CHAPTER 1

       General Considerations,
Preparation of the Present Document,
     and Summary of the Report


GENERAL CONSIDERATIONS

The first major development in the modern history of the effects
of smoking on health occurred in 1950 with the publication of four
retrospective studies on smoking habits among lung cancer pa-
tients and among controls (1, 4, 6, 7). At that time, the question
was, "Are smokers more likely to get lung cancer than nonsmok-
ers?" Although some epidemiologists were satisfied that the an-
swer was in the affirmative, others turned for confirmation to
prospective studies in which the smoking habits of large popula-
tions were recorded and the populations followed to identify sub-
sequent mortality. The first report of Hammond and Horn in 1954
(Z), showed significantly elevated overall death rates for smokers
as compared to nonsmokers. This elevation in death rates, almost
entirely confined to those who smoked cigarettes, together with the
evidence for a gradient according to the amount smoked, changed
the question from one concerning only lung cancer to one concern-
ing overall death rates and from one concerning smoking to one
primarily concerned with cigarette smoking. In effect, the question
became, "Do cigarette smokers have higher overall death rates
than nonsmokers and smokers of pipes and cigars?"

With the publication of the later reports of the major prospec-
tive studies in the late 1950's and early 1960's, it became clear that
cigarette smokers had higher overall death rates than nonsmokers,
as well as higher death rates from a number of individual causes
of death. The question then became, "Why?"

When the Advisory Committee on Smoking and Health to the
Surgeon General was established in 1962, it undertook the evalua-
tion of the scientific evidence up to that time. The conclusion of the
Committee in its 1964 Report was that: "Cigarette smoking is a
health hazard of sufficient importance in the United States to war-
rant appropriate remedial action." Not only did the Committee
conclude that the evidence clearly showed that male cigarette
smokers do in fact have higher death rates than nonsmokers but
that the convergence of epidemiological, experimental, and path-
ological evidence also clearly indicated a cause-and-effect relation-
ship for several of the implicated diseases, particularly cancer of
the lung and chronic bronchitis. In several other important dis-
eases, the evidence on biomechanisms to explain epidemiological

3


associations was felt to be inadequate at that time to draw firm
conclusions about a cause-and-effect relationship.

Three and one-half years later, when The Health Consequences
of Smoking: A Public Health Service Review, 1967 was published,
the conclusions of the 1964 review were taken as a starting point,
and the nature of the task of interpreting the scientific evidence
was restated as follows :

1. How much mortality and excess disability are associated with
smoking?

2. How much of this early mortality and excess disability would
not have occurred if people had not taken up cigarette smoking?

3. How much of this early mortality and excess disability could
be averted by the cessation or-reduction of cigarette smoking?

4. What are the biomechanisms whereby these effects take place
and what are the critical factors in these mechanisms?

That and subsequent reviews in 1968 and 1969 have provided
some answers to these questions, particularly in summarizing the
evidence for various theories as to how cigarette smoking affects
the human organism to produce elevated disease and death rates.

At least five different processes have been suggested whereby
cigarette smokers experience higher mortality or morbidity rates
than do nonsmokers.

1. Cigarette smoking initiates a disease process by producing
progressive irreversible damage. In this case, the total effect would
be approximately proportional to the total accumulated dosage
experienced over the years. Cessation of smoking leaves impaired
function which does not improve appreciably but does not continue
to deteriorate from continued exposure to cigarette smoke. How-
ever, such function may deteriorate through aging or through
exposure to other harmful agents. It appears that such a relation-
ship probably exists for chronic obstructive lung disease and pos-
sibly for the development of atherosclerotic heart disease.

2. Cigarette smoking initiates a disease process with continual
repair and recovery until some critical point is reached at which
the process is no longer reversible. The total effect would therefore
be affected to some extent by accumulated exposure but would be
affected also by the level of contemporary smoking. Cessation of
smoking would result in a rapid reduction of risk provided the
critical level initiating an irreversible process has not been
reached. The evidence supports this kind of mechanism accounting
both for the high dose-response relationship in lung cancer and for
the reduction in risk from lung cancer among ex-smokers.

3. Cigarette smoking promotes a disease process either by
providing positive support to the development of a pathological
condition or by interfering with and diminishing the normal capa-

4


bility of the organism to cope with and defend against a disease
process. This may take place by promoting the development of a
subclinical disease to a clinically recognizable one, by promoting a
mild disease state t.o a more severe form, or by increasing fatality
rates of severe disease states. This type of mechanism could ac-
count for modestly increased mortality rates for a number of se-
vere diseases for which there is no evidence that cigarette smoking
itself has a role in initiating the disease. Some of the excess mor-
tality from infectious respiratory disease and from coronary heart
disease might take place through this kind of mechanism.

4. Cigarette smoking produces a set of temporary conditions
which increase the probability that a critical event will occur with
attendant disability and possibly fatal consequences. For example,
there is evidence to support the theory that each cigarette can pro-
duce a set of conditions which increase the probability of myocar-
dial damage through increased demand for oxygen at a time when
the suppy is diminished. Presumably, once the supply/demand im-
balance is alleviated, the probability of myocardial damage would
revert to its normal level. Cessation of smoking should have an
almost immediate effect of reducing the risk sharply for morbidity
or mortality produced through this mechanism.

5. Cigarette smoking may be artificially related to excess dis-
ability or death by way of a close association with some other con-
dition or exposure which is found at a high level in smokers, but
not in nonsmokers, and is itself responsible for the disease. The one
cause of death for which cigarette smokers have elevated death
rates that is generally interpreted in this way is cirrhosis of the
liver. Since most heavy consumers of alcoholic beverages are smok-
ers, and since alcohol consumption is an important part of the
process that produces cirrhosis of the liver, the high rate of cirrho-
sis among cigarette smokers is discounted as resulting from this
kind of artificial relationship. Some authors have proposed that
there may be genetic factors that link smoking and certain diseases
in this fashion. Obviously, the cessation of smoking would have no
effect on morbidity or mortality from diseases which are artificially
related to smoking.

These different ways in which cigarette smoking can be related
to elevated morbidity and mortality rates are important considera-
tions in attempting to estimate the potential public health benefits
of giving up smoking, For some types of relationship, there would
be no benefits ; for some, rather small benefits ; for some, substan-
tial benefits, taking place over a long period of time; and for
others, substantial benefits taking place rather rapidly.

During the past few years, a sharp reduction has taken place
in the cigarette smoking habits of the U.S. population. The Na-

5


tional Center for Health Statistics has recently published a com-
parison of smoking habits in the US. in 1955 and 1966 based on
two large scale household surveys (5). These showed a drop in
cigarette consumption in men under 55 years of age but no appre-
ciable change among those 55 or over. Among women, every age
group showed an increase in the eleven year period. A recent sur-
vey conducted for the National Clearinghouse for Smoking and
Health, based on a much smaller sample (approximately 5,000
interviews), was conducted in the Spring of 1970 (3) (table 1).
Even with the smaller number of cases, it is clear that a much
larger drop took place in the four years from 1966 to 1970 than
in the eleven years from 1955 to 1966. The drop extended to the
age group 55-64 among men, again with no appreciable drop
among men over age 65. For the first time, the increase in smok-
ing among women leveled off, or even dropped slightly among
women under 55. The increase among women over 55 was of a
lesser magnitude than previously observed.

TABLE I.-Percentage of Current Smokers of Cigarettes (regu-
larly or occasionally) by sex and age. U.S. Surveys: 1955 and
1966 (CPS-Current Population Surveys) and 1970 (NCSH-
Survey conducted for National Clearinghouse for Smoking &
Health) .I

                      Male                      Female
              CPS      CPS      NCSH       CPS      CPS     NCSH
ALW           1955      1966      1'970        1956      1966      1910

18-24 --__------ 53.0     48.3    247.0       33.3     34.7     231.1
25-34 ---------- 63.6     58.9     46.8       39.2     43.2     40.3
35-44 _---_-__-- 62.1     57.0     48.6       35.4     41.1     39.0
45-54 _-_-___--- 58.0     53.1     43.1       25.7     37.3     36.0
55-64 --~_---~-~ 45.8     46.2     37.4       13.4     23.0     24.3
65+ ----__-_-- 25.8     24.6     23.7       4.7      8.1     11.8
11955 survey based on approximately 46,000 persons; 1966 survey based on approximately
35,000 persons; 1970 survey based on approximately 5,000 persons.
2 Estimated.

With the massive changes in smoking behavior which have
taken place among adults in the past few years, largely as an
expression of the desire to protect health, changes should be ex-
pected in mortality rates among those groups which have experi-
enced the greatest reduction both in accumulated dosage and in
concurrent dosage. An analysis of U.S. mortality rates for 1970
and the years to follow will provide a very valuable addition to the
knowledge concerning the effects of smoking on death rates.

  PREPARATION OF THE PRESENT DOCUMENT
Following the publication of Smoking and Health-Report of
the Advisory Committee to the Surgeon General-in 1964, the fol-

6


lowing documents were published as reviews of the medical litera-
ture concerning the health consequences of smoking, as called for
by Public Law 89-92 :

1. The Health Consequences of Smoking, A Public Health Serv-
ice Review: 1967.

2. The Health Consequences of Smoking, 1968 Supplement to
the 1967 PHS Review.

3. The Health Consequences of Smoking, 1969 Supplement to
the 1967 PHS Review.

These documents reviewed the medical literature which had
been published since the original Surgeon General's Report. This
format of publishing a supplement to a supplement has become
unwieldy, particularly in the light of the lack of availability of the
previous reviews to the general public. Therefore, when Public
Law 91-222 was signed into law on April 1, 1970 calling for an
eighteen month interval between the last report and the new re-
port, the decision was made to review the entire field with em-
phasis on the most recent additions to the literature.

The National Clearinghouse for Smoking and Health has the
responsibility for continuous monitoring and compilation of the
medical literature on the health consequences of smoking. This is
accomplished through several mechanisms :

1. A scientific review corporation is on contract to extract arti-
cles on smoking and health from the medical and scientific litera-
ture of the world. This organization provides a semi-weekly acces-
sions list with abstracts and copies of the various articles. Trans-
lations are called for as needed. Articles of pertinence are identi-
fied by a series of code words and phrases.

2. The National Library of Medicine, through the Medlars sys-
tem, sends the National Clearinghouse for Smoking and Health a
monthly listing of articles in the smoking and health area. These
are reviewed, and pertinent articles are ordered.

3. Staff members keep up with the current contents of medical
and scientific literature and identify articles of pertinence.

Initial drafts of the present review were prepared by Clearing-
house staff and consultants who reviewed the previous reports and
identified those articles which have been important in the develop-
ment of knowledge in this field. These were abstracted and placed
into tabular form, and a draft text of the report was prepared.
The first drafts of the individual chapters were sent to experts
for review, criticism, and comment with respect to the articles re-
viewed, those articles not included, and conclusions. The drafts
were then revised on the basis of these comments and rewritten
until they met with general approval of the reviewers. The final

7


drafts were reviewed as a whole by the Director of the National
Clearinghouse for Smoking and Health, the Director of the Na-
tional Cancer Institute, the Director of the National Heart and
Lung Institute, the Director of the National Institute of Environ-
mental Health Sciences, and by six additional experts both within
and outside of the Public Health Service.

SUMMARY OF THE REPORT

CARDIOVASCULAR DISEASES

Comnary Heart Disease

1. Data from numerous prospective and retrospective studies
confirm the judgment that cigarette smoking is a significant risk
factor contributing to the development of coronary heart disease,
including fatal CHD and its most severe expression, sudden and
unexpected death. The risk of CHD incurred by smoking of pipes
and cigars is appreciably less than that incurred by cigarette
smokers.

2. Analysis of other factors associated with CHD (high serum
cholesterol, high blood pressure, and physical inactivity) show
that cigarette smoking operates independently of these other fac-
tors and can act jointly with certain of them to increase the risk
of CHD appreciably.

3. There is evidence that cigarette smoking may accelerate the
pathophysiological changes of pre-existing coronary heart disease
and therefore contributes to sudden death from CHD.
4. Autopsy studies suggest that cigarette smoking is associated
with a significant increase in atherosclerosis of the aorta and
coronary arteries.

5. The cessation of smoking is associated with the decreased
risk of death from CHD.

6. Experimental studies in animals and humans suggest that
cigarette smoking may contribute to the development of CHD and/
or its manifestations by one or more of the following mechanisms :

a. Cigarette smoking, by contributing to the release of catecho-
lamines, causes increased myocardial wall tension, contraction
velocity, and heart rate, and thereby increases the work of the
heart and the myocardial demand for oxygen and other
  nutrients.

b. Among individuals with coronary atherosclerosis, cigarette
smoking appears to create an imbalance between the increased
needs of the myocardium and an insufficient increase in cor-
onary blood flow and oxygenation.

c. Carboxyhemoglobin, formed from the inhaled carbon mon-


oxide, diminishes the availability of oxygen to the myocardium
and may also contribute to the development of atherosclerosis.
d. The impairment of pulmonary function caused by cigarette
smoking may contribute to arterial hypoxemia, thus reducing
the amount of oxygen available to the myocardium.
e. Cigarette smoking may cause an increase in platelet adhesive-
ness which might contribute to acute thrombus formation.

Summary Statement of Recent Additions to Knowledge Relating
Smoking and Coronary Heart Disease.-A number of epidemi-
ologic studies have provided additional evidence concerning ciga-
rette smoking as a significant risk factor in the development of
CHD. Experimental studies on animals have suggested that ciga-
rette smoking, particularly the absorbed nicotine and carbon mon-
oxide, contributes to the development of atherosclerosis.

Cerebrovascular Disease

1. Data from numerous prospective studies indicate that ciga-
rette smoking is associated with increased mortality from cere-
brovascular disease.

2. Experimental evidence concerning the relationship of smok-
ing and cerebrovascular disease is at present insufficient to allow
for conclusions concerning pathogenesis. However, some of the
pathophysiological considerations discussed concerning CHD may
also pertain to the relationship of smoking and CVD, particularly
cerebral infarction.

Nonsyphilitic Aortic Aneurys,m

Cigarette smoking has been observed to increase the risk of
dying from nonsyphilitic aortic aneurysm.

Peripheral Vascular Disease

1. Data from a number of retrospective studies have indicated
that cigarette smoking is a likely risk factor in the development
of peripheral vascular disease. Cigarette smoking also appears to
be a factor in the aggravation of peripheral vascular disease.
2. Cigarette smoking has been observed to alter peripheral blood
flow and peripheral vascular resistance.

CHRONIC OBSTRUCTIVE BRONCHOPULMONARY DISEASE

1. Cigarette smoking is the most important cause of chronic
obstructive bronchopulmonary disease in the United States. Ciga-
rette smoking increases the risk of dying from pulmonary emphy-
sema and chronic bronchitis. Cigarette smokers show an increased
prevalence of respiratory symptoms, including cough, sputum pro-

9


duction, and breathlessness, when compared with nonsmokers.
Ventilatory function is decreased in smokers when compared with
nonsmokers.

2. Cigarette smoking does not appear to be related to death
from bronchial asthma, although it may increase the frequency
and severity of asthmatic attacks in patients already suffering
from this disease.

3. The risk of developing or dying from COPD among pipe and/
or cigar smokers is probably higher than that among nonsmokers,
while clearly less than that among cigarette smokers.

4. Ex-cigarette smokers have lower death rates from COPD
than do continuing smokers. The cessation of cigarette smoking is
associated with improvement in ventilatory function and with a
decrease in pulmonary symptom prevalence.

5. Young, relatively asymptomatic, cigarette smokers show
measurably altered ventilatory function when compared with non-
smokers of the same age.

6. For the bulk of the population of the United States, the im-
portance of cigarette smoking as a cause of COPD is much greater
than that of atmospheric pollution or occupational exposure. How-
ever, exposure to excessive atmospheric pollution or dusty occu-
pational materials and cigarette smoking may act jointly to pro-
duce greater COPD morbidity and mortality.

7. The results of experiments in both animals and humans have
demonstrated that the inhalation of cigarette smoke is associated
with acute and chronic changes in ventilatory function and pul-
monary histology. Cigarette smoking has been shown to alter the
mechanism of pulmonary clearance and adversely affect ciliary
function.

8. Pathological studies have shown that cigarette smokers who
die of diseases other than COPD have histologic changes charac-
teristic of COPD in the bronchial tree and pulmonary parenchyma
more frequently than do nonsmokers.

9. Respiratory infections are more prevalent and severe among
cigarette smokers, particularly heavy smokers, than among
nonsmokers.

10. Cigarette smokers appear to develop postoperative pul-
monary complications more frequently than nonsmokers.
Sunzmal'y Statement of Recent Additions of Knowledge Relat-
kg to Chronic Obstructive n,,onchopul??zonar!! Disease.-Studies
have demonstrated that cigarette smokers show increased symp-
toms and pulmonary dysfunction as well as mortality from COPD
when compared to nonsmokers. Investigations of alpha,-antitryp-
sin deficiency in relationship to pulmonary emphysema have sug-

10


gested that cigarette smoking may act jointly with hereditary fac-
tors in the pathogenesis of pulmonary emphysema. A pathological
study on animals has shown that long-term inhalation of cigarette
smoke produces lesions characteristic of pulmonary emphysema.

Lung Cancer.

CANCER

1. Epidemiological evidence derived from a number of prospec-
tive and retrospective studies, coupled with experimental and
pathological evidence, confirms the conclusion that cigarette smok-
ing is the main cause of lung cancer in men. These studies reveal
that the risk of developing lung cancer increases with the number
of cigarettes smoked per day, the duration of smoking, and earlier
initiation, and diminishes with cessation of smoking.

2. Cigarette smoking is a cause of lung cancer in women but
accounts for a smaller proportion of the cases than in men. The
mortality rates for women who smoke, although significantly
higher than for female nonsmokers, are lower than for men who
smoke. This difference may be at least partially attributable to
differences in exposures : the use of fewer cigarettes per day, the
use of filtered and low "tar" cigarettes, and lower levels of inhala-
tion. Nevertheless, even when women are compared with men who
apparently have similar levels of exposure to cigarette smoke, the
mortality ratios appear to be lower in women.

3. The risk of developing lung cancer among pipe and/or cigar
smokers is higher than for nonsmokers but significantly lower
than for cigarette smokers.

4. The risk of developing lung cancer appears to be higher
among smokers who smoke high "tar" cigarettes, or smoke in such
a manner as to produce higher levels of "tar" in the inhaled
smoke.

5. Ex-cigarette smokers have significantly lower death rates for
lung cancer than continuing smokers. ,There is evidence to support
the view that cessation of smoking by large numbers of cigarette
smokers would be followed by lower lung cancer death rates.

6. Increased death rates from lung cancer have been observed
among urban populations when compared with populations from
rural environments. The evidence concerning the role of air pollu-
tion in the etiology of lung cancer is presently inconclusive. Fac-
tors such as occupational and smoking habit differences may also
contribute to the urban-rural difference observed. Detailed epi-
demiologic surveys have shown that the urban factor exerts a
small influence compared to the overriding effect of cigarette smok-
ing in the development of lung cancer.

11


`7. Certain occupational exposures have been found to be asso-
ciated with an increased risk of dying from lung cancer. Cigarette
smoking interacts with these exposures in the pathogenesis of lung
cancer so as to produce very much higher lung cancer death rates
in those cigarette smokers who are also exposed to such substances.

8. Experimental studies on animals utilizing skin painting,
tracheal instillation or implantation, and inhalation of cigarette
smoke or its component compounds, have confirmed the presence of
complete carcinogens as well as tumor initiators and promoters in
tobacco smoke. Lung cancer has been found in dogs exposed to the
inhalation of cigarette smoke over a period of more than 2 years.

Cancer of the Laqmx

1. Epidemiological, experimental, and pathological studies
support the conclusion that cigarette smoking is a significant fac-
tor in the causation of cancer of the larynx. The risk of develop-
ing laryngeal cancer among cigarette smokers as well as pipe and/
or cigar smokers is significantly higher than among nonsmokers.
The magnitude of the risk for pipe and cigar smokers is about the
same order as that for cigarette smokers, or possibly slightly
lower.

2. Experimental exposure to the passive inhalation of cigarette
smoke has been observed to produce premalignant and malignant
changes in the larynx of hamsters.

Oral Cancer

1. Epidemiological and experimental studies contribute to the
conclusion that smoking is a significant factor in the development
of cancer of the oral cavity and that pipe smoking, alone or in
conjunction with other forms of tobacco use, is causally related to
cancer of the lip.

2. Experimental studies suggest that tobacco extracts and to-
bacco smoke contain initiators and promoters of cancerous changes
in the oral cavity.

Cancer- of the Esophagus

1. Epidemiological studies have demonstrated that cigarette
smoking is associated with the development of cancer of the esoph-
agus. The risk of developing esophageal cancer among pipe and/
or cigar smokers is greater than for nonsmokers and of about the
same order of magnitude as for cigarette smokers, or perhaps
slightly lower.

2. Epidemiological studies have also indicated an association
between esophageal cancer and alcohol consumption and that alco-
hol consumption may interact with cigarette smoking. This com-

12


bination of exposures is associated with especially high rates of
cancer of the esophagus.
Cancer of the Urinary Bladd,er and. Kidney

1. Epidemiological studies have demonstrated an association of
cigarette smoking with cancer of the urinary bladder among men.
The association of tobacco usage and cancer of the kidney is less
clear-cut.

2. Clinical and pathological studies have suggested that tobacco
smoking may be related to alterations in the metabolism of tryp-
tophan and may in this way contribute thereby to the development
of urinary tract cancer.

Cancer of the Pancreas

Epidemiological studies have suggested an association between
cigarette smoking and cancer of the pancreas. The significance of
the relationship is not clear at this time.

Summary Statement of Recent Additions of Knowledge Relating
Smoking and Cancer.-Epidemiological studies have confirmed that
cigarette smokers incur an increased risk of dying from lung can-
cer and that those smokers who switched to filter cigarettes incur
a lesser risk. Pathological studies have shown that cancer of the
lung and cancer of the larynx have been found in animals exposed
to the long-term inhalation of cigarette smoke.

SMOKING AND PREGNANCY

Maternal smoking during pregnancy exerts a retarding influence
on fetal growth as manifested by decreased infant birthweight and
an increased incidence of prematurity, defined by weight alone.
There is strong evidence to support the view that smoking mothers
have a significantly greater number of unsuccessful pregnancies
due to stillbirth and neonatal death as compared to nonsmoking
mothers. There is insufficient evidence to support a comparable
statement for abortions. The recently published Second Report of
the 1958 British Perinatal Mortality Survey, a carefully designed
and controlled prospective study involving large numbers of
Patients, adds further support to the conclusions.

PEPTICULCER

Cigarette smoking males have an increased prevalence of peptic
ulcer disease and a greater peptic ulcer mortality ratio. These
relationships are stronger for gastric ulcer than for duodenal
ulcer. Smoking appears to reduce the effectiveness of standard
Peptic ulcer treatment and to slow the rate of ulcer healing.

13


TOBACCO AMBLYOPIA

Tobacco amblyopia is presently a rare disorder in the United
States. The evidence suggests that this disorder is related to nutri-
tional or idiopathic deficiencies in certain detoxification mecha-
nisms, particularly in handling the cyanide component of tobacco
smoke.

INTRODUCTION REFERENCES

(I ) DOLL, R., HILL, A. B., Smoking and carcinoma of the lung. Preliminary
  report. British Medical Journal 2: `739-748, September 23, 1950.
(2) HAMMOND, E. C., HORN, D. The relationship between human smoking
   habits and death rates. Journal of the American Medical Association
   155: 1316-1328, August 7, 1954.

(3) HORN, D. Address given at National Conference on Smoking and Health,
   San Diego, Calif., September 9-11, 1970. 13 pp.
(4) LEVIN, M. L., GOLDSTEIN, H., GERHARDT, P. R. Cancer and tobacco smok-
   ing.  A preliminary report. Journal of the American Medical Asso-
   ciation 143(4) : 336-338, May 27, 1950.
(5) NATIONAL CENTER FOR HEALTH STATISTICS. Changes in cigarette smoking
  habits between 1955 and 1966. U.S. Department of Health, Education,
   and Welfare, April 1970. 33 pp.

(6) SCHREK, R., BAKER, L. A., BALLARD, G. P., DOLGOFF, S. Tobacco smoking
   as an etiologic factor in disease.  I. Cancer.  Cancer Research 10:
   49-58, 1950.

(7) WYNDER, E. L., GRAHAM, E. A. Tobacco smoking as a possible etiologic
  factor in bronchiogenic carcinoma. A study of six hundred and eighty
   four proved cases.  Journal of the American Medical Association
   143(4) : 329-336, May 27, 1950.

14


CHAPTER 2

           Cardiovascular Diseases


Page
21
38
38
39
40

Introduction  ........................................
Epidemiological Studies. ..............................
  Coronary Heart Disease Mortality  .................
  Coronary Heart Disease Morbidity  .................
  Retrospective Studies. ............................
  The Interaction of Cigarette Smoking and Other CHD
    Risk Factors  ..................................
    Smoking and Serum Lipids  ...................
    Smoking and Hypertension. ...................
    Smoking and Physical Inactivity  ...............
    Smoking and Obesity  .........................
    Smoking and Electrocardiographic Abnormalities.
    Smoking and Heart Rate  .....................
The Effect of Cessation of Cigarette Smoking on Coronary
Heart Disease .....................................
The Constitutional Hypothesis  ........................
Autopsy Studies Relating Smoking, Atherosclerosis, and
SuddenCHDDeath  ................................
Experimental Studies Concerning the Relationship of
Coronary Heart Disease and Smoking  ................
  Cardiovascular Effects of Cigarette Smoke and
   Nicotine.. ....................................
  Coronary Blood Flow  ............................
  Cardiovascular Effects of Carbon Monoxide  .........
  Effects of Smoking on the Formation of Atherosclerotic
   Lesions .......................................
  The Effect of Smoking on Serum Lipid Levels  ........
  The Effect of Smoking on Thrombosis  ..............
  Other Areas of Investigation. .....................
Cerebrovascular Disease  .............................
Nonsyphilitic Aortic Aneurysm  ........................
Peripheral Arteriosclerosis  ...........................
  Experimental Evidence. ..........................
Thromboangiitis Obliterans ...........................
Summary and Conclusions  ............................

40
41
41
41
43
47
47

47
48

52

56

56
58
59

63
65
66
66
66
67
72
73
73
74

17


  Coronary Heart Disease  ..........................
  Cerebrovascular Disease  ..........................
  Nonsyphilitic Aortic Aneurysm  ....................
  Peripheral Vascular Disease  ......................
References ..........................................

FIGURES

1. National Cooperative Pooling Project, Inter-Society Com-
  mission for Heart Disease Resources . . . . . . . . . . . . . . .
2. Risk of coronary heart disease (12 years) according to
  cigarette smoking habit and presence of "predisposing
   factors" (men 30-59 at entry). Framingham Heart
  Study..........................................
3. Estimated coronary heart disease death ratios in a 17-51
  year follow-up, and frequencies of paired combinations
  of six high-risk characteristics in college, for all ages
   at death  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4. Relationship between smoking status and serum choles-
  terol level at initial examination, and incidence of clin-
  ical coronary heart disease in men originally age 40-59
  free of definite CHD. Peoples Gas Light and Coke
  Company Study,1958-1962.......................
5. Average annual incidence of first myocardial infarction
  among men in relation to overall physical activity,
  class, and smoking habits (age-adjusted rates per
  1,000) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

LIST OF TABLES

(A indicates tables located in Appendix at end of Chapter)

1. Sudden death and acute mortality with first major
   coronary episodes . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Coronary heart disease mortality ratios related to
   smoking-prospective studies . . . . . . , . . . . . . . . . . .
3. Sudden death from coronary heart disease related to
   smoking.....................................
4. Coronary heart disease morbidity as related to
   smoking.....................................
5. Coronary heart disease morbidity as related to smok-
   ing-angina pectoris-prospective studies . . . . . . .
A 6. Coronary heart disease morbidity and mortality-
   retrospective studies . . . . . . . . . . . . . . . . . . . . . . . .
A 7. Differences in serum lipids between smokers and non-
    smokers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Page
74
75
75
75
75

23

24

25

43

44

23


26


30


32


37


93


98

18


LIST OF TABLES (CONT.)

(A indicates tables located in Appendix at end of Chapter)

A 8. Blood pressure differences between smokers and non-
    smokers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9. Death rates from coronary heart disease, by systolic
   blood pressure: ILWU mortality study, 1951-1961
10. Death rates from coronary heart disease, by diastolic
   blood pressure: ILWU mortality study, 1951-1961
11. Death rates from coronary heart disease, among hy-
   pertensives and nonhypertensives : ILWU mortality
    study, 1951-1961.............................
12. Death rates from coronary heart disease among men
   without abnormalities related to cardiopulmonary
    diseases by weight classification in 1951: ILWU
   mortality study, 1951-1961 . . . . . . . . . . . . . . . . . .
13. Death rates from coronary heart disease, by electro-
   cardiographic findings in 1951: ILWU mortality
    study, 1951-1961.............................
14. 1958 status with respect to heart rate, blood pressure,
    cigarette smoking, and ten-year mortality rates, by
    cause (1,329 men originally age 40-59 and free of
   definite coronary heart disease) Peoples Gas Com-
    pany Study,1958-1968.......................
15. The effect of the cessation of cigarette smoking on the
    incidence of CHD . . . . . . . . . . . . . . . . _...........
16. Annual probability of death from coronary heart dis-
    ease, in current and discontinued smokers, by age,
    maximum amount smoked, and age started smoking
A 17. Incidence of new coronary heart disease by smoking
    category and behavior type for men 39-49 years
    of age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
A 18. Incidence of new coronary heart disease by smoking
    category and behavior type for men 50-59 years
   of age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
19. Autopsy studies of atherosclerosis . . . . . . . . . . . . . . . .
A 20. Experiments concerning the effects of smoking and
    nicotine on animal cardiovascular function . . . . . .
A 21. Experiments concerning the effects of smoking and
    nicotine on the cardiovascular system of humans. .
-422. Experiments concerning the effect of nicotine or
    smoking on catecholamine levels . . . . . . . . . . . . . . .
x 23. Experiments concerning the atherogenic effect of
    nicotine administration, . . . . . . . . . . . . . . . . . . . . .

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42

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45

45

45

46

46

105

106
53


107


113


119


120



19


LIST OF TABLES (CONT.)

(A indicates tales located in Appendix at end of Chapter)

24. Experiments concerning the atherogenic effect of
    carbon monoxide exposure and hypoxia . . . . . . . . .
A 25. Experiments concerning the effect of smoking and
    nicotine upon blood lipids (Human Studies) . . . . . .
A 25a. Experiments concerning the effect of smoking and
    nicotine upon blood lipids (Animal Studies) . . . . . .
A 26. Experiments concerning the effect of carbon mon-
    oxide exposure upon blood lipids . . . . . . _ . . . . . . . .
A 27. Smoking and thrombosis . . . . . . . . . . . . . . . . . . . . . . . .
28. Deaths from cerebrovascular disease related to
    smoking.....................................
29. Deaths from nonsyphilitic aortic aneurysm related to
    smoking-prospective studies . . . . . . . . . . . . . . . . . .
A 30. Experiments concerning the effect of nicotine and
   smoking upon the peripheral vascular system . . . .

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64

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127

129
130

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20


INTRODUCTION

Coronary Heart Disease (CHD) cuts short the lives of many
men in the Western World in their prime productive years. More
Americans die from heart disease than from any other disease. In
196'7, in this country, a total of 345,154 men and 227,999 women
were classified as dying of arteriosclerotic heart disease (ASHD)
(196)) a category which consists largely of what is commonly
called CHD. During the years from 1950 to 1967, the age-adjusted
death rate from ASHD increased 15.1 percent (196, 197).

Besides the many deaths attributed to CHD, much morbidity
results from this disease. The National Health Examination Sur-
vey of 1960-1962 estimated that 3.1 million American adults, ages
18 to 79, had definite CHD and 2.4 million had suspect CHD,
togethes representing about 5 percent of the population. It was
further estimated that of Americans under age 65, almost 1.8 mil-
lion had definite CHD and 1.6 million had suspect CHD (195).

`There are several manifestations of CHD, all related in part to
the basic process of severe atherosclerosis, a disease of arteries in
which fatty materials (lipids) accumulate in the form of plaques
in the walls of medium and large arteries. This process, as it occurs
in the coronary arteries, leads to stiffening of the wall and narrow-
ing of the lumen which, when severe, result in a diminution in the
blood supply to the cardiac muscle. Angina pectoris, a major mani-
festation of CHD, results from diminution in blood supply relative
to the needs of the myocardium. If the blood supply to a portion
of the myocardium is completely obstructed, due for example to the
formation of a thrombus at the site of atherosclerotic narrowing,
necrosis or death of a portion of heart muscle may occur. This
occurrence is known as a myocardial infarction. In many cases, a
disturbance of cardiac rhythm occurs at the time of thrombosis,
and the patient may die immediately. It is estimated that approxi-
mately 25 percent of patients suffering coronary artery occlusion
die within the first three hours following the occlusion (table 1)
(88). Not infrequently, sudden death occurs in patients with severe
coronary atherosclerosis but without a demonstrable arterial occlu-
sion. In these cases, it is thought that the meager blood flow to a
Portion of the myocardium becomes so diminished with respect to
cardiac needs as to lead to a fatal arrhythmia, as well as to, per-
haps, a myocardial infarction.

21


CIGARIEITE SMOKING(S) AT ENTRY-WITH CONTROL OF SERUM CHOLESTEROL (C) AND DIASTOLIC BLOOD PRESSURE (W-AND TEN YEAR INCIDENCE
AND MORTALITY RATES. 7,594 WHITE MALES AGE 30-59 AT ENTRY, POOLING PROJECT

RATE
PER 1.000
150-

FIRST MAJOR
CORONARY EVENT

RATE
PER 1,000
150-

ALL CHD DEATHS

82

loo-

92

loo-

            7 I    ,,_(_
                               1 ju
50-         45                                   50-
W-I                         ).
                      .i' (,
     20                                 '*a,,'
                                      (_
                                      '.1.
                                       /"
o-

RISK     NONE     S    C OR H S+C OR
FACTORS   OF 3    ONLY    ONLY   SSH

NUMBER 28      97      74     167
OF EVENTS

C+H   C+H           NONE     S
     +s            OF 3    ONLY

31      82             17      50

384     595           1,249    2,018    1,302    1,794     384     595

NUMBER   1,249    2,018    1,302   1.794
OF MEN

National Cooperative Pooling Project; smoking status at entry and IO-year age-adjusted rates per 1,000 men for first major coronary event (incling nonfatal MI.
fatal MI. and sudden death due to CHD) and any coronary death. U.S. white males age 30-59 at entry. Al! rates age.adjusted b
white male population 1960. Graphs present rates for noncigarette VS. cigarette smokers at entry wdh srmultaneous control o { IO-year age groups to the U.S.
                                                                  blood pressure and serum cho-

lesterol level. For this latter analysis, the following cutting points were used:
     (a) Cigarette smoking   S -any use at entry
     (b) Serum cholesterol C -   250 mg./dl.
     (c) Diastolic blood pressure H -   90 mm. Hg.
SOURCE: Inter-Society Commission for Heart Disease Resources. National Cooperative Pooling Project Data (88).

C OR H S+C    C+H    C+H
ONLY OR S-j-H         +s

41      90      12      42


FIGURE l-National Cooperative Pooling Project; smoking status at entry and IO-year age-adjusted rates per 1,000 men for
first major coronary event (includes nonfatal MI, fatal MI, and sudden death due to CHD) and any coronary death. U.S.
  white males age 30-59 at entry. All rates age-adjusted by 10 year age groups to the U.S. white male population 1960.
Graphs present rates for noncigarette vs. cigarette smokers at entry with simultaneous control of blood pressure and serum
cholesterol level. For this latter analysis, the following cutting points were used:
    (a) Cigarette smoking-S-any use at entry
    (b) Serum cholesterol-C-2250 mg./dl.
    (c) Diastolic blood pressure-H-290 mm. Hg.

SOURCE: Inter-Society Commission for Heart Disease Resources. National Cooperative Pooling Project Data (88).

TABLE l.-Szcldden death and acute mortality with first major coronary episodes

Author. year.   Number and
country,      type of
reference    population

Data
collection

Event

Number
of
events

Proportion per
1,000 events
(as calculated on
the basis of age-
adjusted rates)

Comment

Pooling
Project.
American
Heart
Association,
1970.
U.S.A.
(88).

7,594 males    Medical exam-  All first major coronary
males 30-59    ination and   episodes, nonfatal and fatal.     501        l,ooo.o
yem-s of age   follow-up.   Sudden death (death
at entry.               within 3 hours of onset
Ten-year               of acute illness).           123         245.5
experience.             All acute deaths with
                   first episodes.             166         329.3

Data from the Pooling Project, Council on
Epidemiology. American Heart Association.
a national cooperative project for pooling
data from the Albany civil servant. Chicago
Peoples Gas Co., Chicago Western Electric
Co., Framingham Community, Los Angela
civil servant, Minneapolis-St. Paul business
men,  and other prospective epidemiologic
studies of adult cardiovascular disease in the
United States.

SOURCE: Inter-Society Commission for Heart Disease Resources (88).
Representative references include: (54. 9L, 14.9. 177) and others listed as
6a-6k in Inter-Society Commission for Heart Disease Resources report.


,-









I -







I

CIGARETTE SMOKING:

0 NONE

>l PKG./DAY               196'

123

NONE             ANY ONE

12
9.7

PREDISPOSING FACTORS (CHOLESTEROL 3250, HYPERTENSION, DIABETES)
`SIGNIFICANTLY DIFFERENT FROM "NONSMOKER" P<.O5

FIGURE 2-Risk of coronary heart disease (12 years) according to cigarette
smoking habit and presence of "predisposing factors" (men 30-59 at entry).
Framingham Heart Study.

SOURCE: Kannel, W. B., et al. (94).

Numerous epidemiological studies have indicated that cigarette
smokers have increased mortality ratios for CHD ; that is, cigarette
smokers show significantly increased death rates compared with
nonsmokers (table 2). The risk incurred by cigarette smoking in-
creases with increasing dosage and, as measured by mortality
ratios, is more marked for men in the younger age groups, under
age 60, although the absolute increment in death rates experienced
by smokers over that of nonsmokers continues to increase with
increasing age. Table 2 lists the mortality ratios found in the major
studies. Certain of these studies, including those at Framingham,
Massachusetts, the He&h Insurance Plan of New York City
(HIP), and at Tecumseh, Michigan, have analyzed morbidity as
well as mortality from CHD and have indicated that the risk of
developing fatal and nonfatal CHD is greater among cigarette
smokers than among nonsmokers (tables 3 and 4). Conflicting
evidence has been published concerning the relationship of ciga-
rette smoking and the incidence of angina pectoris. While some

24


I







I


)



I


,



I



0







2


1



0

Cl#lrcttcr -A
No SC-M -6

    1.0   1.2   354
1.0           5Zk
mL
66    31   483

175 85   1112

Clsarttbr -A
M./JK<12.9 -6

20

    15       96
       1.3   122
10   279
fld
       153
391   469   289
978

Cigarettes -A
$3. BP 130+ -B

Cigarettes -A
Height <66 -B

1.5

2.4
i5i
140

2.0
9s
124

Cigarettes -A

Parent dead -9

1.6

No sport -A
Ht.,  %<lt.9 -B

No sport-A
$3. BP 130+ -B

No sport -A
Hctght<BB -B

No sport -A

Parent dead -6

Sp. BP 130+ -B

A- A+ A- Ai    A- A+ A- At
B- B- B+ 9+    B- B- B+ Bt

Ht.l'%<l2.9 -A
Height <68 --B

Ht./w<l2.9 -A
Pwcnt dead -Et

Sp. BP 130+ -A

Height<68 -B        3

Sys. BP 130+ -A

Parent dead -B

       2.5
     73
        69
1.4

3

3

Height<68 -A

Parent dead --B

1.6

A- A+ A- A+

B- E- S+ B+

      PRESENCE (+) OR ABSENCE (-) OF CHARACTERISTICS (1 w B)
Top numberr in ban me CHD decedents wth paired cambinatlonr of charactsrirtlcr: bottom numben,
control subjects with comblnrtiont.
`1.8= 354 x 175
   66   524

FIGURE S-Estimated coronary heart disease death ratios in a 17-51 year
follow-up, and frequencies of paired combinations of six high-risk charac-
teristics in college, for all ages at death.
SOURCE: Paffenbarger, R. S., et al. (1.46).

25