea. bronchi, and alveoli. Measurements were made in 65 adults
including 14 nonsmokers, 2!1 current cigarette smokers. six elderly
bronchitic patients, and one young asthmatic. Larger particles Were
deposited in the upper airways by turbulent, precipitation with only
the small particles of 011~' to five micron size reaching the lower air-
ways. The cigarette smokers. bronchitics. and the asthmatic had a
higher proportion of palticlrs deposited in the tracheobronchial area
than nonsmokers. ,is a result, fewer particles reached the alveoli in
these patients. These findings may be the result of a decrease in the
diameter of the small bronchioles due to inflammation, mucus, or
bronchoconstriction.

hlbert.. et al. (3) studied the effects of cigarette smoking on the
kinetics of bronc.hial clearance in a group of volunteers most of whom
also participated in the previous study. X two-phase clearance pattern
was described for many subjects. The first, a short, rapid clearance
phase, was completed within a few hours and probably represented
cle.arance of the upper airways. The second phase varied in durat.ion
from a few hours to 1 dal: and represented clearance of particles
deposited in the distal portions of the bronchial tree. The average
clearance time was 126 minutes in 18 nonsmokers, 170 minutes in 19 of
the smokers, and 288 minutes in the six patients with bronchitis, most
of whom hat1 been heal-y cigarette smokers for many years. Much vari-
ation in clearance rates was found among smoke.rs. Cigarette smoking
resultrtl in diminislletl pulmotlary clearance in the upper airways first.
-1s a result. mucus cleared from the lowr airways accumulated in the
larger airways where stasis occurred. In severe cases, stasis was more
generalized throughout the bronchial tree.

Snnchis, et al. (7'4) also studied lung cle,arance mechanisms in nine
adult, females who had smoked more. than 1.5 cigarettes a day fol..more
than 5 years a.nd who had no evidence of bronchitis or respiratory
disease. ,\ group of nonsmoking females matched for age served as
controls. A heterodisperse aerosol of 113' tagged human albumin was
inhaled by the volunteers. and measurements of radioactivity were
made over three crcscentic areas of the right lung which corresponded
to large ciliated airways. intrrrnrtliatr bronchi. and nonciliated periph-
eral airways and alveoli. (`igarcttt> snlokers exhibited a slowing of the
rapid c~lcarance phase of the la1.g~ ciliated airwl>-s and also a relative
acceleration in the swond c*le:irnnc~e pliasc resulting in an accuniula-
t,ion of activity at the hilar area. (`oml)aring the clearance among

52


smokers and nonsmokers, the authors found that the nonsmokers re-
tained tv,-ice as much activity in the lung at the end of 2-Z hours as did
the smokers. This finding resulted from the, deposition of much more
of the aerosol distal to the ciliated airways in nonsmokers t,han in
smokers suggesting that seemingly health\- smokers may have obstruc-
t.ion of the small airways.

Camne.r, et al. (II) examined the short-term effects of heavy cigar-
&e smoking on mucocilary transport using the ,same methods as in his
previous studies (10. /A?). The subjects weie 13 men aged ~27 to 38 1~110
had been habitual srnok(~rs for several )-cilrs. Raselinr clearance rates
\vere measured after refrainin p from cigarette smoking for 1 hour.
The subjects t.hen repented t.he test but were instructed to "chain smoke"
by inhaling the smoke as deeply and as frequent,ly as possible, but
Ivithout coughing. Subjects snlokcd much more intensely than under
normal circumst~ancrs. The speed of mucocilary transport was sig-
Iiificantly higher durin, (r intensive cigaret,te smoking than when tlley
nere not smoking (P<O.Ol). These results differ from the results of
odier investigat.ors. The effect of the deep regular inhalation patterns
used during the period of heavy- smoking on clearance rates remains
uncertain.

Studies in Animals

Rylander (7~) studied the effect, of cigaret,te smoke on the clearance
of radioactively tagged particles and viable bacteria in t.he lungs of
111 experimental and control guinea pigs. The cle.arance of particles
lllPasures mucus transport whereas the clearance of viable bacteria is a
Ilartial indicator of phagwyt.ic a.ct,ivitJ. Inhalation of smoke from
l.igarett,es \yith varying levels of "tar" resulted in similar decreases in
ibotb the mechanical and bactericidal clearance. In each case, t,he me-
~,hical clearance appeared to be affected earlier t.han t,he bactericidal
I'learance. Jvhen phenylmethyloxadiazole (PMO) was added to the
~~~~Mcc.o~ neither the mechanical nor bact.ericidal clearance was affected
`5' cigarette smoke.

1)alhamn and Ry1ande.r (14) also reported that phenylvinyloxadia-
zok (PVO) and phrn~lmethyloxadiazole. (I'MO) , when added to
`Ol)WCO, were effective in reducing the ciliotoxic effects of cigarette
-llloke in in viva c,at trachea. preparat.ions.

Phagocytosi.3

R!lander (7%) studied the effect of acute and chronic exposure to
I r:\Wte smoke 011 the numt>er* of alveolar ~~uxroplqges in the guinea
i"rI. .\cute exposure to t.he smoke of five or more cipatMes. re&ted in

53


a significant (P~0.05) reduction in the number of alveolar macro-
phages. With more prolonged exposure to c,igarette smoke, an increase
occurred in the number of alveolar macrophages over control values.

The effect of nitrogen dioxide (KO,), a compound found in cigar-
ette smoke, on alveolar macrophapes in rabbits was studied by Acton
and Myrvik (I). Phagoc-ytir: activity and virus-induced resistance to
rabbit.pox virus were suppressed by esposure to 15 p.p.m. of NO, over
a a-hour period.

Bacterial a,nd Mycological Xtudies

The prevalence of fungi in the t,hroat was examined by Martin, et al,
(567 in a populat.ion of 365 male and 103 female European patients in
South Africa who were hospitalized for a variety of conditions. Throat,
swabs were taken shortly after admission and plated on appropriate
culture media. The yeasts isolated were Rhodotorula mucilaginosa.
Torulopsis glabrata. and seven species of Candida. h seasonal varia-
tion in prevalence. was noted with a decline in the winter and with
peaks in t.he spring and summer. Smokers of more than 30 cigarettes a
da.y had a higher prevalence of pharyngeal fungi than nonsmokers or
those smoking less than this amount. So effect of age or disease category
on the prevalence of pharyqeal fungi was found.

The bact,erial flora in respiratory tree secretions obtained at bron-
rhoscopg from `20'i patients with chronic lung disease and 48 controls
were characterized by Dobisova, et al. in a study from Germany (15).
So relationship was found between smoking or severity of respiratory
symptoms and the composition of the bacterial flora. They also reported
that smokers comprised 84.6 percent of those with chronic cough hut
only 58.3 percent. of the cont,rols.

The effects of nitrogen dioxide and cigarette smoke. on t.he retention
of inhaled bacteria wcreinvrstig~ted by IIenry, et al. (52). Male goldw
hamsters were exposed to an wrosol of Kle.bsiclla prwumoniar follow-
ing exposure to SO? and/or cigarette smoke. AI control group was ex-
posed to the pathogen without pretreatment. .Icutc rxposurc to ritlwl
SO, or cigarette smoke rcslllted in an increased mortality and de-
c~reascd survival time from Iilebsirlla infections. E:sposuw to both NO:
and cigaret.te smoke reduced the rate of clearance. of viable bacterin
from thr lungs to a greater extent than exposure to either substance
alone, The increase in lethal effects of Klebsiella exposure may hare
rcslllted from inhibition of the mucociliar~ transport system or reduc-
tion of phagocytic cal)acity of the alveolar macrophages.

54


The Surfactant System

Finley and Ladman (80) measured pulmonary surfactant in ciga-
rette smokers and nonsmokers. The surfactant was recovered after en-
dobronchial lavage. The lipid cont.ent of surfactant in smokers and
nonsmoke.rs was qualitatively similar; however smokers had on t,he
average only 14.5 percent of the surfactant levels found in nonsmokers.
Their levels of su.rfact.ant returned promptly to levels found in non-
smokers following cessation of smoking. Cigaret.te smoking may re-
duce the quantity of surface a&\-e material lining the alveolar walls
through either decreased production, an increased removal, or a dilu,-
tion wit,h mucus from the airways.

Summary of Recent Nonneoplastic Bronchopulmonary
           Findings

In addition to the summary presented in the introduction of this
r,hapter, based on previous reports of the health consequences of smok-.
itig, the following statements are made to emphasize the recent develop-
ments in the field :

1. Epidemiological and clinical studies from several countries con-
firm that cigarette smoking by both men and women is associated
with an increased prevalence of respiratory symptoms and de-
creased pulmonary function compared to nonsmokers.
2. The regular use of filter cigarettes is associated with less cough
and sputum production compared with the regular use of non-
filter cigarettes.

3. Cigarette smoking in combination with certain occupational ex-
posures is associa.ted with a higher prevalence of respiratory
symptoms and COPD than is observed with either cigarette
smoking or occupational exposure alone. Byssinosis is found more
frequently in cotton mill employees who smoke cigarettes than
in nonsmoking workers.

-j. Recent autopsy studies confirm that pulmonary emphysema is
much more frequent and severe in cigarett