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
   microclreulation by direct visualization. Giomale Italian0 di Oardiologla
   1: 401-408, September-October 1971.

(9) BIRNSTINGL, M. A, BILIXSON, K., ,CHAKRABA~TI, B. K. The effect of short-
   term exposure to carbon monoxide on platelet stickiness. British Journal
   of Surgery 5S(ll) : F37-839, November 1971.
(IO) BOFDIK. F. Srdecni infarkt a koureni. (Myocardial infarction and smok-

*L t  , -
/'   --.ing@asopis Lekaru Ceskych llO(26) : 614-820, July 25,1971.
  (II) BVJBN~ S. W., ENSLFZN, K. Investigation of changes in clinical laboratory
L== tests related to aging and smoking. Aging and Human Development
       3( 1) : 95-101, February 1972.

(12) CASCTV, G., MAIUUCCINI, L., ZEDDA, S., CARTA, G. FUL(IILEWJ, G. Sulla
   frequenza delle cardiorasculopatie tra gli operai dell' industrla estrattiva

della sardegna. Sota II: Incidenza in rapport0 all'abitudine al fumo e
all'alcool. (On the incidence of cardiovascular disease among the workers
of the mining industry of Sardinia. Second communication : Incidence in
relation to habitual smoking and consumption of alcohol.) Rassegna

   - *edi? Sarda 71( Supplement 1) : lQl-200,1968.
m>J. C. Summary of major flndings of the Evans County cardlo
     vascular studies. Archives of Internal Medicine 128(6) : 887-339, De
      cember 1971.

24


(14) OASSU, J. C., HEYDEN, S., Baarxr., A. G., KAPLAN, B. H., Txaom!x%, H. A.,
   COBNONI, J. C., HAMES, C. G. Occupation and physical activity and coro-
   nary heart disease. archives of Internal Medicine 123(6) : !%?&%X$ De-
    cember 1971.

(15) CIAMPOLINI, E., DBINBOLI, R., RAVAIOLI, P. Azione de1 fumo di sigarette su
   aleuni parametrl de1 ricambio lipidico. (Action of cigarette smoking on
   several parameters of lipid metabolism.) Atti dell'Accademia dei
   Fisiocritici in Siena ; Sesione Medico-Fisica 17 : 47m, 1968.
    _ ----

(fG~-c'o~s~ocx,~. W. Fatal arteriosclerotic heart disease, water hardness at
   homeyand socioeconomic characteristics. American Journal of Epidemi-
   ology 94(l) : l-10, July 1971.

(17) E~TANDIA CANO, A., ESQUIVEL A~Iu, J., Jim CAMACHO, II., Fzazz
   SANTANDER, S., LEON MONTANEZ, E. Infarto juvenil de1 miocardio. (Myo-
   cardial infarction in the younger age groups.) Archives de1 Instituto de
   ardiologia de Mexico 41(Z) : 137-150, March-April 1971.
(18) FACCHINI, G., SEMEMRO, S., DI BIAS& G., TABARBONI, F., SPA~NOLQ D.,
   BUTORE, A., BONA~ITA,  E. Modificazioni nel soggetto anziano della
   reattivita al fumo di sigaretta : Ricerche sull'equilibrlo emocoagulativo e
   fibrinolitico e au1 circolo perlferico. (Modifications of the reactivity to
   cigarette smoke in old subjects: Research on the hemocoagulative and
   fibrlnolytic equilibrium and on the peripheral circulation.) Giornale di
  Gemlql lS( 10) : 77f+784,1972.
(19) EMNLEIB, M. Venous thrombosis in relation to cigarette smoking, physical
----%%%yTand seasonal factors. Milbank Memorial Fund Quarterly 5S(l,
   Part 2) : 123-141, January 1972.

(20) GIBBONS, G. F., MITROPOUI,OS, K. A. lnhibition of cholesterol biosynthesis
   by carbon monoxide : Accumulation of lanosterol and 24,25-dihydrolano-
   sterol. Biochemical Journal 127(l) : 3X-317, March 1972.
(21) GOLOVCHINEB, I. Y. Nekotoryye sotsial'nyye faktory zabolerayemosti infark-
   tom miodarda. (Some social factors in the incidence of myocardial in-
   farct.) Zdravookhranenie Rossiiskoi Federatsii 15(S) : 12-14, 1971.
(88) GORDON, T., Soamp; P., KANNEL, W. B. Section 27. Coronary heart disease,
   atherothrombotic brain infarction, intermittent claudication-a multi-
   variate analysis of some factors related to their incidence: The Fram-

and Cerebro-

   333-386, December 1971.
Ir4) HEISTAD, D. D ., WHEELER, R. C. Effect of carbon monoxide on reflex vase
   constriction in man. Journal of Applied Physiology 32( 1) : 7-11, January
   1972.

";) B~LLBERQ, K., WAYLAND. H., RICKART, A. I,., BINC, R. J. Studies on the
    coronary microcirculation by direct visualization. American Journal of
-:y 29 : 593697, May 1972.
`~2 Rxvnm, CASSEL, J. C., BARTEI., A., TYROLER, H. A., HAMES, C. G., COR-
    SoNI, J. C. Body weight. and cirgarettc smoking as risk factors. Archives
, -,,- edicine 128(6) : 915919, December 1971.
~,&$~-~YAMA, T. Smoking in relation to the death rates of 265,118 men and
    women in Japan. A report of five years of followup. Presented at the
   American Cancer Society's Fourteenth Science Writers' Seminar, Clear-
    water Beach, Florida, March 27,1972,15 pp.

25


(.?8) ISAAC. P. F., RAND, M. J. Cigarette smoking and plasma levels of nicotine.
   Nature 236( 5345) : 303-310, April 7,1972.
(29) ISACSSON, S. 0. \-enous oc8clusion I~lethgsmogral)h~ in 55year-old men. A
   population study in >ialmJ, Sweden. Acta Medica Scandinavica (Supple.
    ment 537) : 1972,62 pp.

(SO) JAKUBZEWSKA, R. Zawal serca u osob mlodych. (alyocardial infarction in
   young subjects.) Wiadomosci Lekarskie 22( 19) : 174&1752, October 1,
    1969.

(91) KAQAN, A., RHOAD, G. G., ZEEQEN, P. D., NICHAMAN, M. Z. Coronary heart
    disease among men of .Japanese ancestry in Hawaii. The Honolulu Heart
   Study. Israel .Journal of Medical Sciences 7( 12) : 157331577, December
    1971.

(32) KAPPEBT, A. Tobacco and diabetic anglopathy. Acta Diametologlca Latiua
    S( Supplement 1) : 429433, September 1971.
(39) KATTUS, A. A., JORGENSEN, C. R., WORWX, R. E., ALVARO, A. B. ST-segment
    depression with near-maximal exercise in detection of preclinical cor-
      ary heart disease. Circulation 44(4) : 5S5595, October 1971.
@jS2& ., ARA~ANI~, C., BLACXBVRN, H., VAN BUCHEM, F. S. P., BUZINA, Ft.,
-

   DJ~RDJEVIC, B. S., FIDANZA, E'., KARVONEN, M. J., MENOTTI, A., PUDDU, V.,
   TAYLOR, H. L. Probability of middle-aged men developing coronary heart
   disease in five years. Circulation 45(4) : 815-828, April 1972.
(35) KORNITZER, M., DEMEESTER, M., DELCOURT, R., BERNARD, R. Cardiopathies
   ischemiques dans une population d'employes de Bruxelles. Etude de la
    prevalence des cardiopathies ischemiques en fonction de la classe socio
   economique. (Ischemic heart disease in a Brussels bank clerk population.
    Study of the prevalence of ischemir heart diseases as a function of do-
    economic class.) Revue d'Epidemiologie, Medecine Sociale et Sante Pub-
    lique 19 (7) : 599-612, October-November 1971.
(46) KOR~ITZER, U., DEMEESTER, >I., DELCOURT, R., GOOMENS, A., BERNARD, R.
    Enquete cardio-vasculaire prospective dans une population s&ctionnPe.
    Resultats de l'enquete initiale. (Prospective cardiovascular studies in a
    selected population. Results of the initial study.) Acta Cardiologlca 26:
    286343, 1971.

(87) KORNITZER, M., DE~~EESTER, JI., J)EXOLI~, H. Enqutte dans une population
     d'employes. Relation des hnbitudes taljagiques avec d'autres parametres.
     (Investigation of a white-collar lnmulation. Relation of tobacco bahits
     to other parameters.) Bruselles Jlrdical 51 (10) : 687-691, Ortolwr 1971.
           ---
i p8) KOZAREVIC, D., PIRC, B., DAWBER. T. R., KAHN, H. A., ZUKEL, W. J. Prev-
     alence and incidence of coronary disease in a population study. The
     Yugoslavia Cardiovascular Disease Study. dournal of Chronic Diseases
     24(7/S) : 495-505, September 1971.

(39) KRADJIAX, R., Bow~.ks, I,. T., E~WAH~S, W. S. Peripheral arterial disease
     in (`eylon. Surge- 69( 4 ) : .523-525, Allril 1971.
(60) KUPKE, I. R. Biosynthesis of lipids in lterfused dog aorta and coronary
    artery. II. Incorporation of (2-V) acetate into lipids of two aortic
    layers and of the coronary artery under the influence of nicotine. .Journal
     of ~Iolecular and Cellular Cardiology -1(l) : 27-38, February 1972.
( iI) MATHES, I'., Rrva~. J. The effect of nicotine on regional blood ilow in the
    panine heart. Proceedings of the SfK+?ty for Experimental Biology and
     Medicine 13S(l) : 361-364, Clr?ober 1971.
        ..--
~L?ATs~BARA,`~~., SANO. T. Effect of cigarette smoking on human precapillary
    sphincfers. British .J~mrnal of l'harmacology 45( 1) : 13-20, May 1972.
(43) )hTURZYNSK-4-STRYJECKA, H., \f.IDOMSKA-CZEKaJSKA, T., RUPNIEWSKA, z.
    M. Wplyw palenia l)apierosow na lipernie l,o posilku tluszczowym. (The

26


;,I REECE. \V. 0.. Barr., R. A. Inhaled cigarette smoke and treadmill-esercised
   dogs. Archives of Environmental Health 2-i(4) : 262-270. Al)ril 1972.
  ROM~LO, I. Distribution of serum lilntls in Sorwrgiarl recruits. Acta Medica
   Scandinavica 190 (5) : 401-406, Sorember 1971.
;;  S~HIEVELBEIN, H.. EBERIIARDT, R. Cardiovascular actions of nicotine and
   smoking. ,Journal of the Sational (`ancer 1nstitut.e 4S(6) : 17X5-1794,
   June 1972.
;.;  SCHMAUSS, A. K., ARLT. I:. Jlorl)hologische Refunde, 1n)xtoperatire Kompli-
   kationen, T,rtalitiit ufld Liegedaurr nach Anilnitation vvtgen Durcliblut-
   ungsstiirungen. (Morphological findings. postoperative complications,
   mortality and duration of Iled rest folIoWing amlmtations occasioned by
   disorders of the peripheral circulation) Seitschrift fiir iirztliche Fort-
   bildung 64 (2) : &87, January 15,197O.
;r;  BcnW~~~~, I>., RICHARD, .J. I>., J,EI.LOIJCII, J., CLAUDE, J. R. Serum lipids,
   smoking and bodg t~uiltl. Studs of 7.972 actively empltr.vrd ~nales. Revue
  Furopwnnr d'Etudes (`liniqurs et I(iologiqurs 16 : 529536, l!)il.
  sll I'RTLEFF. I). Section `) -6. So~ue charactrristic-s related to the incidence of
   cardiovascular discnsc and death : Framinglmni Stud,v. IO-gear followul).
  Z)) : Kannel. W. B., Gordon, T. ( Editors ), The Fran~inglmn~ Study. d11
   ~t)iclrmiologic~nl Inrrstigation of ~`:trdic~rasculnr Insease. I.S. Del)art-
   tttent of Health, Education. and 1Velfarr. I'ublic IIralth Srrricr. Sational
  Ittstltutrs of Health. JVashington. I,.(`.. December 1970, 35 1~).
  Qn-GH. A, I'., SISGII. S. I'. C`oro~mry heart disease-some epidrmiologiral,
   cllJ)l(.al. and rlrctr(n ardioaral)hic obs~~rvations. .Journal of the, Associa-
  tion of l'hysicians of India 191 !+I : ti2!M35. Srl~tt~tnbrr 7971.

  effect of acute experiment of cigaalutte smoking on lipaemia following fat
  meal.) Polski Tugodnik Lekarski 25(T) : 251-253, February 16, 1970.
/ i$l MIYAI.AKI, AI. Studies on cerebral circulation bF the ultrasonic Doppler
  technique-with special reference tl) clinical al)l)lication of the technique.
  In: Meyer, J. S., Schade, J. I'. (Editors). Progress: in Rrain Research,
   Volume 35. Cerebral Blood Flovv, Amsterdam, Sethrrlands, Elserier Pub-
  lishing Co., 1972, 1~). 1-23.

i.7) ORLOVA, S. P. Some parallels between the blood roa_gulation activity and the
   condition of adrenrrgic and cholinerglc sFstrm of the organism. Teralwv-
   ticheskii Arkhir 43 : 5%4X, February 1971.
if;) PAFFENBARGER, R. S., Jr., \VISG, A. L. Chronic disease in former college
  students. XI. Early lnecursors of nonfatal stroke. American Journal of
  Epidemiology 94 ( 6) : 5'1.1-530. I)rc*rmllrr 1971.
i: I PANDET, JI. R. JI~ocardial infarction in Sel)al. Tntlian Heart .Journal 22t 2) :
   73-82, Al)ril 1970.

iq) PINCHERLE, G. Factors affecting thr mean serum chc)lesterol. .Journal of
  Chronic Diseases 2415) : L'S!~~!)`i. ;\ngust 1971.
)!,I I'rsN~y, F.. nKJ.%RDIX. J.. Dssoass~. R. l%rrr. .J. AI. Jluscnlar exercise
  during intoxication 11~ carl)on mclnosidr. .J()urnal of Applied Plissiologs
  31(4) : 5i3-575. 0ctol)er 1971.

;`)l PREUSS, E.-G., EDER, H. 'WELLER. I?. Risikofaktoren bei peripheren arteriel-
   len ~er~l~lussl~r:~J~kl~eiterl utltrrschieldliclie~i SchWcregrades. (Risk fac-
   tors in occlusive diseases of thr l~eril~l~rral arteries. of raving severity.)
   Zeitschrift fiir die gesamtr iinmre Jledizin und Ihre Grenzgebiete 25(10) :
   464468, May 15, 1970.

;I ) PUXSAR, S. Tulrakointi ja srl)elvaltimotauti. (Cigarette smoking and cor-
  onary heart disease.) Suomen Laakarilehti 26(1/2) : 27-32, Januam !A
   1973.

27


(63)

(64)

(65)

(66)

(67)

(68)

SMYTII. .I. .J.. .inw. H.. LAXGLEY. R. B. An epidemiological survey op
iwhaemic~ heart disease. Sew Zealand Medical .Journal 71 (X56) : 28+-?&$
May 1970.
STORCH, II., ENGELL~SS, I... KOHLER, H. Der Herzinfarkt im jiingeren
Legensalter. (Jlyocardial infarct in young people.) Deutsche Gesund.
heitswesen 26(34) : 1593-1600, August 1971.

Snlawms. D. S., RICHMOND, S.. WECIISLER, B. ,\I. Cigarette smoke: Effects
on lactate extraction in the presence of severe coronary atherosclerosis.
American Heart .Journal R"(4) : 45M67, October 1971.
T.S. PI-BLIC HEALTH SERVICE. The Health Consequences of Smoking. A
Public Health Service Review : 1967. U.S. Department of Health, Educa-
tion, and Welfare. Washington. Public Health Service Publication No.
1696, Revised .January 1968. `127 pp.

L'.S. PUBLIC HEALTH SERVICE. The IIealth Consequences of Smoking. 1968
Supplement to the 1967 Put~lic Health Service Review. U.S. Department
of Health, Education, and Welfare. Washington, Public Health Service
Publication 1696, 1968, 117 ltp.

U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking. 1969
&Supplement to the 1967 Public Health Service Review. U.S. Department of
Health. Education, and Welfare. Washington. Public Health Service
Publication 1696-2, 1969. 98 pp.

U.S. PC-BLIC HEALTH SERVICE. The Health Consequences of Smoking. A
Report of the Surgeon General : 19il. U.S. Department of Health, Educa-
tion, and Welfare. Washington, DHEW Publication So. (HYJI) 71-7513,
1971, 458 pp.

U.S. PUBLXC HEALTH SERVICE. The Health Consequences of Smoking. A
Report of the Surgeon General : 1972. U.S. Department of Health, Educa-
tion, and Welfare. Washington, DHEW Publication So. (HSM) 72-6516,
197%. 158 pp.

U.S. PUBLIC HEALTH SERVICE. Smoking and Health. Report of the Advisory
Committee to the Rurgeou General of the Public Health Service. Washing.
ton, U.S. Department of Health, Education, and Welfare, Public Health
Service Publication No. 1103. 1961. 387 pp.

VAN Bvcmbr, F. S. P.. DRION, E., WIGBOUT, JI., BOEBCHIETER, E. Het
voorkomen en de betekenis van een depressie van het ST-segment in het
elektrocardiogram bij mannen zonder andere rerschijnselen. Een 7-jarige
longitudinate studie (II). (The occurrence and the significance of a

28


  depression of the ST segment in the ECG of men free from other wmp-
  toms. A longitudinal study of 7 years (II) ,) Sederlands Tijdschrift voor
   Geneeskunde 114(X) : 320-331, February 21, 1970.
,691 VAN BUCHEM, F. S. P., DRION, E.. WIGBOTT. >I., BOGSCIIIETER. E., FRIM% J. R.
  Het voorkomen en de betekenis rau extrasrstolen en geleidingsstoornissen.
  Een 7-jarige longitudinale studie (I). (The occurrence and significance
   of extrasystoles and conduction tlisnrders. .4 longitudinal study over 7
  years (I). ) Kederlands Ti jdschrift voor Geneeskuudc 114 (7) : 281-286,
   February 14,197O.

170) VLAICU, R., MACAVEI, E., PATIU, I. Studio transversal ("cross-sectional")
  al presiunii arteriale si al lipidelor wrice la coronarieni fumatori si
  nefumatori. (Cross-sectional study of arterial pressure and serum lipids
  in coronary smokers and nonsmokers. ) Mediriua Iuterna 23 (8) : 925-930.
   August 1971.

71) VOQEL, J. A., GLESER. X -4. Effect of cnrbou monoxide on os.vgen transport
  during exercise. Journal of ;ipplied Ph,ysiology 32 (2) : 234-239. Fehruar~
   1972.

`7') VOGEL, J. A.. GLESER, JI. A., WHEELER, R. <`.. WHIT~EX, B. K. Carbon mon-
   oxide and physical work cal)ac'it:-. Awllives of Enrironmentat Health
X(3-, March 1972.
`:9) WEISE, N. S.  iparette smoking and arteriosclerosis obliterans : An epi-
  demiologic approach. American Journal of Epidemiology 95 (1) : 17-25,
   Januaq 1972.

74) WILBEBT, L. Xikotinkonsum und arterielle Verschlusskrankheit. (Nicotine
  consumption and arterial occlusive disease.) Nedizinische Klinik 66(36) :
   1190-1192, September 3,197l.

751 WELAY, R., DEPALMA. R. G.. HIJB.~Y. C'. H. 1,ate occlusion of aortofemoral
  bypass grafts: Influence of cigarette nnioking. Surgery 70(6) : 969-973.
   December 1971.

:h^) WYGOKINSKI, Z. Effects of tobacco smoking on certain parameters reflecting
  the condition of the circulatory system at rest and during exercise. Polish
  Medical Science and History Bulletin 14(2) : 73-76, Spril 1971.

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 cigarette smokers than in
nonsmokers.

:. Several recent investigations have confirmed that cigarette smok-
ing exerts adverse effects on pulmonary clearance and macro-
phage. funct,ion.

55


Bronchopulmonary References

(I) AGPON, J. D., MYBVIK, Q. 2;. Nitrogen dioxide effects on alveolar macro-
   phages. Archiv-es of Environmental Health 24(l) : 48-52, January 1972.
(2) AKQ~~N, S., Cizotixt$ H. Smoking and lung function measurements, Aeta
   Medica Turcica 8 (1) : 3444, 1971.

(3) ALBERT, R. E., LIPPMANN, M., PETERSON. H. T., Jr. The effects of cigaret.te
   smoking on the kinetics of bronchial clearance in humans and donkeys,
   In: Walton, W. H. (Editor). Inhaled Particles III. Proceedings of an
   International Symposium organized by the British Occupational Hygiene
   Society, London, Sept. 14-23, 1970. Surres. England. Unwin Brothers,
   Ltd.;-The Gresham Press, 1970, pp. 165182.

(4) AUERBACH,~~., Hallr~ox~, I;. C., GARFINKEL, L., BENANTE, 0. Relation of
:- -  smoking and age to emph.vsema. Whole-lung section study. New England
    Journal of Medicine 2% ( 16) : K%`!-857, Apr. 20,1972.
(5) BATAWI, M. -4. EL Health problems of industrial workers in Egypt. In-
    dustrial Medicine and Sllrgery 41(2) : 1323, February 1972.
(6) BECKLAKE, M. R., FOURNIER-MASSEY. G.. ROSSITER, C. E., MCDONALD, J. C.
    Lung function in chrysotile asbestos mine and mill workers of Quebec.
    Archives of Environmental Health 24(6) : 401409, June 19'72.
(7) BLORMKE, M., DEPSER, R., GR~~NTZIG, A., KOSCHORRECK, B.. STEIZER, 0.
    Uber Unterschiede in der HemLungenfunktion und Befindiichkeit bei
    Miinnern mit verschiedenen Rauchgewohnheiter. (On differences in the
    heart-and-lung function and feeling healthy in men with different smok-
    ing habits.) Zeitschrift fiir Praventivmedizin 14(4) : 235-242, July-
    August 1969.

(8) BOUHUYS, A., WOLFXON, R. I,.. HORNER, D. TV.. BRAIN, J. D., ZUGKIN, E.
   Byssinosis in cotton textile workers. Respiratory survey of a mill with
   rapid labor turnover. Annals of Internal Medicine 71(2) : 257-269, Au-
   gust 1969.

(9) BBOWNINQ, W. H. Deleteriotm effects of cigarette smoking and 100 percent
   oxygen on aircrew members in high-performance aircraft. Aerospace
   ,Medicine 41(l) : 3942, January 1970.

(10) CAMNER. P., PJIILIPSOX, K. Trachetrbronchial clearance in smoking-discord-
   ant twins. Archives of Fmvironmental Health 25(l) : 6963, July 1972.
(II) CAMNER, P., PHILIPSON, K., L\~~~~~~~~, T. Cigarette smoking in man. Short-
   term effect on mucociliary transport. Srchives of Environmental Health
    23(6) : 421426, December 1971.
(1.9) CAMNER, P.. PIIILIPSON, K., FRIBERG,  I,. Traclieol)roncbial clearance in
    twins. Srchives of Environmental Health W(2) : 82287, February 1972.
(IS) COUDRAY, P., SERISE. Jl., FREOUR, P. Recherche epidemiologique sur les
   bronchites rhroniques et Ies insufb.sances respiratoires. etude de pi+
    valence dans un echantillrm de femmes de 30 a 70 ans. (Epidemiologic
   study of chronic bronchiti?; and rrspirator~ insufficiency. Prevalence in
    a sample of women 30 to 70 years of age.) Revue de Tnberculose et de
   Pneumologie 33 (6) : iGDSi80, September-October 1969.
(24) DALHAMN, T., RYLAXDER. R. Reduction of cigarette smoke ciliotoxicitg ly
   certain tobacco additives, American Review of Respiratory Disease
    103(6) : 355-35i, June 1971.

(15) DOBISOVA, ,\I., TRXKA, L., FISEX, F., TOXASEK. A. Ahbiingigkeit der mikro-
    biellen Flora im Bronchh~lbaum van der Bronchialsrkretion und den
   hustens~mpttnnen bei chronisch Lungenkranken. (Dependence of the
   bronchial secretion and cough symptoms on the microbial flora in the

56


bronchial tree of chronic lung disease patients.) Praxis der Pneumologie
25(5) : 249-254, May 1971.

(16) EGLE, J. L. Single-breath retention of acetaldehgde in man. .4rchives of
   Environmental Health 23(6) : 427133, December 1971.
(17) ELLEFSEN, P., Tos, M. Goblet cells in the human trachea. Quantitative
   studies of a pathological biopsy material. Srchives of Otolar~ngologS
   95(6) : 517-555. *June 1972.

(18) EVANS, >I. a.. STEPHENJB, R. J.. CABRAL, I,. J., FREEMAN, G. Cell renewal
   in the lungs of rats exposed to low levels of SO?. Archives of Enriron-

  .-.  mental.He~lth 24 (3) : lt?&188, March 1972.
<(.I&) FINGERLA~~, 3, HUSAK. T.. BENDLOYA. J. Cflntribution to the inwstiga-
    tion of the effect of cigarette smoking. Shomik Vedeckych Praci Le-
   karskr FiIkUltS KarloTT University v Hradci Kralove 14(2) : 221-233,
     1971.

110) FINLEY, T. fi., LADA~AN, A. J. Low yield of pulmonan surfactant in Ciga-
   rette smokers. New England Journal of Medicine 286(5) : 223-227,
   Feb. 3, 1972.

ief) FOURNIER. E.. ZIVY, P. Poumon et tabae. (Lung and tobacco.) Poumon
   et le Coeur 26(H) : 1109-1125, 1970.

18) FREEDMAX, S., FLEWHEX, C. M., FIELD, G. B. Effects of smoking modified
   cigarettes on respiratory symptoms and vrntilatorr capacity. Journal
   of the National Cancer Institute 48(6) : 1805-1810, June 1972.
`2.7) FICEOUR, P., COUDRAY, P. Le probleme des bronchites chroniques a Bordeaux
   et en Gironde. Etudes epidemiologiques. (The problem of chronic bron-
   chitis at Bordeaux and at Gironde. Epidemiological studies.) Bordeaux
   Medical 3( ?h ) : 1745-1779, July-August 1970.
`24) G~LLI, V. Etude epidemiologique des bronchopathies non specifiques.
   (Epidemiological  study of nonspecific bronchopathies.) Branches
   a(5) : 313-330, September-October 1970.
`25) GOLLI, V., L'Influence de l'usage du tabac et de l'emoussi6rage sur la
   ftiquence des bronchites chroniques. (The effect of the use of tobacco
   and the inhalation of dust on the frequency of chronic bronchitis.) La
   Presse MCdicale 78: 1542-1543, July 2EcAug. 1, 1970.
`?6) GOLLI Jr. STEF.~NIN, E., ST.0, R.. TURNESCU, B. Etude sur la prevalence
       7 I
   actuelle de la bronchite chronique dans une population urbaine. (Study
   of current prevalence of chronic bronchitis in an urban population.)
   Acta Tuberculosea et Pneumologica Belgica 60(5) : 714-725, September-
    October 1969.

`?:) GRACZYK, J., BUKALSKA, Z. Przewlekle zapalenie oskrzeli i ocena
   \vSdolnosci oddechowej u ozdrowiencow z gruzlicy. (Chronic bronchitis
   and assessment of respiratory function in convalescents after tuber-
   culosis.) Gruzlica i Chorohy Pluc 39( 7) : 61W15, .July X971.
""I GREGORY, J. A study of 340 cases of chronic bronchitis. Archives of En-
   vironmental Health 22(4) : 42.%4%, April X971.
.`!`I 1IAaER. J.. HORVATII, R., KISHIXDI KISS, K., PAL, I., SI~ION. Z., ZIB~TWS, H.
   h dohanyzas es felso leguti hurut koroki szerepe a Pecsi szenbangaszok
   kronikns bronchitiseben. (Smoking and upper airway catarrh as factors
   causing chronic bronchitis in coal miners from the city of Pers.) Orvosi
   Hetilap 112(233) : 13441:&R, .June 6, 1971.
"" ~~AOERUP, L., LARSEX, &!I. Tobaksrygning og respiratoriskr syml?tomer i en
  Dansk populatiou. Fra 50 ars undersogelseu i Glostrup. (Tobacco smok-
  lflg and rwl)iratory symptoms in a Wtnish prqmhtion. From R .-X-year
   stlldy in Glostmlx) I'geskrift for Larger 1X3(27) : l~W2-1Xs(wi. Jnly 9.
   1971.

57


($1) HABRIE, T. R., MERCHAXT, J. A.. KILBC'RN, K. H., HAMILTON, J. D. Byssino-
    sis and respiratory diseases of cotton mill workers. Journal of Occupa-
     tional Medicine 14 (3) : 199296. March 1972.
(8.3) HENBY, M. C., SPANGLER, J., FINDLAY, J., EHRLICH, R. Effects of nitrogen
      dioxide and tobacco smoke on retention of inhaled bacteria. In: Wal-
     ton, W. H. (Editor). Inhaled Particles III. Proceedings of an Inter-
    national Symposium organized by the British Occupational Hygiene
     Society, London, Sept. 14-23, 1970. Surrey, England, Unwin Brothers,
     Ltd., The Gresham Press, .1970, pp. 527533.
($8) HUNTER, M. B. Symptomatology. In: Key, M. M., Kerr, L. E., Bundy, M.
     (Editors). Pulmonary Reactions to Coal Dust. A Review of U.S. Experi-
     ence, New York, Academic Press, 1971, pp. 57-69.
(84) H~TTEMAN, T., OSWALD, P., LODE, H., HVCKAUF, H. Veriinderungen der
     Lungenfunktion Jugendlicher als Folge langjiihrigen ZigareMenrau-
    chens. (Changes in pulmonary function of young people as a result of
     cigarette smoking over many years.) Deutsche Medizinische Wochen-
._-..- -.@h&ft 96 (46) : 1791-1793. Nov. 12, 1971.
( (35) INQBAM; R. H., Jr., O'CAIN. C. F. Frequency dependence of compliance in
`- ,---

    apparently healthy smokers versus nonsmokers. Bulletin de Physio-
   Pathologie Respiration 7 : 195-212, January-February 1971.
($6) JANCIK, E. Pneumopathies rhroniques non specifiques: Enquate epidemio-
   logique a Brno. Rapport prelminaire. (Chronic nonspecific lung diseases :
   Epidemiological investigation ; at Brno. Preliminary report.) Branches
   lS(2) : 185-199, Alarch-April 1969.

(37) JANCIK, E. Quelques don&es et correlations provenant dune Qtude epi-
    demilogique sur l'incidence des symptomes caracteristiques des maladies
    respiratoires chroniques non speciilques. (Some facts and correlations
    from an epidemiologic study on the incidence of symptoms character-
    istic to chronic nonspecfic lung diseases.) Revue de Tuberculose et de
    Pneumologie 34(5) : 749-752, July-August 1970.
(38) JANCIK, E.,  JANCIK-11~~. 11. Chronische unspezifische Lungenerkrankun-
    gen. (Chronic nonspecific I ung diseases. ) Praxis der Pneumologie vere-
    inigt mit "Der Tuberkulosrarzt" 2 6( 2) : 6981, February 1972.
($9) JONES, R., BOLDUC, P., REJU, L. Protection of rat bronchial epithelium
    against tobacco smoke. British 1Iedical Journal 2(5806) : 142-144, Apr.
    15, 1972.

(40) KEY, M. M., KERR, L. E., BXTNDY, >I. (Editors). Pulmonary Reactions to
   Coal Dust. .4 Review of U.S. Experience. Environmental Science Series.
   Sew York, Academic Prrss. 1971. 215 pp.

(41) KHOSLA, T. Indices of vmtilatory measurements, British Journal of Pre
   ventive and Social Jledirinc 25(4) : 203-209, Sorember 1971.
(@) KIRCHKNOPF, M., YOVAGO. 11. AZ idiilt. hiirghurut elofordulasa az Ozdi

   kohaszati iizemrk flnombrngrrmili dolgowi kiireben. (The incidence rate
   of chronic bronchitis among the precision calendering workers at the
   foundry of Ozd.) Orrosi Hetilal) llO( 44) : 258+2586, Nov. 2, 1969.
(4.3) KORNITZER, >I., DE~IEESTER, M. La symptomatologie respiratoire en epi+
    demiologio. Resultats de l'enquett~ effectuee dans une banque Bruxelloise.
    (Respiratory symlrtomatology in epidemiology. Results from a survey
   effected in a bank in Brussels.) Acta Tuberculosea et Pneumologica
   Belgica 61(5/6) : -iSl-566, September-December 1970.
(44) LAINHART. W. Y., MORGAN, \V. K. C. Extent and distribution of respira-
   tory effects. In: Key, 11. M., Kerr, L. E., Bundy. M. (Editors). Pulmonary
    Reactions to Coal Dust. A Review of U.S. ExlErience. New York. Aca-
   demic Press, 1971. B[J. 29-56.


145) LA~YGLASDS. .r. H. >I.. WALLACE. I\`. F. .\I., ~IxPSON, Jf. .I. f?. hSllkitiOII
   workers in Belfast. 2. Morbidity in men still at. work. British Journal of
    Industrial .\Iedicine %(3) : 217-25, .July 1971.
(4s) Law, S. L., HAXKISSOS, J. I,., BURGESS. D. B., O'BRIEX, R. Changes in
    rentilatory function in coal miners after a work shift. Archives of En-
    vironmental Health 24(3) : 26-208, March 1972.
I',;) LAPP. S. I,.. SEATOS, A., KAPL~S, K. C., HUSSAKEK, 11. R., MORG~S, TV. K. C.
   Pulmonaq- hemodynamics in s.vmptomatic coal miners. American Re-
   view of Respiratory Disease 104 (3) : 41s-LPO. September 1971.
($8) LATIMER, R. G., I)ICKM.~S. 11.. Dal-. I\`. c`.. GI-SS, JI. I,., SCIIJIIDT, f!. D.

7-enti1ator.v 1)attrms and 1mImonar.v wmplications after upper ahdomi-
nal surgery determined 1,s ltreoperative illlfl lmstolwratire computerized
spir0metr.v and 1110~~~ gas anal.vsis. American Journal of Surgery 122 i 5) :
622-632. Sorenlller 1971.

($9) LEE. D. H. K. Etiology. Iw: Key. 31. AI.. Kerr, I,. E., Bund~. AI. (Editors).
   Pu1monar.r Reactions to Coal Dust. A Review of U.S. Esperience. New
   Tork, Academic Press, 1971. 1)p. lS9-195.

(50) LIPPMANS, XI.. ALBERT. R. E.. PETERSOS, H. T., Jr. The regional deposition
    of inlialH1 aerosols in man. 171: Walton, W. II. (Editor), 1nh:~letl Par-
    ticles III. Proceedings of an International Sgtnl)nsium organized br the
    British OccuI~ational Hygiene Societ.v. Tmdrm. Sept. l&23. l!X'O. Surrey,
   England, Unwin Brothers, Ltd.. The Gresham Press, 1970. pp. 103-122.
(51) LOWE, C. R., KIIOSLA, T. Chronic bronchitis in es-coal miners working in
    the steel industry. British dournal of Industrial Medicine 29( 1) : 4%I9.
     1972.

(52) LYOSS, J. P., RYUER, R.. CAMPBELL. H., GOLWH. J. Pulmonary disabi1it.r in
    coal workers' pneumoconiosis. British Medical .Journal 1(5X02) : 713-
   716, Mar. 18, 1972.

(58) MCDONALD, J. c., BECKLAKE, 11. R.. FOURSIER-lIASSEY, G.. ROSSITER. C. E.
    Respiratory symptoms in chrysolite asbestos mine and mill workers of
    Quebec. Archives of Environmental Health 24(s) : 3W-363, Mar 1972.
(54) MCKERROW, (1. B., QCHILLIS~, R. S. F. A pilot enquiv- into bsssinosis in
    two cotton mills in the United States. Journal of the American Medical
   Association iii (12) : 85X+53, Sept. 23, 1961.
!s.i) JIANU, P.. DUMITRIU, >I., GIIISE, O., ConrasEscr. (`. (`ercetari el)idrmio-
   logice privind bronsita cronica la un lot din populatia generala a orasului
    Bucuresti. (Epidemiological studies on chronic bronchitis in a sample of
    the general population of Bucharest.) JIedicina Jnterna 22(!)1 : 1123-
    1134. September 1970.

(-56) ~IAKTIS. I'.. K~SAREK. D.. ZWI. S., Born, A. V.. K~ORSHOF, H. .T. The inci-
    dence of fungi in the throat. Mgcolmthologia et JIYcologia A%l)l)lic:ita 45
    (2) : 16~187, oet. 13, 1!)71.

(X' I J~A\~I~ESLEY-`~HO~~AS, I,. E.. HEALXY, I'., B.~RHY, D. II. Experimental hron-
    chitis in animals due to sullmur dioside and cigarette smol~e. An auto-
    mated quantitative studs. In: Walton. I\`. H. (Editor I Inhaled Particles
    III. Proceedings of an International S~ml)osium organized by the British
    ( Wupational Hygiene Society. I~~ndon. Sept. l-L-23, 1970. Surrey, Eng-
    land. J~nwin Brr)thers, I,ttl.. The Gresham Press. 1970. lq). 509526.
`.;h') lIERC'EI.4ST. J. Ai., IiII,HYRS. Ii. II., O'FALLOS. I\`. 31.. IhMILTOS. .J. D.,
    LU.\~SIXS. J. C. B.vssinosis and chronic Inwrmhitis amc)ilg cotton textile
    worlirrs. AtlllilIS of Internal Medicine X(3) : &X3--133. March 1972.
`.;9) lIlLLE:R. G. .J., i\SII(%OFT. 1I. T. A\ comnlunit~ surrf~y of rrsl)ir:rttrr~ disease
    among East Intlian ant1 .\friwn adults iii (:uay;)na. Thorax %( 3) : X31-
    338. Nay 1971.

59


(60) MITCHELL R. S.. MAISEL. J. C.. DART, G. A.. SILVEHS, G. TV. The nwura~p
    of the death certifiwte in reliorting cnusr of death in iIdllltS. with special
    reference to chronic bronchitis :tntl eml)hysema. American Review of
    ResDir;Story Disease 1M Cfi) : X+-X50, Dewmlwr 1971.
trill ;\IORGAN. 1V. K. C'., HVKQ~:SS. I). JS.. LAPP. N. I,.. SEATOS. A\.. REOER, R. R,
   Hyperlnflation of the lungs in NI:II miners. Thorax L%(J) : 5h.%590,
    Septemltier l!)Tl.

(62) NAEYE. R. J,. Structural features in Alq)alnchinn con1 workers, Zn: Key.
    AL. 11.. Kerr, I,. E., ~undy. 11. (Editors I. Pulmowr;\ Keartions to (`oal
    Dust. A Review of U.S. E:sl~erirnce. Sew York. Academic Press. 1971,
    -pp.93-110.

, (/C'S) NAEYE, R. I,., DELHSGER. `W'. S. Pulmonary nrtrrial ch::nges with z~pe and
-.

   smoking. Lirrhires of Pathology *`L(4) : 2X1-%%, October 1971.
(64) ~WSINSKI. 6.. .JANu~, 'l`.. MYSTIK, AI. Wystgwwanie l~rzemleklych nies-
    woistych choroh nkladu oddechowego (IJ.n.ch.u.r). ) wrod l~racownikoa
    zaklatlu przemgslu giDso\vego "Dolin? Uidv" w Gnckaclr. (Occurrence
                                 c- .
    of chronic unsI)ecific diseases of the resI)iratory sgstrm among workers
    in the plaster works at "Dolinn i%idy" in Garki.) Przeglad J,ekarski 2~
    (i) : 17C%SO. 1971.

(65) PANDE, pi. S.. MARW~I~A. R. K.. PATEL, N. .\I. Smoking :11x1 lung function.
    Indian I'rartitioner 1 (i) : 3.53-357, July 19il.
(66) RACOVEASU, C.. .\IANICATII)E. 11.. SICOLAESCI-. V. Cerwtari r~~idrniiologice
    :\supra I\ronxitei croniw in duoa zone f;lra l)olunre :ttmosferiw indus-
    trial& ( ElJidemiological study of chronic bronchitis in two regions with-
    out industrial air lwllutinn.) Studii si rerwtari dr .\Irdicin;t Interna
    X2(4) : 359-367.1971.

(67) REOAX, G. 31.. TAGQ. JL. \V.~LFORI), J.. THOMSOS. ,\I. J,. Thr relative imI)or-
    tance of ~liniral. radiological, and lmlmonnry function vurial)les in eral-
    rmting nsbestosis and chronic obstructive airway disrnsr in ;lsbestos
    workers. Clinic%1 Scienw -kl : 56~5%. 1971.

(68) REICHWI., G. Effect of air lrollution on the Prevalence of respiratory dis-
    PHSW in West (;erln;ln~. In: England. Il. 11. Beerr, W. T. (Editors).
    Proceedings of The Second Internatirrm~l (`lean Air Congress. Washing-
    ton, D.V.. Dw. e-11, 1970. Ac;tdemic Press. Sew York, 1971. 1~1~. l%-191.
(69) REICHEL. G., lT~~~~~. W. `I'., IKOS-OXIDES. S. 2. Einfliisse der Raucherge-
    wohnheiten auf die IIhdlgkeit unslwzifischer Atelii~~egserkr:lrikn!Igrn.
    III. Mitteilung. (Influence of smoking hal)its cm the inctidenre of non-
    sl)erific respiratory dist*nses.  III. (~ornmlunirntion.) Internntitmnlr
    Archir fiir Airlwitsnlrdizin 2i (l/2) : -i!biZ, Oct. 30, 1970.
(711) REID, D. D. Ilronc,hitis among the British. Israel .Journal of Medical
    Werices 7( 12) : l~i@L1572, December 1971.

(7'1) RIMIXGTOS, $1. Phlegm nrtd filters. Rritish Medical .Tournxl 2(58OS) :
    262-%A, Apr. ,"), 1972.
17.2) HYLASDEE. R. Free Iung cell studies in cigarette smoke inhalation es-
    lwriments. Scandinavian .Jwrn:ll of ReslJiratory Diseases 52(Z) : 1%
     12X. 1971.

(7.f) RYIASIJEH. R. J,r~ng (~l(~nr:~nc~e elf llarticles and bnvteria. ICffects of cigarette
    smoke eslJosure. Archirw of I*:nvirnnmental Health 23(C) : 321-326.
     ~S~~vemtwr 1!)71.

l?i I Sast 111s. .1.. Do~ovrcII. 11.. ('HALVERS, Ii., SEWIIOI~SE. 31. T. Regional
     tli*trilliltillll ;lntl lllnr 1~lt5ltxncv niwli:rnism~ in smnkvrs :ind nom
    winkers. 2~: Walton, W. 1-I. I Editor). Inlmled I'articles III. l'rweedings
    of an Interiinticbnal S.rmlwaium organized by the Uritish Occupntional

60


   Hygiene Society, London, Sept. 14-23, 1970. Surrey, England, Unwin
   Brothers, Ltd., The Gresham Press, 1970. pp. 183-191.
(75) SCHF~AG, P. E., GULLETT, A. D. Byssinosis in cotton textile mills. American
   Review of Respiratory Disease lOl(4) : 497-503, April 1970.
(76) SEATON, A., LAPP, N. L., MORGAP~, W'. K. C. Relationship of pulmonary
   impairment in simple coal workers' pneumoconiosis to type of radio-
   graphic opacity. British Journal of Industrial Medicine 29(l) : 50-55,
     1972.
(77) SHERWIN, R. P., DIBBLE, J., WEINER, J. Alveolar wall cells of the guinea
    pig. Increase in response to 2 p.p.m. nitrogen dioxide. Archives of En-
    vironmental Health 24 (1) : 4347, January 1972.
(78) SOBONYA, R. E.. KLEISERJIAN, J. Jlorl~hometric studies of bronchi in
   young smokers. American Review of Respiratory Disease 105(5) :
   768-775, Xay 1972.
(L?) STANESCU,II). C. Age and smoking dependency of the single-breath oxygen
  - - ---7--~

   test in health)- subjects. Pneumonologie l-IT(l) : 46-51, 1972.
(80) STEPHENS, R. J., FREE~~AX, G., EVASS, 11. J. Early response of lungs to
    low levels of nitrogen dioxide.  Archives of Environmental Health
    24 (3) : X0-179, March 1972.

(81) SYZGANOV, A. N., GOLO~I~, Y. A., TIWITSKAYA, T. G. 0 rliranii tabachnogo
    dyma pri kurenii na organr dgkhaniya v eksperimente. (Experiments
    on the influence of tobacco smoke on the respirators organs during
    smoking.) Eksperimental'naia  Khirurgiia i Anesteziologiia 16(6) :
    2326,1971.

(88) SZYMCZYKIEWICZ, K. E., KUSSKI, H., GIELEC, L. Clinical evaluation of the
   respiratory system in cotton workers. Bulletin of Polish Medical Science
   and History 13 (3) : 110-114, Juls 1970.

(83) TECULESCU, D. B. Validity, variabi1it.v. and reproducibility of single-
    breath total lung capacity determination in normal subjects. Bulletin
    de Phgsio-Pathologie Respiratoire 7 (3) : 645-658, IfaJ--June 1971.
(84) TF.CULESCU, D., STANESCU, D. Ventilatia si misica pulmonara la barbati
    tineri sanatosi, fumatori si nefumatori. (Pulmonary ventilation and
   distribution in young healthy males, smokers and nonsmokers.) Studdi
    si Cercetari de Medicina Interna 5 (11) : 419423,197O.
(85) TSUN~VSHI, Y., SHI~~IZU, T., TAKAHASHI, H., ICHINOS~~A, A., UEDA, M.,
  NAKAYAMA, N., YABLAGATA, Y., OHSHINO, A. Epidemiological study of
    chronic bronchitis with special reference to effect of air pollution.
    Internationales Archir fur Arbeitsmedizin 29 (1 j : l-27,1971.
(86) ULMEB, 1%`. T. Emphysema of the lung: Clinical and experimental investi-
   gations of its pathogenesis. Geriaterics : 25(5) :  161-165, 168-169,
-.zaay 1970.
($"W. T. Lung function studies in epidemiologic investigations of
    respiratory diseases. Bulletin  de Phxsio-Pathologie Respiratoire
   6 : 6&-616,1970.

(88) UL~WXR, W. T., REICHEL, G. Zur Epidemiologie der chronischen Bronchitis
   und deren Zusammenhang mit der Luftverschmutzung. (A contribution
    to the epidemologv of chronic t,ronchitis and to its relation to air
   pollution.) Deutsche Mrdizinsche Wochenschrift 95(51) : m9-2554,
    Dec. 18, 1970.

(89) ULRICII, L., ~~AI.IK, E. Chronic bronrhitis in agricultural and chemical
   workers. Arhir za Higijrnu Rada i Toksikologiju 21( 1) : 3.5-47, 1970.
'$0) U.S. DEPARTVENT OF 'TRANSPORTATION. $%X,ERAI. i\5'1,4TI(,S .~~)~~ISISTR.~TIO~.
   T!.s. I)bX'AliTlIEXl. OF Hs~1.1.11. I.:I,I~(~Al.IO~. AS,, \VEI.I.AK,:. Na',`I(,X,iI.
   INSTITI'T~: FOR Oc~cr~r.~l'~ox~r. SAFETY .4sn HEAI,TH. TIwltl, .\slwts of

61


(91)

(92)

(9.3)

(91)

(95)

(96)

(97)


(98)



(99)



( 100)

Smoking in Transport Aircraft. U.S. Department of Healt.11, Education,
and Welfare, Public Health Service. Health Services and Mental Health
Administration. Sational Institute for Occu]rational Safety and Health,
Rockville. Md., AD-73fOQ7. December 1971, 85 pp.
U.S. PUBLIC HEALTH SEWICE. Smoking and Health. Report of the Advisory
Committee to the Surgeon General of the Public Health Service. Wash-
ington, U.S. Department of Health, Education, and Welfare, Public
Health Service Publication So. 1103, 1X%, 387 pp.
U.S. PCBLIC HEALTH SEKVICE. The Health Consequences of Smoking. A
Public Health Service Review: 1967. U.S. Department of Health, Edn-
cation, and Welfare. Washington, Public Health Service Publication
No. 1696, Revised January lQ&S, 227 pp,
U.S. PGTBLIC HEALTH SERIICE. The Health Consequences of Smoking. 196s
Supplement to the lQ67 IW1lic Health Srrviee Review. U.S. Department
of Health, Education. and Welfare. Washington, Public Health Servire
Publication 16Q6, 196x, 117 pp.
U.S. PUBLIC HEALTII S.ERWE. The Health Consequtwws of Smoking. 1989
Supplement to the lQG7 Public Health Service Review. 1i.S. Department
of Health, Eduration. and Welfare. Washington. Public Health Service
Puhlicatinn lti!W-2, l!HiQ). QX iq1.
U.S. PUBLIC HEALTH Stxvrre. The Health Consequenc~es of Smoking. A
Report of the Surgeon General: lD71. U.S. Department of Health, Edu-
cation. and Welfare. Washington, DHEW Publication So. (HSJI) 71-
7513, 1X1, 458 pl1.
U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking. A
Report of the Surgeon General: 1072. U.S. Department of Health, Edu-
cation, and Welfare. Wasl1ington. DHE\V I'ul1liration So. t HSM) 7%
&5X, 1972, 153 pp.

VALIC, F., STAHCLJ~IC, 11. B. Kronicni hronhitis U pekara. (Chronic hrnn-
chitis in Ipakers.) Lijecnic~ki Vjesnik Q3t 7) : 7329-748, 1971.
VAN GAXSE, W. F., FERRIS. Ii. G.. *Jr., COTES. J. E. Cigarette smoking and
pulmonary diffusing c.aI)acity (transfer factor). American Review of
Respiratory Disease 105(I) : R&-41. ,January lQ72.
WALKER, D. D., ARCHEL~LD, 1~. JI., ATTFIELD, M. D. Brornhitis in men
employed in the coke industry. British dournal of Industrial Medicine
t's(4) : 358-363, O(toher 7Q71.

YOKOYAMA, K., PERA, Y.. Kor~snrrrc~. T.. MAT~UMOTO. T., SAGOSHI, S..
hsaar. T., SAKAI. II., Hrw.ina, K. 1IanSei kikanshien no ekigakuteki
kenkyu. (El1idemitdogical survey of cl~rtrnic l1ronehitis.) Ir.v11 24(2) :
10.5-114, Frlumary 1970.

ZI~Y, I'. I*% l1nenn1othon1 s spontanG dea fumrurs. 1.e l1ounion tal1nglclur.

Tabaglsme alveolaire et troubles metaholiques. (Sponta11eous pneumo-
thorax of sml1kers : t1)lM(Y'O lung : alveolar nicotinism a11d 111etaI)olic
disorders.) Revue de Tuherculose et de Pneumologie 34(l) : 125-153.
1970.

62


CHAPTER 3

Cancer


Contents

Page

Introduction-_-_-------------------------------- --------    67
LungCancer__-______________________________----------- 68
Epidemiological Studies- _ _ _ _ _ _ _ _ _ _ _ _ - _ _ _ _ _ _ _ _ _ - - - _ _ _ _ _    68
Es-Smokers_- -__________________ --- ___________ - _____    71
Uranium Mining and Exposure to Radioactivity.. _ - - - _ _ _ _ _    72
Air Pollution---------------------------------------- 72
Asbestos___-________-------------------------------- 73
Autopsy and Cytological Studies------- _____ --_-_-- _____    73
OralCancer------_--------------------- ____ ---- ____ ---_    74
Cancerof theEsophagus_-- _______ ---_- _____ ---_---__-___    76
Cancer of the Larynx------------------------------------    76
Cancer of the Pancreas------------------..---------------    77
Cancer of the Kidney and Urinary Bladder------------_----    77
Experimental Carcinogenesis-_---------------------------- 78
Respiratory Tract Carcinogenesti- _ - _ - _ _ _ _ _ _ _ _ _ _ _ _ _ - _ _ _ _    78
Experiments in Mice----- ____ ----_-- ____________-____    80
Aryl Hydrocarbon Hydroxylase (AHH)-- _ _ _ _ _ _ _ _ _ _ - - - - -    82
  Cell and Tissue Culture Studies- _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ - - - - -    84
Binding of Polycyclic Hydrocarbons to DNA and RNA- _ _ _    86
  N-Nitrosamines in Tobacco Smoke ____ - _ __ _ _ _ _ _ _ _ _ _ - - - - -    87
Yummary of Recent Cancer Findings-------------------w--    88
References---- _______ -_-__-- _____________-_____--------    88

List of Figures

Figure l.-Standardized lung cancer mortality ratios of
Jltpanese by number of cigarettes smoked (1966-70) _ _ _ - - - -    69
Figure 2.-Lung cancer mortality ratios of Japanese by age
at initiat,ion of cigarette smoking (1966-70)--_ _-_ _ _-_ _ _-- -    69
Figure S.-The survival of ex-smokers and cont,inuing smokers
who were treat*ed for a primary cancer of the oral cavity,
pharynx,orlarynx--- ______ ----___- ____ _______-_ ----    7.5

65


List of Tables

Page

Table l.-Age-standardized lung cancer death rates of British
physicians and the population of England and Wales at
various time periods-- ______ - _________ - _____ - _____ ---__    70
Table 2.-N-dimethylnitrosamine (DANA) content of con-
densates obtained from :several tobaccos grown in both
"high" and r`lo~v" nitrogen soils_-- ___________ -_--__-_-_-    87

66


Introduction

This introduction is a brief summary of the major relationships
between smoking and cancer which have been established in previous
reports on the health consequences of smoking (91, %`,93,94,95,96).

Cigarette smoking has been clearly identified as t,he major cause of
lung cancer in the United States. This conclusion is based on detailed
apidemiological, clinical, autopsy, and experimental data which have
accumulated over a period of more than 20 years. For both men and
women, the risk of developing lung cancer is directly related to total
exposure to cigaret,te smoke as measured by the number of cigarettes
smoked per day, the total lifetime number of cigarettes smoked, the
duration of smoking in years, the age at initiation of smoking, the
depth of inhalation of tobacco smoke, and the "tar" and nicotine levels
in the cigarettes smoked, Lung cancer death rates, however, are lower
for women than they are for men, a finding due, in part, to a difference
in exposure. Women smokers use fewer cigarettes a day, choose filtered
cigarettes with lower "tar" and nicotine values, and also tend to inhale
less. However, even when women experience comparable levels of ex-
posure to cigarette smoke as men, their mortality rates for lung c,ancer
still remain somewhat lower.

Those who stop smoking experience a decline in the risk of develop-
ing lung cancer relative to continuing smokers. The air pollution
commonly found in an urban setting appears to result in elevated lung
cancer death rates; however? t,his effect is relatively small compared to
the overriding effect of cigarette smoking.

Certain occupational exposures have been found to be associated
with an increased risk of dying from lung cancer. Cigarette smoking
interacts with many of these exposures to produce much higher death
rates from lung cancer than would result from one exposure alone.
Interact.ing exposure factors may be experienced simultaneously or at
different times. The uranium mining and asbestos industries are exam-
ples of occupations in which this interaction occurs.
The bronchial epithelium of smokers often shows premalignant
changes including squamous metaplasia, atypical squamous metaplasia,
ancl carcinoma in situ.

Pipe and/or cigar smokers experience a risk of developing lung
cancer that. is higher than the risk of nonsmokers; howrver. it remains

195~(128 O-73-6

67


significantly lower than the risk of cigarette smokers. A more complete
discussion of the risks from pipe and cigar smoking is found in
another chapter of this report.

Epidemiological, e,xperimental, and aut.opsy data have demonstrated
that cigarette smoking is a significant. fact,or in the development of
cancer of the larynx, oral cavity. esophagus? and urinary bladder.
B-naphthylamine, a carcinogen known to cause cancer of the urinary
bladder in humans! has been identified in cigarette smoke. There is also
an association bet,ween cigarette smoking and cancer of the pancreas.
Experimental studies with animals in which cigarette smoke or one of
its constituent compounds is administered in a variety of assays have
confirmed the presence of complete carcinogens, cocarcinogens such as
tumor initiators and tumor promoters. and tumor accelerators in
cigarette smoke.

Recently, additional epidemiological, autopsy, and experimental
studies have added bo our understanding of these relationships.

Lung Cancer

An ongoing prospective ep-idemiological study conducted in Japan
provides a unique opportunity to examine the relationship of cigarette
smoking to death rates in a populat.ion with genetic? dietary, and
other cultural differences from previously examined Western popula-
tions. Hirayama (37) has now reported 5-year followup data on
265,118 me.n and women aged 40 years and older. This represented 91 to
99 percent of the total populal-ion in the area of the 29 health districts
where the study was conducted. A total of 11,858 deaths occurred dur-
ing the 5-year period which included a total of 1,269,382 person-years
of observation. Both men anal women who smoked cigarettes expe,ri-
enced higher death rates from lung cancer than nonsmokers. Among
smokers, the lung cancer mortalitv ratio was 3.85 for men and 2.44 for
women as compared to nonsmokers (P<O.OOl) . Ijose-response relation-
ships were demonstrated for the number of cigarettes smoked per day
and the age at initiation of smoking (figs. 1 and 2). These mortality
ratios are considerably lower than those reported for the I'nitetl States.
(`anada. ant1 Great 13ritain3 and maI reflect a lower average number of
cigarettes smoked a day, au older age, at initiation of smoking. or re-
tluced inhalation of cigarette ,smoke among the Japanese. In spite of
thew tliffercnces. the overall wsults of this study. including the dose-
I'esponse relationsl~i~~s , arc similar to the results of all the other nlajor


rl~idemiological investigations. Thus, the reliabilit,y and accuracy of the
lnethods of population select,ion and analysis used in previous st.udies
based on population samples, and the conclusion that cigarette smok-
ing is t,he major cause of lung cancer are agaiu confirmed.

Figure 1 .-Standardized lung cancer mortality ratios of Japanese by number of
     cigarettes smoked (1966-1970).

9.0

8.0

7.0

6.0

5.0

4.0

3.0

L                            7.8

c            3.6

lJTzl-b
     1.0

2.0

1.0

0

          Non.
         smoker

SOURCE: Hlrayama, T. (37).

1-14     15-24    x4      Ex-
  cigarettes per day         smoker

Figure 2 .-Lung cancer mortality ratios of Japanese by age at initiation of
     cigarette smoking (1966-1970).

5.0

4.0

3.0

2.0

1.0

0

Non-      >25      ~24      <19
smoker       Age at initiation of smoking

SOURCE: Hirayama, T. (37).

69


TABLE 1 .-Age-standardized lung cancer death rates of British physicians
and the population of England and Wales at var';ous t,ime periods

Lung cancer standardized death rate per 1,ooO men per year in-

                                  Doctors        England and Wales
                            ---_I_-__ ---I_--__
Years ._........ . . . . . . .._.._......._..._ . . . . . ~... 19E3-57  19574  1961-65  1954-57  195W31  1962-65

Deathrateper 1,000._----- __... --_-. 1. 10 0.85 0.83 1.49 1.71   1. 88

Source: Doll, R., Pike, M. C. ifs).

Kennedy (45) studied primary lung cancer in 29 men and 11 women
diagnosed before the age of 40 and found a strong associat,ion between
cigarette smoking and the development of this disease.

Boucot, et al. (11) further characterized the 121 cases of lung
cancer detected in the population of the Philadelphia pulmonary
neoplasm research project,. The risk of developing lung cancer in-
creased with age, was higher in nonwhites than in whites, and increased
sharply with increased cigarette consumption.

The relationship between cigarett,e smoking and lung cancer was
investigated in a retrospective study by Ferrara (25) in La Plata,
Argentina. The smoking habi'ts of 144 lung cancer patients were con-
trasted with those of 386 controls. A dose-response relationship was
found between cigarette usage measured by the number of cigarettes
smoked per day and the duration of smoking and the risk of developing
lung cancer.

A high incidence of lung cancer is reported from the island of
Jersey in the Channel Isles compared to England and Wales. The
island has no heavy industry and only minimal levels of air pollution.

;i i-`i Cragg (16) studied 144 patients who developed lung cancer on Jersey
   during a 4-year study period. Only three nonsmokers were found
   among the 113 patients for whom histories were available.

Fingerland, et al. (.%`G) determined the prevalence of lung cancer
and certain other diseases in an autopsy series of 1,338 adults in
Czechoslovakia. Some 198 cases of primary lung cancer were identified.
In the autopsy population,, 1.4sercent of the nonsmokers? 14.1 percent
of those smoking less than ?f `I O&O00 lifetime cigarettes, and 33.3 pe.rcent
of those smoking more thaII 500,000 lifetime cigarettes had lung
cancer.           ?1 FL\
Rickard and Sampson (71) studied 94 Negro patients with lung

cancer in Washington, B.C.! and found that 57 (92 percent) of 63
patients whose smoking history was available were regular smokers.

Epidemiological studies conduct,ed in Italy (IO), Sweden (48),
Poland (46)) Russia (&), Cuba (73), Mexico (13), and the Nether-
lands (98) demonstrate an association between cigarette smoking and
lung cancer.

70


Berg, et al. (5) examined the incidence of recurrent primary cancers
following initial primary cancers of the respiratory and upper di-
gestive systems in Eew York. During 83,802 man-years of observation
in 9,415 patients with an initial squamous cell cancer, 518 second
cancers developed at other sites. Patients whose first primary cancer
was in the lung had an observed to expected relative risk ratio of 5.7
(P<O.O5) for- subsequent cancers of the respiratory or upper GI
system. Patients with the first cancer in the oral cavity or larynx
frequently developed a second cancer in the lung. Medical records
confirmed long smoking histories among almost all of these patients
do developed second cancers.

Cancer of the lung, oral cavity? larynx, and esophagus were reported
by Schmidt and De T,int (79) to be common causes of death among
6,578 men and wonwn who had received treatment for alcoholism in
Toronto. The. authors attributed this finding to the strong assocGa-
tion that, exists between alcohol and tobacco use and not to the effect of
alcohol alone.

Carcinoma of the trachea is a relatively rare condition with only
about 400 cases having been reported in thr literature. III a study of 41
patients with carcinoma of the trachea, Hajdu, et. al. (32) found an
apparent association bet.wectn cigarette smoking and the development
of epidermoid cancers of this structure.
An association betwern cigarette smoking and the development of
bronchiole-alveolar carcinoma in 71 pat ielrts w-as described by Delarue!
et al. (18).

Ex-smokers

Those who stop smoking experience a decline. in the risk of develop-
ing lung cancer relative to continuing smokers. Doll and Pike (-On")
i*onducted a study of the smoking habits and causes of death of 40,000
British physicians. Smoking habits were surveyed in 1951, 1957, and
l!KXi. I)urinp the study Iwriwl, II~OI`E than 3,;iOO physicians 1)ecanie ex-
~lokers. The a:re-stalltlar.dizrtl percentage of es-smokers anlong phy-
sicians 35 to 6-i years of age rose, from 18.1 percent in 1951 to "6.5 per-
wit in 19% and 29.5 I)ercent in l!Nti. (`oncurrently, the percentage of
physicians smoking vigawttcs fthll from 44.1 lwcrnt~ to 2~0 percent.
nhilr over t,he siinir Iwriotl estitimtrs of the per capita cigarWe con-
;mnption for the adult male Iwpulation in tbc 1-nited Kingdom sug-
Zrste(l a slight increase in cigarette con~unlI)tion. Over this l.i-year
period, the mortality f ronl lung caiicei~ among physicinnS dropped con-
5iclcrxMy while lung cancer dcatll rates among the male I)opulat.ion in
F:ngIantl and Wales incrcasetl to sonic extent (table 1 j. -ilthougIi ccr-

71


tnin limitations apply to the interpretations derived from secular data,
analysis of the study design and the magnitude of the results indi-
cate that, this stntly constitut-es important evidence of some of the bene.
tits t.hat result, f ram the cessation of cigaret.to smoking.

Epidemiological evidence supported by autopsy studies has estab-
lished that airborne radiation. particularly in synergistic combination
with cigarette smoking, is the major cause of the excess of respiratory
cancers among uranium miners.

Lundin, et al. (53) considered quantitative and temporal aspects
of radon daughter exposure and respiratory cancer in a report from the
Epidemiological Study of Tlnited States T-ranium Miners. They ob-
served a st,atistically signific,ant excess of respiratory cancer a1no11g
white uranium miners at each cnn~ulative radiation exposure category
down to and including 1204~9 WL1\I (working level months). The
authors noted that' although cigarette smoking alone entailed a risk of
the development of cancer o-f the respiratory tract, in miners just, as
it does in nonmincrs, cigarette smoking in combination with radon
daughter exposure appeared to result in an CVEII greater risk.

Several aut.hors (30,JJ. K?. 84. 104) continlle to report the presence
of polonium-210 or one of the thorium isotopes in tobacco leaf, tobacco
smoke, or the lungs of smokers.

Ah Pollution

Data standardized for cigarette smoking indicate the existence of an
urban factor in the development of lung cancer: it is likely that air pol-
lution, frequently part of tile city environment, is a component of the
urban fact.or.

The Kational .Icademy of >iciences published a revirw (61) of the
biolog.ical effects of utmospllrric pollution by 1)articulate polycyclir
organtc matter. Detailed epidcmiologicnl, exl)erimental, physical, and
chemical data were reviewed. It ~--as concluded that air pollution, as
commonly found in urhnn settings, was found to bc associated with in-
creased lung cancer mortality in cities. An examination of the data
presented, however, indicates that cigar&e smoking is, in most cases,
the overriding factor in the drvelopment of lung cancer. Polvcvclic
hydrocarbons and related com~)ounds which are known to cause`cancer
of the lung and other organs in experimental animals were found to

71


be present in relatively high concentrations in cigarette smoke, in large
quantities in the air of industries iu which workers have high-lung
cancer rates, and also in the air of urban communities.

Sterling and Pollack (86) reviewed the etiects of air pollution on
death rates from lung cancer. They suggested that particles resulting
from the combustion of organic fuels may br more strongly related to
the incidence of lung cancer in the population than cigarette smoking.
The cumulat,ed epidemiological data regarding cigarette smoking and
lung cancer were not. considered by the authors in this report.

Asbestos

Cigarette smoking asbestos workers havr markedly elevated lung
cancer death rates compared to nonsmoking asbestos workers. 1)err.y
(6) examined the combined effect of asljcsto-: exposure and smoking on
mortality from lung cancer among 1,400 nralr and 480 female asbestos
factory workers over a lo-year period. Tllerc was no significant in-
crease in lung cancer mortality among smoking or nonsmoking workers
with a low-to-moderate exposure to asbestos. However, among smokers
who had heavy exposure to asbestos, 32 lung cancer deaths occurred
among 663 men (9.8 expected), and there were 18 deaths among 292
women (1.4 expected). This confirms the greatly increa.sed risk of de-
veloping lung cancer among asbestos workers who smoke cigarettes.

Autopsy and Cytological Studies

The respiratory tract of cigarette smokers examined at, autopsy fre-
quently demonstrates cpithelial changes considered to be precursors of
bronchogenic carcinoma. Such changes include squamous metaplasia,
atypical squamous metaplasia, and carcinoma in situ. Herrold (35)
studied histologic types of prinlary lung cancer in 1T.S. veterans who
were subjects of the Darn study. Of a total of 2,241 white male vet-
erans who died of lung cancer over an 8-year pwiod. histologic mate-
rial was available for review in 1.177 patients. Histologic t.ypes were
grouped according to the Kreybcrg classification of Groups I and II
tumors. Group I tumors, rpidcrnloid and oat-cell carcirromas. were
prweiit, in Y7.3 pc>rccnt of the 5.; nonsmo1wrs and were prewnt in 57.1
percent of the li'2 "currout sn~ol~r~~s of cigarettes only." The ditferencr
We statisticbally signiticant (P<O.OOl). confirming tllc strong associa-
tion between (bigarrtte smoking and Iircyberg Groltl) I tumors.

73


Auerbach et al. (2) examined epithelial changes in the bronchial tree
of 456 men and 302 women who had died of a cancer other than lung
cancer. There were 72 ex-smokers among the men, all of whom had
smoked for 10 years or more but had quit smoking for at least 5 years
prior to deat,h. Atypical cells were present in 93.2 percent of the current
smokers, 6.0 percent of the ex-smokers, and 1.2 percent of the non-
smokers. Areas of epithelium composed entirely of atypical cells devoid
of cilia were found in the bronchial tree of 8 percent of the current
smokers, 0.2 percent of the ex-smokers, and none of the nonsmokers.
Unusual cells with disintegrating or fading nuclei were found exclu-
sively in 15 percent of the ex-smokers.

The prevalence of atypical cells (hyperplastic and metaplastic) in
the sputum of 122 male and 1.28 female lvorkers was examined by Rob-
bins (72). These smokers, all under the age of 19, were matched wit,h
a control group drawn from a population of college students. Atypical
cells were found in 14 percent of the smokers and 5 percent of the non-
smokers.

Oral Cancer

Data from the large Japanese prospective study by Hirayama (37)
indicate that mortality rates from cancer of the oral cavity among
males are higher in smokers than nonsmokers. A dose-response rela-
Gonship was demonstrated for the age at initiation of smoking. The
standardized mortality ratio among cigarette smokers \vas 10.0 for
men (PCO.001) and 1.22 for wonlen compared to nonsmokers. These
ratios are not stable due to the few deaths that occurred from oral can-
cer in this study.

Certain relationships be,tween cigarette smoking and cancer of the
oral cavity, pharynx, and larynx were investigated by Moore (59).
Over a IS-year period, 1,000 patients wit11 invasive squamous carci-
noma at these sites were treated in Kentucky. Of these patients, 208
had a history of cigarette smoking and had had no recurrence of
cancer for a period of ~3 years l)r more. This group was further divided
on the basis of current smoking habits. Of the 122 who continued to
smoke, -IS (10 percent) evcntllnlly de\-eloped a second cancer at. these
sites, whereas only five (6 percbent) of the 81 who stopped smoking de-
veloped a second maliplancy. This sixfold difference is statistically
significant (P<O.OOl). The survival curves for these two groups are
presented in figure 3.

74


Figure 3.-The survival of ex-smokers and continuing smokers who were treated
     for a primary cancer of the oral cavity, pharynx, or larynx.
  100

80

20

10

0

o---4 Ex-smokers
- Continuing Smokers

I                                       I

3    4    5    6    7    8    9    10    11   12    13

              Follow-Up (yr)

SOURCE: Moore, c. (591.

Martinez (57) studied the relationship between smoking in various
forms and cancer of the oral cavity in a retrospective study of 153
patients with this disease. Dose-response relationships were demon-
strated for the amount smoked; the amount of alcohol consumed, and
the development of cancer of the oral cavity.
Tyldesley (90) examined the prevalence of leukoplakia among 402
English coal miners of whom 280 smoked and chewed tobacco. Tobacco
chewing was commonly found to be a substitute for smoking in under-
ground conditions where smoking was impossible. Leukoplakia \vas
found in 3.6 percent of the chewers. whereas no leukoplakia was found
among the nonchewers.

Nelson and Ship (62) determined the relative influence of eight
variable fact.ors on the development of oral cancer in relation to age
at the onset of disease in a population of 191 patients with a confirmed
diagnosis of a primary squamous cell carcinoma of the oral cavity.
The factors considered included age, sex, race, consumption of alco-
1101 and tobacco, certain systemic diseases, and oral trauma. The
Prevalence of heavy tobacco use was more common among the younger
Patients. While 91 percent of the cancer patients under the age of 45
smoked more than 20 cigarettes a day. only 59 percent of the patients
orer 65 smoked this heavily.

75


Reverse smoking is a common practice in some parts of India,
rrhereby the light,ed end of a homemade cigar is held inside t,he mouth.
Pindborg, et al. (64) conducted an epidemiological survey of 10,169
villagers in the Srikakulam distric.t of south India and found that
43.8 percent of those interviewed practiced reverse smoking. Leuko.
plakia wan found in 8.8 percent of reverse smokers compared to 0.1
percent in nonsmokers. The 10 pat,ients found to have oral cancer
were all reverse smokers. Reddy, et al. (68) found t,hat reverse smoking
was practiced by 73 of 100 patients with oral cancer. Reddy, et al.
(66, 67) reported chara&eristic histologic findings of the oral cav$
in biopsies obtained from reverse smokers. In t,wo other studies fronl
India, changes in the ult,rast,ructure of the oral mucosa of chewers
(54) and smokers (65) are described.

Cancer of the Esophagus

In the Japanese prospective study, Hirayama (37) reported that
male smokers had a mortality ratio for cancer of the esophagus of
2.24 compared to nonsmokers (P<O.OOl). Martinez (57) studied the
relationship between smoking in various forms and the development
of cancer of the esophagus in a retrospective study of 179 patients.
Dose-response relat,ionships were demonstrated for the amount smoked
and alcohol consumpt.ion and the development of cancer of the
esophagus.

Cancer of the Larynx

The mortality ratios for cancer of the larynx in the large Japanese
prospective study were reported by Hirayama (37) to be 11.0 for male
cigarette smokers and !I.0 for female cigarette smokers compared to
nonsmokers ( P <O.OOl ) .
Stell (83) conducted :I retrospective study of 190 patients with

carcinoma of the larynx. Only 13 percent of the patients were non-
smokers or ex-smokers compared with 41 percent of the controls. The
relative risk ratio for heavy cigarette smokers ins 3.48 comparerl
to nonsmokers. The relative risk n-as 1.34 for smokers of pipes a~1
cigars.

Moore (.5,9) reported the occurwnre of second primary cancers in
203 smokers who had heen surgically treated for cancer of the oral
cavity. pharynx. or larynx, without recurrence for a period of 3 years.

76


Within an average followup period of 7 years, 40 percent of the 122
patients who continued to smoke develolwd second primary GLIKCI`S
of the upper respiratory or digwtivr tract, but only 6 percent of the
patients who stopped smoking developed second cancers. A total of
i0 patients wit11 cancer of the I;~rynx underwent laryngectomy. Of
the 16 who continued to snloke. tllree devcloprd a second cancer,
whereas none of the 3-& ex-smokers without a larynx derelolwd a
second primary malignamy.

Cancer of the Pancreas

Hirayama (37) reported a signiticant association between cigarette
smoking and the derelopnlent of cancer of the pancreas. The mortality
ratios were 2.05 (P<O.OOl) for 111en and 1.9 (l'<O.OS) for women.
Krain (47) reviewed a number of environmental factors that may
be associated with the 15 percent annual increase in the death rate
from cancer of the pancreas found in the I-nited States. The strongest
associations appeared to be with cigarette smoking and cert.ain
occupational exposures.

Cancer of the Kidney and Urinary Bladder

Hirayama (37) reported a mortality ratio of 2.71 for cancer of
the kidney and bladder in women who smoke cigarettes (P<O.OOl) .
The mortality ratio of 1.07 for men who smoked compared to non-
smoke,rs was not significant ; however, the few deaths from this cancer
among men in the Japanese study did not allow conclusions to be
drawn.

Hoover and Cole (39) examined the strength of the association
between cigarette smoking and the development of bladder cancer in
successive birth cohorts of men and women in the Vnitrd States,
Denmark, England, and Wales. Increasing rates of bladder cancer
tvere observed in populations characterized bv an increase in cigarette
smoking among successive birth cohorts. The association was con-
sistent in both men and Tomen, and was also consistent for different
uationalitirs and urban and rural groups. These findings suggest a
rausal role for cigarette smoking in the development. of bladder cancer.

In a retrospective study from Germany. Fischer (27) examined the
smoking habits of 18% men with bladder cancer and a control group of
1:M men who had benign prostatic hypertrophy. The relative risk

77


ratio was 6.4 for smokers of fewer than 15 cigarettes a day, and 27.5
for smokers using more than this amount. Only 3 percent of the rnen
with bladder cancer were nonsmokers.

Xipell (103) studied renal nodules in 250 patients in Australia w]le
came to autopsy. Benign adenonias were ,thc most common lesions
and were found in 22 percent of the patients. The remaining nodules
were cysts, thrombosed veins, abscesses, granulomas, and metastatie
lesions. A statistically significant difference between the smoking
habits of those with adenomas and those with the miscellaneous lesions
was reported (P<O.OU). All the adenomas were found in smokers.

Cole, et al. (14) conducted a retrospective study of 461 persons
with transitional or squamous cell carcinoma of the lower urinary
tract. After the dam \rere controlled for cigarette smoking, occupy.
tional exposure appe,ared to comribute t,o 18 percent of the lower
urinary tract cancer among men aged 20 to 80 compared to the 39
percent, attributed to cigarette smoking in men in a previous
report (1.5).

Werf-Messing and Kaalen (200) examined the association of
occupational exposure and smoking in the development of bladder
cancer in 346 males in the Netherlands who had this disease. The
smoking habits of cancer and control patients in each group were
nearly identical; however. patients \vith bladder cancer had a longer
exposure to hazardous \vorking conditions than did controls.

Experimental Carcinogenesis

Experimental studies, mainly in aninlals. have added to an under-
standing of many of the processes involved in tobacco carc.inogenesis.
Possible mechanisms of chemical carcillogenesis were reviewed by
Miller and JIiller (158), Ryser (7'6'). and Leone (51). Electron spin
resonance studies of carcinogenesis were reviewed by Smartz (87).
Franke (28) discusset the posible role of Ilydrophobic interactions
of polycyclic aromatic hydrocarbons with 7)rotein in chemical CRT-
cinogenesis. Chemiral carcinogencsis in Syrian hamsters was reviewed
by Shubik (89) and Hornburger (.?a).

Epidemiological, clinical, and autopsy data from studies of humans
have est,ablished c*ip:lrette smoking as the major cause of lung cancer
in the 7-nitcd States. One of the reasons it has not been possible to

78


,nlwacterize fully the mechanisms responsible for this causal relation-
&l) is the lack of an ideal animal nlodel in which to study respiratory
tract carcinogenesis in the laboratorg. Exposing animals to cigarette
woke in a closed chamber does not rrl)licate the kinds of exposure
waking humans receive, although some recently developed smoking
Awbers provide conditions similar to tlw c~sposure experienced by
human smokers. Many anhal .-j arc obligatory 11osr breathers and,
in them, a large portion of the particulate phase of cigarette smoke
~n;ly be removed bv turbulent ljrecipitation in the nasal ljassages or
hryis before rcncliiiig tlic sites in tlw lung ilrost coninionly exposed
in humans . ,1ucrbacb. et al. (.i) first dcliloilstl,:lt,etl tliat malignant
hng tunlors could be l)rodwetl in snlokill g clogs \VllO \vere taught to
snlokc through a tracheostoma. Scvcral inrc~stipators hart recently
rsr\uGned resl)irntorv tYilCt c~ilIYiIl(~g~lleSis in ;tilinuls using intra-
tr:~c~lle:~l instillations of cllrltlical c~rc~inoge~~s fo11nt1 in c~igarrttc smoke.
iwlnding benzo( a) pywie and ITH-dibenz (dg) carbazolc. Tumors
rtwilting from this type of trwltnwnt art frqurntly sinlilar to lung
t~111ors found in humans (24 .iJ. .1-J. .16. ;I';". 80).

Harris, et al. (03) examined the acute nlt.rastrlwtural efiects of
1wnzo (a ) pyrene carried on ferric oxide part,icles on the trachco-
t)rowhial rpithclium of the Svrian Golden Ilamster. Trsh substances
wre administered br intrntrache,ll instillation. Ferric oxide. alone
resulted in some f&al replacement of columnar epithelium wit.h
~)olygonal basal cells. This effert. was reversed by termination of the
treatment . After treatment with benzo (a) pyrene and ferric~ oxide.
fwal replacement of the columnar cells with pleomorphic ~11s oc-
wrred. These pleomorphic cells had t.he ultrastructural fe.atures of
:ttypical squamous ~11s and v-erc similar to thr hyperplastic tpithelial
~11s described in the bronchi of smoking do,? and the neoplastic
~~l~amous cells found in hlmlan lwonchogenic carcinoma.

111 an extension of this Ptudy, Harris? et al. ($2) reporte,d t.hat' vita-
Cl1 -1 deficiency or the application of benzo(a) pyrene-ferric. oxide
througl~ intratr~chcal instillation resulted in squamous met.apl:& of
the tl*acheil. I{otIl lesions appeared to he morphologically similar by
light n~icmxwq~~, but at the ultrastructural level significant differ-
ices were obser\-ed. Squnn~~~ nwtnplasia induced by lWllzo(a) py~-
rent-ferric oxide was c~haractrrizecl bv defects in thr basement,
~11embranc. enlarged nuclei witIr cytoplasnlic invaginat.ions, and
l~leonlorphic nucleoli not well following vitamin h deficiency.

Scllakumar and Shubik (80) treated Goldt~n Syrian hamsters with
\`mklv intratrachrul instillations of XI-dihenz(c.p) carbazolc (7H-
l)lN`j snsp~~~drd with q11a1 anloullts of ferric oxide in a saline solu-
h. 011~ gt`0tl1) of 3s llamsters 1va.s t.rented with 45 111g. of the
(`;lfGnopen :uld a sct~oiid group was trrated with 15 mp. JIore than
G pcrceilt. of the aiiinra15 in each group developed respiratory tract

79


tumors. Most of the tlumorr: occurred in the, major airways and were
squ:1*110us cell carcinomas -. Adenocarcinomas and annplastic. carcino,nas
were found less frequently.

Safiotti, et al. (77) examined t,he carcinogenic effects of henzo ( a~
pyrenc prepared as a slispension of fine crystalline part,icles at.
tached to ferric: oxide in a physiologic. saline solution and adminis.
tered by intratrnche.al applications to Syrian Golden hamsters, Vari.
ous concentrations of benzo( a) pyrenc and fe.rric oxide mere used iI,
single and multiple applications . A single administrat,ion of 3$.5 mgS
of benzo(a) pyrene with 12.5 mg. of ferric oxide resulted in five
bronchogenic carcinomas and five histologically benign respiratory
tumors in a total of 61 hamsters. Following multiple administrnt,io&
bronchogenic carcinomas including anaplastic and squamous cell tylRs
were induced in all dosage groups and a positive dose-response rela.
tionship was demonstrated.

Feron (24) studied reqkntory tract tumors in Syrian Golden
hamsters following tracheal instillations of furfural and/or benzo(a!
1)yrene. Of the 62 hamsters. 41 developed respiratory tract tumors of
which squamous cell carcinoma of the t,rachex was the most frequent
type observed. Furfural ir, combination with benzo (a) pyrene resulted
in :I liipher yield of tumors than was seen with benzo (a) pyrene alone.
Furfural alone possessed no carcinogenic activity.

Shabad (81) and one of his collaborators. Yanyshevn, produced
benigll and nlalignant epidrrmoid lung tunlors in rats following
single and nlnltiple administrations of bcnzo( a) pyrene by intra-
trachr>al instillation. Dose-response relationships were demonstrated.

Errperiments in Mice

Cigarette snloke condensate (CSC), various fractions of CSC? and
manly clwnlic*al coInpounds identified in CSC have been tested for
tunlorigvnic* ;lctiyity in mice. by a variety of nwthods, including skin
i):iinting and S11~JCllt~lleOll:` injections. complete mrcinogens and in-
cwiil)lcte 1.8 rcainogens. wl:icli include tumor initiators? tumor pro-
nwtew, and tmtlor ac~,*clerators llave been described. Several recent
studies lI:lve been conducted usin g mice as the experimental animal
which examine further the mechanisms involved in tobacco wrcino-
genesis.

IRC and O'SeilI (50) llwasnrrd the effect of duration and closnp(~
of lwnzo(n ) l)yrkbne applicntiolls on tllc rate of de\-elol)nlent of benip)
xnd nialig1Lant kin tiunors in niiw. The incidence rate for tuniol
fornlation \v:~s tlirectly proportional to both tinle and dose. TIRV
tl:lta caollforllled q"ite. c~lo:t~ly to l)o~tulatcd n~ntllen1:~tical models of
t11e rate of tllllwr dcwlop1llellt.

80


Davies and Whitehead (17) studied the effect of alt,ering the "tar?'
:uld nicotine ratio of cigarettes on experimental carcinogenesis. No
significant diEerence in tumor yield was found between condensates
obtained from the smoke of cigarettes containing 16.6 mg. "tar:: a,nd
1.75) mg. nicotine and other cigarettes containing 10.0 mg. "tar:' and
131 mg. nicotine.
Several st.udies by Bock, et al. (7? 8, 9) have examined t.he tumor
jwinotinp activity of a number of fractions of cigarett.e smoke con-
drusate (C'S(J). ,I number of subfractions of the neutral fraction
of (`SC were tested for tumor promoting activity in mice pretreated
\\ it11 i.l"-dinIcth?-lbenz (a) anthracene. as a tumor initiator (8). The
tnost polar subfractions and the fraction containing bcnzo(a)pyrene
were the lrlost actiw tumor promoting fractions. In anot1~e.r st,udy
(!,I, the weak acid fraction of CSC was found to be a very weak
complete carcinogen whiclL probably acts primarily as a tumor pro-
moting agent. The promoting activity depended primarily on the
non\-olatilv constituents of this frac.tion. More recently. Hock. et. al.
(7') reviewed the tumor promoting effects of CSC and extracts of
tobacco leaves. .I colubinntion of two subfractions of the tobacco ex-
tracts. as well as five major fractions of CSC, were found to have.
tul~lor pronioting activity. The fraction containing the polynuclear
aromatic hydrocarbons was found to be a complete carcinogen. Two
subfractions wew found to be strongly synergistic in their tumor pro-
lwting activity v-hen applied simultaneously to mouse skin.

Lszar, et al. (49) found that hydroquinone applied to mouse skin
in conjunction with the active fractions of CSC accelerated the early
histologic changes that result from the application of %ar" or its
fractions.

Van Duuren, et al. (97) have suggested that. "cocarcinogenesis'? be
different,iated from "tumor promotion" defining "cocarcinogenesis"
as the production of malignant tumors by two or more agents applied
simultaneously or alternately in single or repeated doses to mouse skin
and "tumor promotion" as a single t,reatment. with one agent followed
by single or repeat.ed treatment with il second agent. I-sing these
definitions, the authors found several tumor promoting agents to
pOSSess cocaminogenic activity.

Roe. et al. (74) studied mechanisms of mouse skin cwc%logcwsis
using benzo(a)pyrene and a neutral fraction of (1% applied sillgl?:
or in \-arious combinations with each other. Skin tumor incidcncc rates
increased \\-it11 the dose of applietl material for both the nelltr:tl frar-
tion ilild lpllzo(a) pvrclne. JIisturrb of the ll~~utl?ll frX(*tiOll IVith ~)~~lZO-
(a)pyrelle did not &St intl(~pendently in the production of ill:lligllant
skill tulllors but synergistically, supyesting tll:lt SOlllCb Of th(' (`01111)0-
upntfj of tile llp~ltral fr:lctioii act :lS c~ocarviiiogeils IXtll?~ tll;tll as (`0111-
i'lctecRrcinogcns.

Bl


Schmiihl (7'8) found a direct relationship between the dosage and
durat.ion of subcutaneous injections of tobacco smoke condensates ano
the development of sarcomas in rats.

Maenza, et al. (56) studied t.he effects of a combination of nic.ke]
subsulfide ( Ni3S2) and benzo(a)pyrene on sarcoma induction in rats.
The interval bet,wcen administrat,ion of the carcinogen and the de-
velopment. of sarcomas was significantly short,er (P<O.OOl) in male
Fischer rats given injections of a combination of 10 ,mg. of Ni,S, and
5 mg. of benzo( a)pyrene than in rats given eit.her ingredient alone.
There appeared to be a synergistic interaction between nickel com-
pounds and t.he polycyclic aromatic hydrocarbons.

Healey, et al. (34) added further refinements to a technique for
measuring the nonspecific e&erase activity of mouse skin following
applications of various chemical compounds. With few exceptions.
changes in e&erase activity reflected the known tumor producing
activity of a number of polycyc.lic hydrocarbons and tobaccc
condensates.

Sydnor, et al. (89) examined the effect of an aqueous extract. of
cigarette smoke condensate , on benzo (a) pyrene-induced sarcoma in
female Sprague-Dawley rats. Benzo (a)pyrene was injected subcu-
taneously in various concentrations of 12.5 pg. to 400 pg. per dose dis-
solved in sesame oil. Injections were given on alternate days foi
30 doses. The mea.n tumor induction time was accelerated in five 01
seven groups given the aqueous extract of CSC in their drinking
water. Animals given any benzo (a) pyre,ne eventually developed sar-
comas at the site of injection. Dose-response relationships were demon-
strated for the concent,ration of benzo( a) pyrene administered. It
appeared that aqueous extracts of CSC contained one or more corn-
ponents which functioned as cocarcinogens.

A~yl! Wydrocahm Hydrox~y74ue (,4aH)

Certain of the chemical conlpounds found in the gas and particulate
phase of cigarette smoke are. absorbed through the lung or oral cavity
into the general circulation. Possibly through such absorption some
chemical carcinogens are carried to target organs not directly exposed
to cigarette smoke. Some of these chemical compounds are probnbl!
excreted unchanged while others are nletabolized to various degree
by enzyme systems present in the 1ive.r and many other tissues. The
microsomal mixed-function oxidases are key enzyme systems for the
metabolisnl of a wide variety of chemical compounds including the


chemical carcinogens found in cigarette smoke. Aryl hydrocarbon
hydroxylase (AHH) is a part of the cytochrome P-%50 containing
microsomal enzyme system that is present in several tissues of humans
and many animal species. The activity of this enzyme system is in-
duced following exposure to t.he appropriate chemical stimulus. The
hydroxylation of polycyclic hydrocarbons resu1t.s in the detoxific,ation
of some and the activation of others to reactive carcinogenic forms.
An understanding of the role of -1HH in the metabolism of chemical
carcinogens in man may help clarify some of the mechanisms involved
in tobacco carcinogenesis. Recently, several studies examined -1HH
activity in animals and man.

Studies in Animals

Sydnor, et. al. (88) found that an aqueous extract, of CSC adminis-
tered in the drinking water of rats potentiated benzo(a)pyrene-
induced AHH activity in the liver. The liver AHH activity was
slightly increased by the aqueous extract, of OSC alone.

Rondia and Gielen (75) reported that. rats exposed to various levels
of carbon monoxide developed a decrease in AHH activity in liver
homogenates. The reduction in AHH activity developed after 120
hours exposure t.o levels of carbon monoxide lvhich produced c.arboxy-
hemoglobin levels below 15 percent.
Welch, et al. (99) reported t.hat the administ.ration of benzo(a)-
pyrene to pregnant rats resulted in an increase of the in vitro AHH
activity of maternal liver, placenta, and fetal liver. A twentyfold
higher dose of benzo (a) pyrene was necessary for st,imulation of AHH
activity in fetal liver than in the, placenta or mate,rnal liver.

Studies in Man

Levin, et al. (59) studied t.he induction of AHH actirit,y in human
skin. Human foreskin obtained from circumcised children was main-
tained in t,issue culture medium. Exposure to 10 ,/RI. of benzo(a)py-
rene for 16 hours led to a twofold to fivefold increase in the activity of
AHH in the exposed skin over control values.

whitlock, et al. (101) reported the presence of AHH in human
lymphocytes. The AH11 activit.y of lymphocytes compared to rat liver
or hamster e,mbryo cells is relatively low. Treat,ment with pokeweed
mitogen alone inweased AHH activity about, twofold. Howeve,r: a
threefold to eightfold greater AHH activity was found in cells treat,e,d
with the mitogen and benz (a)anthracene than in resting cells.


In studies of tobacco carcinogenesis, cigarette smoke condensate
(CSC), subfractions of (`SC, and individual chemical compounds
found in CSC have been administered to a variet'y of animals using
several routes of administration. Tests on living animals are frequently
complicated and time consuming. (`cl1 and tissue. culture systems offer
an alternate tool for the study of wrcinogcnesis which, in some in-
stances, is relatively more rapid than animal testing. Specific enzyme
systems and other wllular functions can often be studied in greater
detail using these systems. (`ells obtained from a variety of tissues and
animals c*an be grown or maintained in culture bottles when nourished
with an appropriate nutritive medium in a supportive atmosphere.
When these cultures are exposed to various chemical compounds,
changes can occur which may range from minor morphologic varia-
tions to malignant transformatjon or ccl1 death. Toxic effects on cell
cultures must be ditfercntinted from Inalignant transformation. Sev-
eral studies have recently examined the effect of cigarette sInoke
condensate or individual polycyclic hydrocarbons found in CSC on
various cell and tissue culture systems.

Benedict, et al. (4) studied polycyclic hpdrocarbon produced cyto-
toxicity, Inalignant transformation. and chromosome deformity in a
variet,y of cell lines derived from rats. hamsters, and human tumor
cells. The cytotoxic effect of benzo(a)p~~ene was found to be related
to the aryl hydrocarbon IIxdroxylase activity (AHH) of the given
cell culture. Benzo( a)pyrene was qvtotosic to fetal rat hepatocytes,
but this effect was probably related to the action of the hydroxylated
Inetabolite, 3-1Iydroxybenzo (a) pyrem', since the cytotoxicituv was
blocked when the ,1HH system was o\-crloaded with phenobarbital.
Cell strains not possessing -iHE-I actilitp showed no cytotosic effects
from brnzo ( a) pyrene alone : however. in the presence of fetal rat
hepatocaytes 1)ossessinp A!HH activity. enough benzo( a) pyrene metabo-
lites were secreted into the medium to indncc caytotosic etTects in the
normally resistrnt cell linrs. In hamster secondary cultures, at the
(~IIroIIIosoIne level cytotosicity was associated rrith chromatic1 breaks?
whereas malignant tI.aIIsfl)I,nlatioIl was n1ore closely related to
aneuploidy.

T)ianIond ( 1.9) studied the IlIetabolisIII of bcnzo (a) pyrcne and i'.ld-
dimeth;vlbcnz ( a) anthrawnc ( 1)JIlZ.i ) in Ino~Ise, hnnIst cr, rat. monkey,
;In(l hI~m:In (~11 c~ultnrrs. JletaholisIii of 1Iyd1~0c:I1~1~01is to `*alkali soln-
blr" am1 "water solut~lt~" tlcri\nti\-es WIS measured. The results SUM-
gested tliat tlw l~arcnt ~wIiil~oIInds were first nwtabolizetl to "alkali
extractable" d(~rivittiVcs ant1 t hrIi to ,`\\-ntcI.soliil)le" tlerivati\-es. A111 the
cvll cultures tcstetl \vl~ic~li were sensitive to tlw el.o\~-tli-iiiliihit(~r~
etfcrts of lmzo( 3) ]`yI'eIlc 01' I)JI1{.1 wcrc able to metabolize tlwsc

84


carcinogenic hydrocarbons to "water soluble" derivatives. The data
are consistent with the hypothesis that metabolism of the carcinogen
is required for growth-inhibitory or cytotoxic effects.
Several authors have examined malignant transformation in cell
cultures. Inui and Takayama (41) cultured hamster lung fibroblasts
and then exposed them to crude cigarette "tar" for a period of 3 hours.
between 2 to 48 hours following this exposure? toxic et'Yfects of the
bStar7', including cell necrosis, swelling. vacuolization, and disintegra-
tion of cytoplasm \wre obserj-ed. The death of 40 to 70 percent of
the cells within 72 hours was followetl l)y tlie appearance of trans-
formed cells which ~IIW- at rapid rates. These transformed cells pro-
duced malignant tumors n-hen inoculated in the cheek pouch of ham-
sters. Control cell lines produced 110 changes when inoculated in a
similar fashion.
In a similar study by 1% Paolo, et al. ($21). transformation of pri-
mary hamster cell cultures was induwd by benzo (a) pyrrne. X-methyl-
cholanthrenc, or `i,l~-dimethvllH~llz (a) anthrawne. Transformed cell
lines were established a~~1 subsequently inoculated in hamsters pro-
ducing malignant tumors at various sites. Characteristic chron~osonial
changes in the transformed cells were also described.
An increase in proliferation and tumor production rate of L-Strain
cells produced by treatment with cigarette "tar" was studied by
Inui and Takayama (40). L-Strain cell cultures not exposed to "tar"
did not produce tumors when inoculated in C3H mice. After an
exposure to low concentrations of cigarette "tar" significant. changes
occurred in t,he cultures characterized by enlarged cells with vacuolated
cytoplasm, giant cell formation, and accelerated growth rates. These
transformed cells produced tumors in 70 percent of injected C3H
mice.
Nagata (60) treated cell cultures obtained from kidneys of new-
born mice with 5%methylcholanthrene in various concentrations. Con-
trol cultures could not, be maintained for long; however, the treated
cells formed two permanent cell lines which had a transformed mor-
phology and altered karyotypes. Epithelial carcinomas were produced
after the subcutaneous injection of these transformed cells into un-
conditioned newborn mice.
Freeman, et, al. (29) isolated hamster-specific C-type lZNA viruses
from tumors induced by cell cultures transformed by chemical car-
einogens. Cell cultures \vere prepared from early passage hamster
embryo cells a~~1 treated for 7 days wit,11 S-methylcl~olanthrene or cer-
tain fractions of cigarette smoke condensate. Following treatment,
tt~~~rpl~ologically transformed cell lines were isolated and maintained,
Sttbsequent inoculation in newborn hamsters produced malignant
tuJJJors at t,he site of inoculation. New cell lines WPIT established from
Seme of the resulting tumors. So infectious viruses were isolated from
~11 lines prior to inoculation; however. C-type RN,\ I-irusrs were iso-

                                                        85


lated from tumors and from cell lines derived from tumors. The au-
t,hors concluded that the chemical treatment and activation of viruses
appeared to be related events.

Sivak and Van Duuren (83) developed a cell culture system that
responded with characteristic changes in cell morphology to the appli-
cation of various fractions of tobacco leaf extracts. Certain dose-
response characteristics were demonstrated, suggest.ing a mechanisII1
whereby various tobacco fractions might be rapidly screened foI
tumor-promoting activity.

Dietz and Flaxman (20) studied the toxicit? of aromatic hydro-
carbons on normal human epidermal cells in vitro. Picccs of adult
human abdominal skin were maintained in tissue culture nwtlium aIId
exl)osed to ~-rIIetlIylcl~olantlII~eI~e and benzo (:I) pyrencs at a concentr:I.
tion of 1 ~p./ml, for a periotl of I days. The cultures IveIne then kept foI
an additional 3 months followinp exposure. So n~:Ilign:IIit transfornla.
tioii occu~wd: liowever, giant cells and a more disordei~ly pattern of
growth \\rre observed in the treated cultures weeks earlier than simil:IIa
changes in control cultures.

There is evidence that some chemical carcino,rrcns incliItlin~ certaill
of the polycyclic hydrocarbons found in cigarette smoke con(lensatc
are active t,ecnItse of the, reaction of the carcinogen 01' a reactive iw
taholite with cellulaI~ IIIac~ronIolccrIlrs. 1)IIncan7 et al. (2,`) stridictl a
series of l~iltlio~lCtirr polyc~yclic hydrocarbons jvith respect to their
IrwtabolisIIi and tendency to bintl with cellular 11X-1 and RSA\ in
II~onol:i\-rI2 cultuws of l)rill1ilry IiIouse embryo cells. -111 tlw tcstrtl
II~tlf~oc~;II~~~oiIs were nIc~talwlizrcl to "w:ItCI' soluble" nir~t:Il~olitcs :It
:?I~I~~.oxirn:itcl~ equal rates. -1 **bintling imlex" IT-as c:Ilculntetl to de-
ttlrniine the bindinp of various hydrocarbons to crllIIlar I)S-1 ai111
RS.1. Tlw gi'oiip of hyd~warbons with a lrigh "bin~ling index" con-
sisted of lwtent caI~cino~eiIs, wlIilr aIiotlIer grorI1) v-itlI IiiiIch Ion-w
\~:ilues for the "binding index" were wit11 t)IIt one c~swption now
(3 i~ciiioviis .
(`nrl:Z+nw, et al. (1.2) stiitlicvl the in vi\-0 t)intliIig of benzo( :I)pyr~w~


Alexandrov and Vendrely (I) found that cigarette smoke conden-
sate, the hexane-extracted fraction of CSC, and benzo(a)pyrene all
inhibited RNA synthesis in mouse skin.

N-Nitrosamines in Tobacco Smoke

The largest number of chemical carcinogens which have been iden-
tified in cigarette smoke, condensate are polycyclic hydrocarbons.
N-nitrosamine compounds known for many years to be potent, car-
cinogens have produced malignant tumors in a number of organ sys-
terns of a lvide variety of animals. These compounds were recently
ident,ified in cigarette smoke. Only recently has an association been
found between exposure to N-nitrosamines and malignant tumors in
humans (55). N-nitrosamines are formed chemically by a reaction of
NO and NOz or nitrites with secondary amines. The chemical pre-
cursors of the N-nitrossmines have been identified in cigarette smoke
condensate (CSC) by a number of investigators. These studies were
reviewed by Wynder and Hoff mann (10s). More recently, Rhoades and
Johnson (69) developed a method for the determination of N-nitrosa-
mines in tobacco smoke condensate using gas chromatography. TWO
N-nitrosamines were found in CSC : one was identified as N-dimet,hyl-
nitrosamine (DMNA) and t,he other \vas believed to be N-methyl-
ethylnitrosamine (MENA) (43: 7'0). The concentration of DMNA
per cigarette in nanograms was determined in condensates from ex-
perimental cigarettes made .from single tobacco varieties rather
than a tobacco blend. Each tobacco tested was grown in both a lo~v-
and high-nitrogen soil. High-nitrogen soil conditions resulted in a
considerable increase in nitrosamines. A popular brand of nonfilter
cigarettes was also tested. These results are presented in table 2.

TABLE 2.-N-dimethylnitrosamine (DMNA) content of condensates
obtained from several tobaccos grown in both ((high" and "lozo" nitro-
gen soils

Tobacco type


Summary of Recent Cancer Findings

In atldition to the sununnr~~ presented in the introduction of this
eIlat)ter, based on previous reports of the healtll consequences of smok.
ing, the following statements arc made to ernplrasize the recent devel-
0pnient.s in the field :

1. Krcrnt rll)idrllliologicnl and autopsy studies from several eoun-
tries c*olifilnl that c+arette smoking is the major cause of lung
  cancer.

2. (`ontinued cigarette smoking by lmticnts following successful
surgical removal of iL cancer of the oral cavity, pharynx, or
larynx without tumor recurrence for a l'rriod of 3 years is asso-
ciated with a significant increase (I?< 0.001) in the risk of devd-
opinp a SWOII~ primary cancer of the ul)per respiratory or diges-
tive tracts compared to similar patients who discontinue smoking
at the time of their surgery.

3. The intratracheal administration of certain polycyvlic hydrocar-
hens found in cigarette smoke condensate results in the forma-
tion of annplastic and squamous cell wnwrs of the lung and re-
spiratory tract in hamsters and rats. Many of these tumors are
histologically sinlilar to the lung cancers found most frequently
in cigarette smokers.

4. The .application of ciprette, smoke condensate or polycyclic hy-
drocarbons to various cell cultures often results in transformation
to ~11s wit.h a more rapid and disorderly pnwth pattern. Trans-
formed veil lines frequently produce henign or malignant tumors
whet1 transplanted to exlwrimental allinluls.

.i. S-llit~~os~~nlit~rs 1u1vc hern identified in cigarette smoke. These
~~npounds are known to he lwtent vanwr ca~~sinp chemicals for
a variety of animals. Tlwy al~pear to he formed in higher concen-
t rations from tobaccos raised under hiphnitrogcn soil conditions.

Cancer References

11) ALESANDROV, K.. VENDERCY, (`. Artion de condensats de fum@e du tabac
   SUP la synthese de RS.1 dans la peau des souris. (Action of tobacco
   smoke condensate on the synthesis of RSA in mouse skin.) Chemico-
   Biological Interactions 4(3) : 1.55161, February lS72.
(2) AUFXIACII, O., HAMMOSD. E. C., GA~FISKEL, L. Epithelial changes in es-
   cigarette smokers, Cancer C.vto1og.v 11(l) : 5-12,197l.
(3) ACERRATH, O., Ha~~oxn. E. (`., KIRMAX, I)., GARFISGEI., 1~. Effects of
   cigarette smoking on dogs. II. Pulmonary neoplasms. Archives of En-
   vironmental Health 21 iti) : 754-768. December lS70.


(4) BENEDICT, W. F., GIELEN, J. E., NEBEBT, D. W. Polcyclic hydrocarbon-
  produced toxicity, transformation, and chromosomal aberrations as a
   function of aryl hydrocarbon hydroxylase activity in cell cultures.
   International Journal of Cancer S(2) : 435451, Mar. 5,1972.
(5) BERG, J. W., SCHO?TENFELD, D., RITTER, F. Incidence of multiple primary
   cancers. III. Cancers of the respiratory and upper digestive system as
  multiple primary cancers. Journal of the xational Cancer Institute
   44(2) : 263-274, February 19'70.

(6) BEBRY, G., NEWHOUBE, M. L., Tuaoe, M. Combined effect of asbestos
   exposure and smoking on mortality from lung cancer in factory workers.
   Lancet 2( 7775) : 47%479, Sept. 2,1972.

(7) BOCK, F. G. Tumor promoters in tobacco and cigarette-smoke condensate.
   Journal of the National Cancer Institute 48(6) : 1849-1853, June 1972.
(8) BOCK, F. G., Swn~h-, A. P., STEDUA~S. R. L. Composition studies on tobacco.
  XLI. Carcinogenesis assay of subfractions of the neutral fraction of
   cigarette smoke condensate. Journal of the National Cancer Institute
   44(6) : 1305-1310, June 1970.

(9) BOCK, F. G., SWAIN, A. P., STEDMAN, R. L. Composition studies on tobacco.
   XLIV. Tumor promoting activity of subfractions of the weak acid
   fraction of cigarette smoke condensate. Journal of the National Cancer
   Institute 47(2) : 429436, August 1971.

(10) B~TTEGHELLI. R., DEL;I'ERI, E., MOSASGHINI, 0. Rapporti tra carcinoma
    broncopolmonare primitiro e fumo di tabacco. (Relationship between
    primary bronchopulmonary carcinoma and tobacco smoking.) Minerva
    Medica Giuliana 9 (6) : 289-291, Sovember-December 1969.
    . . . -. --~
cll) BOUCOT, K,,R., WEISS, W.. H!zmsfA?i, H., CAR~AHAK, W. J., COOPEB, D. A.
P-Philadelphia pulmonary neoplasm research project : Basic risk
   factors of lung cancer in dlder men. American Journal of Epidemiology
    95 (1) : 4-16, January 1972.

112) CABLASRARE, F., ANTONELLO. C., BACCICHETI`I, F., MALF'ER, P. On the
    binding of benz (a)pyrenr to DNA  "in vivo". Zeitschrift filr Natur-
   forschung 27 (2) : 20&202, February 1972.
(1s) CAR~ADA BEA~O, T., NUNEZ ;IARQUIN, E. El diaguostico roentgenologico
   de las neoplasias bronchopulmonares primarias. (Reoentgenological
   diagnosis of primary bronchoplumonarg neoplasms.) Revista Mexicana
   de Radiologla 25( 5) : 185-196, September-October 1971.
(14) COLE. P.. HOOVER, R., FRIEDEI.L, G. H. Occupation and cancer of the lower

CT- _-prinary tract. Canrer 29 (5) : 125%1260, May 1972.
,15) COL$ ,P., MOESON, R. R., HANING, H., FRIEDELL, G. H. Smoking and
    cancer of the lower urinary tract. New England Journal of Medicine
    284(3) : 12%134, Jan. 21.1971.

(16) CBAGG, J. Lung cancer in Jersey: Its incidence and associated biochem-
   istrx. British Journal of Clinical Practice 25(8) : 360-365, August 1971.
(17) DAVIEG, R. F., WHITEHEAD, .T. K. A study of the effects of altering the
    tar/nicotine ratio in experimental tobacco carcinogenesis. British
    Journal of Cancer 24 (1 j : 191-194, March 1970.
(18) DELARUE, K. C., ANDERSON, W., SASI)ERS, D., STARR, J. Bronchioloalveolar
   carcinoma. A reappraisal after 24 years. Cancer 29(l) : 90-97, Janu-
    ary 1972.

(19) DIAMOIYD, L. Metabolism of polsc,vrclic hydrocarbons in mammalian cell
    cultures. International Journal of Cancer 8(3) : 451462, Nor. 15, 1971.
(20) DIETZ. M. H., FJ,AIMAN. B. A. Toxicity of aromatic hydrocarbons on
    normal human rpidrrmal cells in vitro. (`ancrr Research 31(S) :
   1206-1208, September 1971.

89


(21) DIPAOLO, J. A., KELSOK, R. L., DO~IOVAX, P. J. Morphological, oncogenlc,
    and karyological characteristics of Syrian hamster embryo cells trans.
   formed in vitro by carcinogenic polycyclic hydrocarbons. Cancer Re-
    search 31(8) : 1118-1127, August 1971.

(62) DOLL, R., PIKE, M. C. Trends in mortality among British doctors in re.
   lation to their smoking habits. Journal of the Royal College of
    Physicians 6 (2) : 216-222, January 1972.
(23) DUNCAN, >I., BFUWKES, P., DIPPLE, A. Metabolism and binding to cellular
    macromolecules of a series of hydrocarbons by mouse embyro cells in
    culture. International Journal of Cancer 4(G) : 813-810, Sov. 15, 1969.
(24) FER~N, V. J. Respiratory tract tumors iu hamsters after intratracheal
   instillations of benzo (a)pyrene alone and with furfural. Cancer Research
   32(l) : 28-36, January 1972.

(65) FERRAR.A, F. A. Ecological analysis of lung cancer in the city of La Plats.
   In : Englund, H. M., Berry, TV. T. (Editors.) Proceedings of the Second
   International Clean Air Congress, Washington, D.C., Dec. 611, 1970.
   Sew York, Academic Press, 1971, pp. 244-247.
      ----.^7

(26) RNOERLAN~, A., HUSAK, T., BENDLOVA, J. Contribution to the investigation
-cofffect of cigarette smoking. Sbornik Vedeckych Praci Lekarske
   Fakulty Karlovy University v Hradci Kralove 14(Z) : 221-234, 1971.
(27) FISCHER, G. Rauchgewohnheiten und Blasentumoren. Eine klinische Un-
   tersuchung. (Smoking habits and bladder tumors. A clinical study.)
   Zeitschrift fur I'rologie und Nephrologle 64(4) : 271-274, Spril 1971.
(28) FIIANKE, R. The possible role of hydrophobic interactions of polycyclic
   aromatic hydrocarbons with protein in chemical carcinogenesis. Molecu-
    lar Pharmacology .5( 6) : &l&657, November lS69.
(29) FREEXIAN, A. E., KELLOFF. G. J.. GILDEX, R. V., LAXE, W. T., SWAIN, A. P.,
   HUF.BNER, R. J. .4ctiration and isolation of hamster-specific Gtype RNA
    viruses from tumors induced by cell cultures transformed by chemical
   carcinogens. Proceedings of the National Academy of Sciences (USA)
    68 (10) : 23862390, October 3971.

(SO) FLXXICA, G., TOADER. JI. Continutul de "OPo in diferlte sorturl de tigari.
    ( Po2'o content in different cigarette blends.) Igiena 18(8) : 469-474,
    August 196S.

(31) HAJDU, S. I., Hcvos, h. G., GOODXER, .J. T., FWE, F. W.. Jr., BEATTIE,
   E. J., Jr. Carcinoma of the trachea. Clinicopathologic study of 41 cases.
    Cancer 25 (6) : 1448-1456, June 1970.

(32) HARRIS, C. C., SPORS, M. B., K~~-F~%As, D. G., SXITII. J. M., JACKSON, F. E.,
   SAFFIOTTI, I-. IIistogrnrsis of squamous mrtnltlasia in the hamster tra-
   cheal epithrlium caused by vitamin A defi&ncy or benzo(a)pyrene-ferric
   oxide. dournnl of tlie Sational Cancer Institute 48(3) : 743-747. 1larch
    1972.

(.!,I) HARRIS. (`. (`.. SPORS. .\I. I%. KAI'FXCAN, I). G., S~~ITI?. a. &I., BAKER, >I. S..
   SAFFIOTTI, I-. Acute ultrastructural effects of llenzo( a)pyrene and ferric
   oxide on the hamster trac~heobronchial epithelium. Cancer Research
   :(1(12) : ISi?-lSH1, Dec~rmber lS71.

iJ$i HEALFX, I'., I\I.~\~I)EsI.E`~.-TIIo\IAs, J,. E., RAHRY, D. H. The effect of some
   polyryelic hydrocarl~ons and tolmrco condensates on nnnspecitlr esterase
   artirity in sebaceous glands of mouse skin. Journal of Pathology 10.5(Z) :
   147-152, October lS71.

(35) IIERILOLI), K. 11~1). Survey of histologic types of ljrimary lung cancer in
    U.S. veterans. Pathology Annual 7 : 4.570. 1972.

.

90


($6) HIB~O, F., FUJISAWA, T., Tswu~a, E., YAMAMUEA, Y. Experimen~l
   cancer of the lung in rabbits induced by chemical carcinogens. Oancer
*   Researeh32 (6) : 1209-1213, June 1972.
`(57) HIRA-4, IT. Smoking in relation to the death rates of 265,118 men and
  -~~ <men in Japan. A report of 5 years of followup. Presented at the
   American Cancer Society's Fourteenth Science Writers' Seminar, Clear-
    water Beach, *la., Mar. 27, 1972, 15 pp.
(58) HONBURGER, F. Chemical carrinogenesis in Syrian hamsters. In: Hom-
   burger, F. (Editor). Progress in Experimental Tumor Research. Path-
.ol_ogssf the Syrian Hamster, Vol. 16, Basel. S. Karger. 1972, pp. 152-176.
(jg) HOOVES,-COLE, P. Population trends in cigarette smoking and bladder
-- --`X&er. American Journal of Epidemiology 94(5) : 40%418, November
     1971.

(/to) INUI, S., TAKAYAMA, S. Acceleration of proliferation and tumor produc-
   tion of rate of L-strain cells bv treatment with cigarette tar. Gann 62(4) :
   315-320, August 1971.

(41) INUI, N., TAKAYANA, S. Effect of cigarette tar upon tissue culture cells.
   Neoplastic transformatioo of hamster lung cells bv tobacco tar in tissue
    culture. British Journal of Cancer 25(3) : 574583, September 1971.
($2) IVAKHSO, G. I. 0 roli kureniva v zaboleva,remosti rakom legkogo. (Role of
   smoking in the incidence of lung cancer.) Vrachebnoe Delo 9: 99-101,
    1971.

($3) JOHXSON, D. E., RHOADE~, J. 11'. N-nitrosamines in smoke condensate from
    several varieties of tobac,co. Journal of the National Cancer Institute
   48( 6) : 1845-1847, June 1972.

(44) JOYET, G. The thorium-series in cigarettes and in lungs of smokers. Experi-
  entia 27'GL: 8589, Jan. 15, 1971.

e) KENNEDY A .Lung canrrr in roung adults. British Journal of Diseases
          L.-:
    of the Chest 66(a) : 147-154, April 1972.
(46) KOSZAROWSKI, T. 0 raku yluca-po 25 latach. (Lung cancer in the course
    of 25 years.) Polski Tygodnik Lekarski 26(47) : l&l&1807, Nov. 22.
    1971.

(47) KRAIN, L. S. Grossing of the mortality curves for stomach and pancreatic
   carcinoma. International Surgery 57 (4) : 3(n-310, April 1972.
(48) LARSSON, S. Aldersspecifik incidms ar primlir lungcancer i srerige. Trenden
   under perioden 1959-66. (Age specific incidence of lung cancer in Sweden.
   The trend during the period 1959-66.) Lakartidningen 68(38) : 4229-
   4236, Sept. X,1971.

`49) LAZAR, P., IZARD, (1.. MOUSE-TESTA, J., CHOFROLTINKOV, I. Interaction
   entre l'hydroquinone et le condesat de fumee de cigarette dans les tests
   cutanes a court tense du pouvoir carcinogene. (Interaction between
   hydroquinone and cigarette smoke condensate in short-term skin tests
   of carcinogenic activity.) Cornptes Rendus Hebdomadaires des Seances
   de 1'Academie des Sciences ; 1) : Sciences Naturelles 27-t : 496499, Jan. 17,
    1972.

(50) LEE, P. S., O'NEILI., J. A. The effect both of time and dose applied on tu-
   mour incidence rate in benzopyrene skiu painting experiments. British
   Journal of Cancer 25(4) : 75!&770. December 19il.
l5j) LW)NE, G. Importanza dei fattori ambientali uella patogenesi dei tumori
   dell' uomo. Ruolo de1 fumo di sigaretta. (Importance of environmental
   factors in the pathogenrsis of tumors in man. The role of cigarette
   smoking.) Minrrra Medica 62( 49) : 2461-2480, ,June 20, 1971.

91


(.j,?) I,SVIS. %`., COSSEY. -1. II., .1LYARES. .i. I'.. MERKATZ, I., KAPPA% A. Induc.
   tion of benzo (a) l,yrw~r hptlrosylasr iu human skin. Scienw 176 (4033) :
    41!&420, Apr. 2s, 1972.

  1.i.t) l,r.snrh, F. E:., .Jr.. ~V.~C.OSEI:. .J. K.. ARCHER, \-. E. Radon daughter exm.
      surge anfl respiratory cuncer qunntitntirr ant1 terupxal aspects. Sationa]
      Institute for Orcxpational Safety and Health, Sntional Institute of En.
      viromental Health Sciences, Joint Jfouograph So. 1, 1071. 177 pp.
  r.if) I,~~T~~RA, 1.. IL, Wooos. D. A.. WAHI, I?. X., GUPTA, M. Vltrastructure of
      hrluian oral mucow flftrr l)rr)longed erlt,jsurr to tobacco. Indian .Journnl
      of ![tdic:rl Research .?91 11 : l.i7-169, .Jan. 1, 1971.
  (.i.T 1 1\Ic ( II..\sII.\x, S. I).. W.~~.TF:HS. (`. I... mr,E.is, A. E. 11. Sitrosamines in
      .\frican alcoholic spirits ant1 owol1h:~pt~:~1 cancer. rmcet 2: 1017. Nov. 9,
       196? L .
  (,56i Jl.~~:sz.~ R. .\I.. PKADHA~. A. >I.. SUXDERMIN, B'. II'., Jr. Rapid induction of
      xarconms in rats Iby cc~rnl~irl;ttion of nicakel sulfide and 3,-i-benepyrene.
       Cauwr Research 31 I 12) : XHi7-LW71. December 1971.
  I :iY 1 ~[.IRTISEZ. I. Retrwlwctiw ;tnd prospective study I)f rnrc,inoma of the
      ~wphagus, moutll, xrltl I,har,rns in Pwrto Rico. Rolrtiu de la Asociacion
       Mtrlica de Puerto Rico 82((i) : IilhliX. June 1970.
  i.iS) \Irr.r.~ri. J. .\.. ~Ill.r.e~, 1.:. (`. f `knri~xl CXrc~iiiogrtlt~siS : ~fec~l~lnisms nnd
      approaches to its control. ( I*Zditoriat.) .Jwrnal of the National Cancer
     ITistitute 47 (3) : r-xiv. Yel~~enitwr l!Kl.
  C.;D\ SIOOR~:C. C'igerette smoking and cancer of the mnutli. lthargns. and larynx.
_- ' ~&ntinuing study. .Journal nf the American Nedical Assoriation 218
      (4 I : .533-,754, Oct. 2.5, 19il.

( tic/ I S.\G.\TA, T. Mulignnrit trnusforliintion of mouse kidney cells in vitro by
    2O-roethSlcholanthrene. Jledical Journal of Shinshu University 1.5(3) :
    1X1--151, October 1970.

( fil) S.1 r1iry.U. Ac,4uEbf~ w ScIExcEs. I'articulate Pnlycyclic Organic Matter.
    Biologic Effects of Atmospheric Pollutants. Committee on Biologic Ef-
    fects of Atmospheric E'cvllutants. Division of Medical Sciences. National
    Research C'ounril. Wn~hinpton. 1972. 361 pp.
C h'!) St?Los. ,1. F.. SErIr. I. I. Intraoral carc*inl~ma : I'rrtlisposing factors and
    their frequency of incidence as related to age at onset. ,Journal of the
    Anrericnn Deutal Association *Z (3) : .X&l-XX, March 1971.
(6.1) SIKoI.ov.\, 11. YP; ILltlic)aktivuyy f:llitor t~ll~;~~~llIl~~o dyma. (Iiadinac+ive
    factors in tobacw smoke.) (;igiena i Sanitariin 35(S) : W-93. August
     1970.

92


(69) RHOADES, J. W., JOHNSON, D. E. Method for the determination of N-nitro-
   samines in tobaco smoke condensate. Journal of the National Cancer
   Institute 48 (6) : 1841-1843, June 1972.

(70) RHOADEG, J. W., JOHNSON, D. E. N-dimethylnitrosamine in tobacco smoke
   condensate. Nature 236 (5345) : 3Oi30X. Apr. 7,1972.
(71) RICKARD, V. D.. SAMPSON, C. C. Incidence of bronchogenic carcinoma in
   Negroes. Statistical analysis of 94 cases. Journal of the National Med-
   ical Association 63(l) : 1@12. January 1971.
172) ROBBINS, \Y. T. Bronchial epithelium in cigarette smoking college students.
   Journal of the American College Healtll Association 20(3) : 209211,
   February 1972.

(73) RODRIGUEZ Rrvs~a, L., ACHON POLHA~~IUS. M., RO~RIGI-sz SILVA, H.,
   DE LA PAZ. E.. PITA DE La VEGA, H.? I~RAIVI) OCIL~MESDI, R., HoLLhT
   GUILARTE, R. Habito de fumar y diagncwtico al alta. Eatudio de 453
   cases. (Analysis of the smoking halbit in tiisclmrgrd patients. Study of
   453 cases.) Rerista Cubana de Medicine s I 6) : 561-367. Dec. 31, 1969.
(74) ROE, F. d. C., PETO, R.. KEARNS, I'., BISIIOP. D. The mechanism of carcino-
   genesis by the neutral fraction of c.igarettr smoke condensate. British
   Journal of Cancer 24 ( 4) : 788-806. Drwmbcr 1970.
17.5) ROSDIA. D. a., GIELEN, J. Influence in vivo de 1'oxFde de carbone a faible
   concentration sur l'actiritr de la benzop~renehydroxylase et de la choles-
   terol-7a-hydroxylase hepatiqur du rat. (In viva influence of carbon mon-
   oxide at low concentrations ou the activity of rat liver benzo (a) pyrene-
   hydroxylase and cholesterol-ia-hydroxyl;lse. ) In: Engluud, H. M., Beery,
   W. T.. (Editors.) Proceediugs of the Second International Clear Air
   Congress, Washington, D.C., Dec. 611. 1970. New York. Academic Press,
   1971, pp. 234-237.

(76) RYSER, H. J.-P. Chemical carcinogenesis. Sew England Journal of Medi-
   cine 285(13) : 721-734. Sept. 23,lWl.

177) SAFFIOTTI, U., MONTEGAKO, R., SELLAKU~IAR, A. R.. CEFIS. F., KAUFMAN,
   D. G. Respiratory tract carcinogenesis in hamsters induced by different
   numbers of administrations of benzo (a ) pyrme and ferric oxide. Cancer
   Research 32 (5) : 10731081, May 1972.

(78) %Hbfi;HL, D. Quantitative Yersuche an Ratten tiber die carcinogene
   Wirksamkeit von Tabakrauchkondensaten. (Quantitative investigations
   of carcinogenic effects of tobacco smoke condensates in rats.) Zeit-
   schrift fiir Krebsforschung und Klinische Onkologie 76(4) : 320-324.
---a

_(79) SCHMIDT W., DE LINT. J. Causes of death of alcoholics. Quarterly Journal
  -dies on Alcohol 33 (1) : 171-185, March 1972.
(80) Sx~LAKrrunn, A., SHUBIK, P. Carcinogenicity of 7H-dibenzo (c,g)carbazole
   in the respiratory tract of hamsters. .Journal of the National Cancer Iu-
    stitute 48 (6) : 1641-1646, June 1972.

(81) SHABAD, L. M. Dose response studies in experimentally induced lung tu-
   mours. Environmental Research 4(4) : 305-315, October 1971.
(82) SHUBIK. P. The use of the Syrian Golden hamster in chronic toxicity test-
   ing. In: Homburger, F. (Editor). Progress in Experimental Tumor Re-
   search. Pathology of the Syrian Hamster, Volume 16. Basel, S. Karger.
   1972, pp. 176184.

(83) SIVAK, A., VAF; DUUREX, B. L. A cell culture system for the assessment of
   tumor-promoting activity. Journal of the Sational Cancer Institute 44
    (Fj) : 1091-1097, May 1970.

93


(92)

( .9.i I

i.Q7)

SOLSIC'XA, H., BISCIIOF', R. 0bsah `l"Pb a *l"Po v nekterych druzich Ceski
slovenskych cigaret. (The assay of n"l'b and 21nPo in a group of Czech
slovakian cigarettes.) Casopis Lrkaru Ceskych lOQ(28) : 654. Juls 1971
STELI. I'. 11. Smokitlg and Iar.rngeal cancer. Lancet l(ii51) : 615-61'
  Mar. le. 197?.    -- -
Srt;RI.ISG, T. D., POLLA~K, 8. V. The incidence of lung cancer in the u.f
_.
since lQS5 iii relation to the etinlogx nf the disease. American Journal v
Public Health 62( 2) : 1X-l.?% February 1072.
S!VARIZ. 11. 1\C. Electron spin resonance studies of carcinogenesis. In
Klein, G., 1Veinhouse. S. (Editors), htlvnnces in Cancer Research, VO!
umc IS, Sew York. Academic Press, 1972, pp. 27-252.
SYIISOR. K. I,.. ALLEN, C., FLEXNEK. J. TV. Potentiation of benzo(a)pyrenc
induced liver enzyme activity in Sllr~~gnr~-I~il\\-l~~~ female rats bg aqueon
estrect of cigarettr smoke condensate. Journal of the Sationnl Canre
Institute 4%(-l) : !)ll-919. April 1972.

SYDSOR, K. I,.. ALLEX. C., tIrc;crsa, B. Effwt of an aqueous extract of cipa
rettkh smoke condensate on benzo(a)y.vrene-intluced sarcoma and hod!
weight in the rat. Journal of the Sational Cancer Institute 46(4) : 893.
909. April 1'372.
TYLIH:SLEY, \V. R. Tobacco chewing in En.gli*h coal miners. A preliminar)
report. British Journal of Oral Surgers- 9(l) : 21-28, Juls 1971.
I-.% l'r-BLIC HEALTIK SERYWE. The Health Consequences of Smoking. A
Pui,Iic Health Service Review : 1967. t-.S. Department of Health, Educn-
tion, and JTelfare. 1Vashington. Public Health Service Publication So.
1dQt;. Revised January lQ6S. 227 pp.

I-.% PIW.IC HEALTH ~L;EXI'ICE. The Health Consequences of Smoking. 191%
S\lpliltwent to the 196i Public Health Service Review. P.S. Department
of IIe;llth. Education, and \Veifare. Washington, PulAic Health Service
Publication 1696, 1968. lli pp.
r S l'r'nr I(' FIE.ILTH SERVICE. The Health Consequences of Smoking. 1969
Su:ll~ltwent to the 196i Puhlir Health Serrirr Review. V.S. Department
of Ilralth. EXuwtion. alld Welfare. Washington. I'utplic Health Service
t'llt~lic~ati~ni 1 t;!)Ct-9. l!W. !)H plj.

94


99) WELCH, R. M., GOMMI, B., ALVARES, A. P., CONNEY, A. H. Effect of enzyme
   induction on the metabolism of benzo(a) pvrene and 3-methyl4-mono-
   methylaminoazobenzene in the pregnant and fetal rat. Cancer Research
   32 (5) : 973-978, May 1972.

30) WEBF-MEBBING, B. VAN DEB, KAALEX, J. G. A. H. Beroepen en rook-
   gewoonten van Rotiersdamse blaascarcinoom-patienten. (Occupations
   and smoking habits of bladder carcinoma patients in Rotterdam.)
   Jaarboek Kankeronderzoek en Kankerkestrijdig 19 : 77-85, 1969.
01) WHITLOCK, J. P., Jr., COOPER, H. L., GELEIOIN, H. V. Aryl hydrocarbon
   (benzopgrene) hydroxylase is stimulated in human lymphocytes by
   mitogens and benz (a )anthracene. Science 177 (4049) : 618-619. Aug. 18,
    1972.

72) WYNDER, E. L., HOFFUANN, D. Tobacco and Tobacco Smoke. Studies in
   Experimental Carcinogenesis. iYew York, Academic Press, 1967, 730 pp.
14) XIP~L, J. M. The incidence of benign renal nodules. (A cliniocopathologic
  study.) Journal of Urology 106(4) : 503-506, October 1971.
74) ZIJLSTRA, V. L. J. Roken, longkanker en radioactief Po'l' (Smoking, lung
  cancer, and radioactive polonium-210.) Tijdschrift voor Sociale Genee-
   skunde 47 (23) : 775-779, So-v. 14,1969.

95


CHAPTER 4

Pregnancy


Contents

                                          Page
Introduction____--______________________----------------   103

Smoking and Birth Weight
Epidemiological Studies

Cigarette Smoking and the Low-Birth-Weight Infant -
Evidence for a Causal Association Between Cigarette
  Smoking and Small-for-Dates Infants- - - _ _ _ - - _ _ _ _
Evidence for an Indirect Association Between Ciga-
  rette Smoking and Small-for-Dates Infants - - - - _ _
Experimental Studies
  Studies in Animals

  Tobacco Smoke----_---_-___-_______________
  Nicotine--- _____ --___- _______ --------__----
  Carbon ?Ilonoside-__---_-__---. -~_----- _----
Polycyclic IIydrocarbons__-___---------------
Studies in Humans

105

106

110

114
115
116
117

118
119
119
119
119

120
121
121
122

Cigarette Smoking and Fetal and Infant ?tf ortali ty
  Introduction--- ______-____ -_____- _____________  ___--   123
SpontaneousAbortion ___-_ --__---__-___-- ____ --__--__   123
   Spontaneous Abortion Summary- - - - - - _ _ - - - - - - - - - _   124
Stillbirth-_-------_--___--_--- ____ -_----__---__~----   124
   Stillbirth S~lmmary-----_-----_______ ____ ---___--   125

495-02s %73-8

99


Page

Cigarette Smoking and Infant Mortality-Con.
  Late Fetal and Neonatal Deaths-__--- ____ --_-_- _______.
   EpidemiologicalStudies --_______ - ____ -_-_----_-__
     Comparisons of the Mortality Risks of Low-
       Birt,h-Weight Infants Born to Smokers and
       Nonsmokers ___---_-____ -_-- ____ ----_-_--_
      Recent Studies _-----_-____ ___- _____ __-_-__-_
     Analysis of Previously Reported Studies- _ _ _ _ _ _ _
     Factors Which Influence Perinatal Mortality
      Other Than Smoking--------__-_---__- ____
    Experimental Studies

126
126

126
128
130

131

      Studiesin Animals ____ -__-----__-_-_--_- ____
      Studiesin Humans ____ ----_--__-_-__- _______
   Significance of the Association_ _ - _ _ _ _ _ - _ - - - - _ - _ _ _ _
   La.te Fetal and Neonatal Death Summary _ - - _ _ _ _ _ _
Sex Ratio_----______-_______________________-----------
  Summary__-_--_--___-___--_-_-__-_-_----___-_______
Congenital Malformations__---_-____________________- ____
Congenital Ma(formation Summary- - _ - - _ _ _ _ _ _ _ - _ _ - _ - - - _
Lactation

132
133
133
134
135
135
136
137

138
138
138

  Nicotine_-_---- _________ --_-- _____ -_--_----
  Influence on the Lactation Process __-__ _ - - _ - - _ _
  Presence of Nicotine in the Milk- - - _ - - _ - _ - - _ - _
Evidence for an Effect Upon the Nursing Off-
  spring__-____-_-_-______________________--
  Nitrosamines--- -_________ -_-- ___-_______ -__
Studies in Humans

138
138
139

139
139

      Nicotine and/or Tobacco Smoke---------_-----
      Influence on t,he Lactation Process __--__ _- _ - -_ _
      Presence of Nicotine in the Milk----_--_-----_
     Evidence for a Clinical Effect Upon the Off-
      spring--_-----__~_--_---------------------
      Vitamin C ______-_______ -_-__- ________ ------
Lactation Summary _____ -__-_--_----__~__-_--________
Preeclampsia ____- - _ _ _ _ - _ _ _ _ _ _ - _ - _ _ _ _ -_ _ _ _ _ _ - __ _ _ __ _ _ _ _ _ _
Sz~mmary___-_-__-___-______--_--_-_____--___--_--_-

139
139
140

140
141
141
142
142

References---_-~_---_------~-------------~---------~~~--   142

100


List of Figures

Figure I.-Alean birth n-eight for week of gestation arcording
to maternrtl smoking habit: control I\-eek singletons_--_- ----
Figure 2.-Percentqe distribution b!- birth n-eight of infants of
mothers \t ho did not smoke during pregnancy and of those
I\ ho smokccl 1 pilck of cGg:arettc* or more per da>----- - - _ - _
Figure X.--Percentage of pregnancies with inftint, \veighing les
than 2,500 grams, by cigarette smoking category--.--------
Figure 4.-mmdrerapc birth \\-eight by maternal smoking habit.
(a) before current pregnancy and (b) during current peg-
ni~t~c\-__------_--_-~--~--~-~----~~-------~----~-------
Figure 5.-Percent of loll- birth weight \r-hite infants b>- smok-
ing status of their nlothers----__-_-_~-_--~------~--~-~--
Figure (I.-Xconatnl mortality rate< among hingle 11 hite births
in hospitals (by detailctl birth x\-eight and ~pccified pe,t ;ttion
grorlp: 1Tnitetl Stntes)-m _ _ _ _ _ - _ - _ - - _ - _ _ - _ - _ _ - _ _ ~. _
Figure 7.--Perinatnl mortalit\- riite l)er 1,000 total births b>.
c.i~urette~;mokingrcateeorv---- ___-_. --_-_--_-_----_--_-

Page

104

105

108

110


113

128

129

List of Tables

Table l.-Infant birth ~v-cight by maternal and paternal smok-
ing habits- __.___ ____ ~__~___-~--~--_----~-------~----   111
Table 2.-Effect, of carbon monoxide exposure of pregnant
rabbit5 on birth \\-ei~ht._--~-_-~-_--_-__-_~-_-__-_~-_-__   117
Table :3.-Comparison of the perinat al mortality for infants
xvrighing less than 2,500 grxm+, of smokers and nonsmokers-   127
Table 4.-Efl'ect of carbon monoxide exposure of pregnant rub-
bits on birth n-eight and ncomctal Inortalitv--_--~-----~--~-   133
Table 5.-Proportion of male infants delivered to smoking and
rlonimokinpmotheri--___-_-~-_-_~-_~__-__-_-_--_--_---   136
Table 6.--Relative risk of congenital malformation for infants
of cigarette smokers and nonsmokers, comparing available
studies with regard to stutly design, sttldy population, samI)lc
size, number of infants with malformations, and definition of
malformation- ____._ ________ --_----_--_--_----_------   137

101


Introduction

Smoking and Birth Weight


frequent among cigarette smokers as among nonsmokers. Subsequent,ly,
Lowe (.&I?) &udied 2,042 women in Birmingham, England, and dem-
onstrated in his ret,rospective study that, the infants of smoking
mothers were delivered oilIs slightly earlier (1.4 days on the average)
than those of nonsmokrrs. He further noted that for gestations of 260
days and over: the infants of smokers were consistently lighter in
weight during each week of gestation than those of the nonsmokers.
This finding has been confirtnrd since, and figure 1 from the British
Perinatal Mortality Study (13) provides illustration of this
relationship.

Given the nearly constant disparity present between the birth
weights of the infants of smokers and nonsmokers for gestations of 260
days and over, but absent prior to that time, and given the similar
birth weights of infants of rlonsmokers and of women who gave up
smoking early in pregnancy ancl did not begin to smoke again, Lowe
inferred that the intluence of smoking upon birth weight might lie
mainly in the later months of pregnancy. He emphasize,d the tentative
nature of this conclusion. since the number of infants with a gestation
of less than 260 thrys and the nunlb~r of women who gave up smoking
early in the pregnancy and did not begin to smoke again were both
small.

Figure 1 .-Mean birth weight for week of gestation according to maternal smok.
     ing habit: control week singletons.'

125

3400
  E"
3150 g
   .5
2900 g
  :
2650 $
    I

85                                       2400

75

2150

3650

36

37

38    39    40    41
Gestation in completed weeks

42    43+

`This term refers to singleton births in England, Scotland, and Wales occurring during the
week of March 3-9, 1958, which are included in the Parinatal Mortality Survey. These
comprise 97 percent of all births notified in England and Wales or registered in Scotland
during this week.

SOURCE: Butler, N. R.. Alberman. E. D. (13).

104


Low found that, the infants whose mothers smoked throughout
pregnancy weighed. on the avtmgr. 170 granls less than those Those
~notller~ did not smoke. In addition, he noted that the entire clistribu-
tion of weights of infants of smokers was shifted to the left (to\\-ard
lower weights) relatii-r to that, for the infants of nonsmokers. This
finding! too, has been confirmed hy other investigators. Figure :! offers
a11 illustration fronl JIacJIahon, et. al. (@).

Given that the infants of smokers and nonsmokel~ differed only
slightly with respect. to the duration of gestation. Lowe concluded that
the lowx birth weight of smokers' infants must be attributed to a
direct retardation of fetal gr0wt.h. In other word+, on the IAs of his
data, the infants of snlokers were small-for-dates: rather than truly
piwiiatnre.

JTany investigators have subsequently confirmed this point (22. 14.
2.5. -3:;. ET 78.85, 113). Buncher (12)) in a study of 49.897 birth5 among
T-3. naval wive.s. in the same, population studied 1)~ I-ndcrwood, et al.
(100). found that, the infants of smokers were, on the avcrapc, de-
livfred only 1 day earlier than those of nonsmokcl~. This finding
awnunted for only 10 percent of the discrepancy in birth n-eight be-
twen the, two groups of infants. The remainder of the studies rvsultcd
in the detection of citlicr siniilnr variations in gwtatinnal length 01
no average difference. In a recent study, JIulcah~ and bIurpll>- (56)Y

Figure 2.- Percentage distribution by birth weight of infants of mothers who did
    not smoke during pregnancy and of those who smoked 1 pack of
     cigarettes or more per day.

INFANT WEIGHT AND PARENTAL SMOKING HABITS

  ,`~`,~~`l~`~1"`1~"1~~`1"~1

10

8

6 7 8 9 10 11

BIRTH WEIGHT (SCALE IN POUNDS; INTERVALS OF 4 OZ.)

SOURCE: MacMahon. et al. (4%.

105


in a sample of 5>099 Irish mot.hers, concluded that although the babies
born to cigarette smokers were delivered slightly earlier t,han those
of nonsmokers, independent of age and parity, the direct effect of
smoking in retarding fetal growth was more significant.
The following points, based upon the results from many different
studies, can be made about the relationship between cigarette smoking
during pregnancy and lower infant birth weight :
1. Women n-ho smoke cigarettes during pregnancy have a higher
  proportion of low-birth-Keight infants than do nonsmokers. This
  excess of low-birth-weight infants among cigarette smokers pre-
  dominantly consists of infants who are small-for-gestational age
  rather than gestationally premature.

2. The entire distribution of birth weights of the infants of ciga-
ret,te smokers is shifted toward lower weights compared to the
birth lyeights of the infants of nonsmokers.
3. The birth weights of the infants of cigarette smokers are con-
sistently lighter t,han those of the infants of nonsmokers when
the birth weights of t,he two sets of infants are compared within
groups of similar gestational age beyond the 36th week of
gestation.

The results of the studies which have been conside.red so far identify
a relationship betPreen cigarette. smoking and lower infant birth
weight and illustrate some aspects of that. relationship, but do not
indicate whether the association is causal or indirect. The succeeding
tn-o sections of this chapter cont.ain evaluations of the available evi-
dence rvhich bears upon the nature of the association bet,ween cigar-
ette smoking during pregnancy and the incidence of small-for-dates
infants.

EVIDENCE FOR A ~A~SAI, A~~~~~~.4~~~~ RETWEEX (~ARETTE SMOHIXG
          AXD S~MALL-FOR-DAWAS INF&~NTS

Evidence prel-iously revien-ed in t.he 19'71 and 1972 reports on t,he
health consequences of smoking (101? 102) suggests that cigarette
smoking is causally associated with the delivery of small-for-dates
infants. Thr follo\Cqz is a summary of this evidence :

1. The reeults from all 30 studies in which the relationship between
smoking and birth weight n-as examined have demonstrated a strong
association betKeen maternal cigarette smoking and delivery of low-
birtll-weight infants. On thla average, the smoker has nearly Wice. the
risk of delivering a lowbirth-Keight infant as that of a nonsmoker

106


(3, 13, 17, 20, 25, 29, 35, 42, jJ3: 46, .$7> 49. 57: 58, 59, 65, 70, 72, 73,
77,78? 80,83,85,90,95,99,1007 113,118).
2. The strong association between cigarette smoking and the de-
livery of small-for-dates infants first demonstrated 1vit.h results from
studies of retrospective design (3! 12, 17, 35, 46, .$7? 49, 57> 58, 59? 65,
70,72? 73, 77,80,85,90,95,9LJ3! ZO!?, 118) has been repeatedly confirmed
subsequently by data from studies of prospective design (.20,25,29,&J,
/$x3', 7483,113).
3. A strong dose-response relationahip has been established between
cigarette smoking and the incidence of lo\~-bil~h-~~-eigl~t infants (25,
49,46,49,100,213).
4. When a variety of knowi or suspected factors which also exert. an
influence upon birth weight have been controlled for, cigarette smok-
ing has always been shown to be independently related to low birth
weight (I, 13, %5, & 46, 7,3,78,&Y).
5. The association has been clenionstrated in many different coun-
tries, among different races and cultures, and in different geographical
settings (13.17.25,29,31i . $2. .$3,69.7.?, 78,80> 113).
6. Prerioiis smoking does not appear to influence birth n-eight if
the mother gives up the habit prior to the start of her pregnancy (2,s.
$6,49,2 13) .
7. The infants of smokers experience an accelerated growth rate
during the first 6 months after delivery, compared to infants of
nonsmokers. This finding is compatible with viewing birth as the re-
moval of the smoker's infant from a toxic influence (8C3).
8. Data from experiments in animals have documented that ex-
posure to tobacco smoke or some of its ingredients results in the
delivery of low-birth-weight offspring (7, 8, 9? 23, 40, 87, 117).
Several recently published studies have provided additional wp-
porting evidence for a causal relationship betjveen cigarette smoking
and small-for-dates infants. The Ontario Perinatal Mortality Study
(66) was conducted among 10 teaching hospitals during 1960 and
1961. The authors of this retrospective study of 50,267 births demon-
strated a significant excess of infants weighing less than 2,,500 grams
among cigarette smokers as compared with nonsmokers (P<O.OOl) .
Smoking was significantly dose-related to the percentage of preg-
iiancies terminating in the delivery of a low-birth-weight. infant
(fig. 3).
Siswander and Gordon (6.3) have recently reported data from the
Collaborative Perinatal Study of the Katioiial Institute of Seuro-
logical Diseases ancl Stroke. In this prospective study of XB,2OO preg-
iiancies, which were nearly equallv clividcd among black and white
                             Y
lvomen? the authors found a significant dose-related excess of 10~
birth-weight infants among smokers of both groups, compared to
nonsmokers of the same race.


                                                       107


Figure 3.- Percentage .of pregnancies with infant weighing less than 2,5ocj
    grams, by cigarette smoking category.

12.0

11.0

10.0

9.0

8.0

g 7.0
fi
k
n 6.0

5.0



4.0



3.0


2.0



1.0


0.0

Nonsmoker

21 pack
per day

Number of
infants weighing
<2,500 grams:   1,322         1,186          793


Total births:   28,358        15,328        6,581
                (P <O.OOl)

SOURCE: Ontario Department of Health (66).

108


Rantakallio (76) carried out a prospective study of 11,905 single
births in Finl,-.nd. Cigarette smoking mothers had significantly more
iflfants \veighing
j l'<O.OOl).   less than +OO grants than did nonsmokers

Rush and Kass (81)) in a prospective stu~l~ of 1,040 pregnancies in
Boston, Xassuchusetts; Domagala. ot al. (19). in a retrospective stucly
nf 1,836 pregnancies in Poland? * and Jlttkht~rjee and Mnkherjee (54):
in a retrospective study of 2.886 l)regnanc~ie- in India: each found a
xignificantly higher incidence of lo\~-bil,tli-\~-eight infants among
cigarette smokers.

Hutler! et al. (IS) hare further analyzed t lie Hritish I'eriuatal Nor-
tality Study data. Ainal~sis of the lri,994 qllt%ionilaires re1.ealed that
40.8 percent of tlw women were ci,rarettr ~1110kcrs before I)regnancy.
.\fter the fourth morltli, tliis perwntage li+l tlecreasctl to 3.4 I)er-
cent. Given ttw large nunlber of \~onwn iI1 the study, and the sig-
trificaut. cl~ariges in smoking behavior \fllir,l~ occurred, Ilutler, et al.
found it possit)le to consider the etfwt of :I cahxnge in smoking be-
havior on birth weight between the Iwginuill p of tllc pregnancy and
the fourth month (after which dinokiilg lwhavior x-as reportedly
Stable). The authors stated, "If sluoking itself (rather than the
type of woman who sntokes) has a cltlcterior~s egec*t on the fetus,
it \vould lbe reasonable to expect tlw motller~ who pal-e up smoking
dwing pregmlncy to show differencaes in tlltl birth weight and peri-
natal mortality of their offspring compare(1 51 ith those \vllo continued
to snloke." Thiir results are presented ill fig1ir.e -1. The birth weights
hr rlnoking categories were estim:ttetl by u3inr a main effect, model
Gthout mediating variables. How\-er, the a1lthor.s reported that when
the nwdiating variables (social ~1x55, niattw~:tl age, parity, maternal
lLeight, sex of infant, gestational age, and I~eritiatal niortality) were
allowed for. the results of the allal)-sis \vere \.cry simil;lr. The eflect
of cigarette smoking before pregnancy wa:, in-ipnificant comparetl to
tllat of smoking regularly after the fourtl, nlonth of gestation. The
authors concluded, `*The finding that a clwnge in maternal smoking
habits during pregnancy had the effect of putting the baby into a
t)irth weight and perinatal mortnlitv c*ategorJ. associated with the new
smoking habits points toward som; kind of cause-effect relationship.
* * * This finding is further strengthened by the birth weight. analysis
\vhich shows that the diminution in birth ncipbt of the offspring of
smoking mothers persists and is intleed little ccl~xngecl wheu allowance
has been made for n number of other social and obstetric mediating
factors."

109


Figure 4 .-Average birth weight by maternal smoking habit (a) before current
      pregnancy and (b) during current oreanancv.

Number of cigarettes/&
in current pregnancy,
after the fourth month

       0       l-4       5-9      lo-19     2(1-30   Total
      Number of cigarettes/day before current pregnancy     births:

SOURCE: Adapted from Butler, et al. (15).                    21,671

EVIDENCE FOR AN INDIRECT ASSOCIATION BETWEEN CIGARXTTE SMOKING
         AND SMALL-FOR-DATES INFANTS

Yerushalmy (113,114,115) has suggested that smoking is an index
to a particular type of reproductive outcome and thus does not play a
causal role in the produotion of small-for-dates infants. He has de-
veloped several lines of support for this hypothesis, from an analysis
of data from the prospective investigation of 13,083 mothers in the
Oakland Child Health and Development Study. He has emphasized
t,hat ineffective randomization and `the phenomenon of self-selection
complicate the development of appropriate jnferences Rith regard
to causality. Such difficuhies do not prevent the identification of
causal associations, bu,t they demand careful and critical analysis of
the data. Yerushalmy has questioned the causal nature of the relation-
ship between cigarette smoking and small-for-dates infants because
of: (a) The relationship between the smoking habit of the father
and low birth weight of the infant, (b) behavioral differences between
smokers and nonsmokers, and (c) comparison of the birth reights

110


111


somatic complaint score bet ween smokers and nonsmokers. However,
when smokers were compared with nonsmokers of the same parity,
education, work history: and psychosomatic complaint, score, cigarette
smokers s&ill had a significantly higher proportion of small infants
tllan did nonsmokers. As pwviously mentioned, whenever ot,her factors
known or suspected to influence birth weight have been controlled,
cigaret,te smoking has always been demonstrated to have an in&-
pendent and significant effect.

Ounsted (69) offered evidence that the best predictor of the birth
wright of a mother's future offspring was the birth weight of her
previous children. Herriott, et al. (37) found prematurity rates for
previous pregnancies among smokers to be markedly higher thaiI
among nonsmokers, independent of parity, height, and social class.
Evidently a woman whose previous infants have been small tends to
continue to have relatively smaller than average infants in subsequriit
pregnancies. The question is, will those infants be even smaller thaiI
expected if she smokes?

Goldstein, et al. (28) : in a comprehensive review, proposed a research
design in which a woman would serve as her own control to compare
outcomes of pregnancies during which she smoked with those during
which she did not with consideration of the effect of parity on the
outcome. Yerushalmy (11%) has recently tested this type of research
design, using data from his Oakland Growth Study. With information
on t,he age at which a woman began t.o smoke cigarettes, her smoking
st,atus during the pregnancy actually studied, her prior reproductive
experience: and the outcome of her present pregnancy, the author
compared the outcomes of pregnancy during periods of smoking and
nonsmoking using the woman as her own control. ,4s the author noted.
"If smoking c0use.9 the increase in lo\~~-birth-\~eiglIt infants, then the
incidence of low birth weight for infants born to smoking mothers
during the period before they acquired the smoking habit, should be
relatively low. If, on the other hand, the high incidence of low birth
weight is due to the smoker. then it. should be high for infantsof future
smokers also n-hen they Kere born before their mothers started to
smoke."

Yerushalmy then proceeded to compare the reproductive experiences
of four groups of women: (a) Those who smoked in none of their
pregnancies, (b) those who smoked in all of t,heir pregnancies, (r)
those who were smoking now but previously had not smoked during
some pregnancies (future smokers), and (d) those who were ex-
smokers now but had previously smoked during some pregnancies.
These outcomes are shown in figure 5. The incidence of low-birth-
weight, infants in the pregnancies of the future smokers, before they
started to smoke, was similar to that, for women mho smoked in every
pregnancy, which was significantly higher than that of infants from

112


nlothers ~llo had never smoked. IIe also noted that ex-smokers: during
the period before they quit , ga1.e birth to relatively few low-birth-
wight infants; the incidence was significantly lower than for mothers
~110 smoked during all of their pregnancies. EIe roncluded that. the
iintlings cannot be easily reconciled with a cause-effect basis for smok-
~rrg and birth weight. Ile said, `6 Rather the evidence appears to support
the hypothesis that the higher incidence of low-birtll-nejFllt infants is
IIUC to tl1c S///O~P/`. not tllc .W?OX~il/~."
There are sewral considerations which limit, the interpretations
rrllich can be drawn from this study. The information on smoking
llrharior of the women during past pregnancies was apparently de-
rived from the woman's age when she began to smoke, her smoking
Savior early in the stud< pre~~uncy. and the age. at which she had
lwr prior pregnancies. Tl;us. if the Roman reported that. she began
~lnoking at a certain age, :~nd that she. was still smoking at the time of
the study, it was apparently inferred that she had smoked during all of
l~e~,pregllancic~. ,Sinre no questions were specifically asked about. actual
:nloking behx\-ior during each previous pregnCanc.yy it is possible that.
the w.m1an indeed had not smoked during every prep1anc.y or that
rhe amount. or way she smoked had dithered from current smoking

Figure 5.--Percent of low birth weight white infants bv smoking status of their

mothers.

Gravidas' smoking habits
in previous pregnancies ,

Percent low birth weight infants

Nonsmoker
(during all pregnancies)

Nonsmoker
(future smoker)

Smoker
(during all pregnancies)

o ?         2,076

Smoker
(future ex-smoker)

**               651

2 4 6 8 10
    Percent

`Difference is statistically significant (P <O.Ol).
"Difference is statistically significant (P <0.02).
w'JRCE: Adapted from Yerushalmy. J. (112).

113


habits. This would be important to know given t.he strong do%.
response relationship Rhich has been established between cigarette
smoking and low birth weight, and would tend to make the reproduo
tive outcomes for ex-smokers similar to those of nonsmokers, and
different from those of women who smoked in all pregnancies.
For ex-smoker-s, the age at which smoking began was not elicited,
Hence, some of the infants of ex-smokers may have been born before
their mothers acquired the smoking habit. This would also tend t,,
make the reproductive experiences of ex-smokers more like t.hose of
nonsmokers and different from those of women who smoked in all
pregnancies.

No direct adjustment for age, parity, and other variables was
reported, although Yerushalmy stated that the study population was
limited to the births that occurred to women at age 25 years or less.
He noted that., "In order to adjust for parity, the same comparisons
were performed for f&&born infants only. The numbers were reduced
considerably, but the same tendencies as found above were. noted."
However, no dat,a were presented. Primiparous births and births in
teenagers are strongly associated with the delivery of low-birth-weight
infants. If the pregnancies which occurred among future smoker-s
included a predominance of very young women and primiparous
births, the reproductive experiences of future smokers would tend to
be similar to those of women who smoked during all pregnancies, and
different from those of nonsmokers. In the absence of more precise
information on actual smoking behavior during pregnancy and more
rigorous adjustment for mat,ernal age, t,his study does not provide
a critical test of the hypothesis that, it is the smoking during pregnancy
which is responsible for the high proportion of small-for-dates in-
f ants born to women who smoke.

Experim.ental Studies

STUDIES IX AKIMALS

Tobacco Smoke

Several investigators have demonstrated that, exposure of pregnant
rats or rabbits to tobacco smoke leads to a reduction of birth weight
in the offspring, as compared to controls (ZJ? 87,117). Younoszai, et al.
(127) reported data from studies in rats whic.1~ indicated that some
agent present in cigarette smoke other than nicotine was responsible
for the reduction in birth weight' observed. The authors suggested that
carbon monoxide might also not be responsible for the retardation of


fetal growth ; however, the evidence presented was inadequate to
support a firm conclusion.
Haworth and Ford (33) recently extended the experiments of
Younoszai. A group of pregnant rats w-as exposed to cigarette tobacco
smoke for 6 to 8 minutes, fire times a day, from days 3 to 20 of ges-
tation. These rats were compared with another group whose food
intake was restricted to the amount actually consumed by the tobacco-
(Lsposed rats, and both were compared to a well-fed control group.
`IIe animals in both experiments were killed on the 21st day of
pesbation, and weights of the entire body, the liver, and the kidney
of each fetus were recorded. The total average fetal weight of the
group exposed to tobacco smoke was significantly lower than that of
!)oth the food-restricted and control groups. The fetal weigllts of the
lutter two groups were quite similar. Protein and DSA analyses were
performed separately on the entire forebrains and hindbrains of the
fetuses and on the entire carcass. Both DSAI and protein were sig-
nificantly and proportionatelr reduced in the carcass and hindbrams
                        Y
IJf the animals exposed to tobacco smoke. This implies that cell number
\\-as reduced and cell size was normal, and suggests that the exposure
10 tobacco smoke either inhibited cellular proliferation or accelerated
Alular destruction.

Nicotine

Several lvorkers have demonstrated that chronic injections of large
`loses of nicotine into pregnant rats resulted in a reduction of birth
wight of the offspring (7, 8: 9, $23, &I,). Other investigators have de-
rwmined that tritium-labelled nicotine injected into pregnant rabbits
;Illd C14-labelled nicotine injected into pregnant mice crossed the
IJlacenta to the developing embryo and fetus (89, 98). Kirschbaum,
Vt al. (41) found no significant acute effects of small doses of nicotine,
:nje.cted intravenously into near-term sheep, on blood gas composition,
1111, blood pressure, Or heart rate in eit.her the ewes or their fetuses.
`rlw authors concluded that the influence of maternal smoking upon
rl~p fetus must result from chronic effects or through the effects of
`It her variables which they did not study.
I<ecently, Suzuki, et al. (94) evaluated the short-term effects of in-
iWed nicotine on the cardiovascular performance, acid-base status,
"I~(~ oxvgenation of pregnant female Rhesus monkeys and their infants
`illr&' the second half of gestation using the mothers as their o~vn
."ntrols Nicotine wa5 administered either as a single intravenous
"`NJ of ij.6 to 1.0 mg br as a continuous infusion of 100 pg./kg. over
                _-
   495-028 O--73---$)

115


a 2%minute period. The injection of nicotine in the larger, single dose
into the mother produced a rise in maternal blood pressure and a
fall in maternal heart rate, and an immediate fall in both fetal blood
pressure and fetal heart rate followed by persistent hypotension and
tachycardia in the fetus. Subsequent to the injection of 1.0 mg./kg. of
nicotine into pregnant monkeys, in a single dose, significant changes
in the arterial blood of the older fetuses included a fall in pH, a rise
in base deficit, and a fall in oxygen tension. Carbon dioxide tension
remained unchanged. Nicot,ine injected directly into the fetus prompted
an immediate rise in fetal blood pressure and a fall in fetal heart
rate. These responses were similar to those previously seen in the
mothers following a direct injection of nicotine. The changes mere more
prominent in older rather than in younger fetuses. The authors surn-
marized their findings by stating that : (a) fetuses in different ges-
tational stages are differentially responsive to a given dose of nico-
tine, probably because of the different stages of development of the
autonomic nervous system: (b)  d iminished intervillous space per-
fusion resulting from rasoconstriction in the uterine circulation ap-
pears to be mainly responsible for the fetal asphyxia following the
injection into the mother, because fetal hypotension and bradycardia
were not preceded by the transient hypertension seen following the
direct administration of nicotine to the fetus; (c) the differences be-
tvveen the results obtained by Kirschbaum and by Suzuki, et al. may
reflect either the considerable dosage differences or species differences;
and (d) the doses which the authors employed were much larger than
those which a human mother would absorb from usual cigarette smok-
ing. but that differences in tolerance to nicotine between the Rhesus
monkey and humans would imply that the dosages were, in fact, com-
parable and that, "Hence, it can be envisaged that the concentration
of nicotine which could be reached in the organism of a smoking
mother would reduce oxygen availability to the fetus."

Carbon Monoxide

1,ongo (45) has reviewed the work of several investigators which
has demonstrated the transplacental passage of carbon monoxide from
mother to fetus in animals. .I recent study \\-hich related CO to birth
weight was publishrd by ,Istrup (?). He found that continuous ex-
posure throughout gestation of pregnant rabbits to different levels
of ambient carbon monoxide resulted in a statistically significant dose-
related reduction in birth vveight (table 2). The actual significance
level was not reported.

116


TABLE 2.-Eject qf carbon monoxide exposure qf pregnant rabbits
            on birth zceight

-

Group 2,      Group 3.
8 to~~lxcent  16 to 16 percent
            COHb

Number of pregnant rabbits- _ _ _ - - _ -
Total number of t)abies~--_----_----~~
Average weight of bal)ie\ in grams.. _ -



SOURCE: A&up, P. (2).

17        14         17
116        81         123
53. 7       51. 0       44. 7

Polycyclic aromatic I~~drocnrbons (I'AEI) such as benzo (a ) pyrene
(BAP) are constituents of cigarette suloke which llave been impli-
cated in the generation of cancers in many animal species (211). No
studies presentIT ayailnble wlatc brwzo( a) pzrene to i\ reduction in
birth weight of exposed offspring. Evidence suggests? however: that
RAP does reach and cross the placenta. li~y1 hydrocarbon hydrosylase
(AHH) is a part of the cytochrome PAX- containing microsomal
enzyme system, present in many tissues of difl'erent species. This
enzyme system is induced to hydroxylate polycFclic aromatic hydro-
carbons after exposure of cells to PAIII. Several investigators have.
utilized the inducibility of the enzyme system to de.monstrate indirectly
that benzo (a) pyrene and other polycyclic hydrocarbons reach the
placenta and fetus.

Welch, et al. (108) extended this work by administering the poly-
cyclic hydrocarbon, 3-metl~ylcl~olnnthrene (&MC) ? to rats during late
ge&at,ion. The meta.bolism of benzo(a)pyrenc was studied in viva (US-
ing tritium-labelled benzo (a) pyrene) and in vitro. AHH activity was
increased in fetal livers to adult. levels by pretreatment wit,h 3%MC
Since a relatively high dose of polycyclic hydrocarbon was required
to stimulate enz$ne activity in the fetus, compared to the dose which
stimulated placental enzyme activity, the authors suggested that. t.he
placenta may protect the fetus from exposure to polycyclic hydro-
carbons. However, immaturity of the fetal enzyme system might also
awount for its apparent relative insensitivity to pol:cFclic hydro-
carbons. Therefore. an exposure of the fetus to levels of poly-
cyclic hvdrocarbon similar to those c>xperienced by the mother cannot
h rulei out by the available data.

117


Schlede and Merker (86) have studied the effect of benzo (a) pgre,ne
administration on aryl hydrocarbon hydroxylase activity in the mater-
nal liver, place.nta. and fetus of the rat during the latter half of
gestation. The pregnant animals were. treated with large oral doses
of benzo (a) pyrene d-1 hours prior to sacrifice. Control rats had no
det,ect.able levels of aryl hydrocarbon hydroxylase in their placentas.
Treat.ment wit,11 benzo (a) pyrene resulted in barely detectable placenta]
levels on gestation day 13. but steadily rising values until day 15, and
then constant levels thereafter. Ko activity was detected in the fetuses
of untreated controls. In t,he treated animals, the fetal enzyme activity
rose steadily from the 1M to the 18th day of gestation. The authors
concluded that the stimulatory effect of benzo (a) pyrene treatment, on
aryl hydrocarbon hydroxylase activity in the fetus demonstrates that
benzo( a) pyrene readily crosses the rat placenta.

Carbon Monoxide

Smokers and their newborn infants have significantly elevated levels
of carbon monoxide as compared with nonsmokers and their infants
(3f,3& 88,116). Recently, Raribaud, et al. (5) studied 50 nonsmokers
and 27 cigarette smokers and their newborns. All smokers inhaled. The
authors found that the mean level of CO content in the blood of non-
smokers was 0.211 volunies percent compared with 0.672 volumes per-
cent in the blood of smokers. The values for blood samples from the
umbilical cords of their newborns were ().%?r! and 0.949 volumes per-
cent, respectively. Moreover. a definite dose relationship was found
between CO levels and number of cigarettes smoked.
Younoszai, et al. (Ill;) found, in addition to elevated carboxyhemo-
plobin levels among the infants of smoking mothers, significant
elevation of mean capillary hemotorrits and significant reduction of
standard bicarbonate level', as compared to the infants of nonsmoking
mothers. Since no el.idencr for nicotine efl'ects upon blood glucose,
serum FFA lrrels~ or urinary catecholamines, or for hypoxia was
present, they concluded that the higher hematocrit levels in the infants
of smoking mothers may hare represented a compensatory response
to the decreased oxygen-carrying capacity of the blood due to the
presence of carboxyhemoglobin.

1,ongo {dlj) pointed out that a level of 9 percent carboxyhemoglobin
in the fetus is the equivalent of a 41 lwrcent decreasr in fetal blood
flow or fetal Iwmoglobin concentration. In reviewing the studies of
CO levels in human niothcrs nud their uewborus. he made the follow

118


ing comments: "These samples were obtained at the time of vaginal
delivery or Cesarean section and may not accurately reflect the normal
values of (COHb), for se.veral reasons. The number of cigarettes
smoked by the mothers during labor may be less than their normal
consumption and was not specified in these studies. The blood sam-
ples were collected at varyin g time periods following the cessation
of smoking. In addition, many of the samples were probably taken
early in the day before COHb levels had built up to the levels reached
after prolonged periods of smokin g. Thus actual levels of (COHb)~r
and (COHb) F may be higher than the reported values."

Polycyclic Hydrocarbons

The results of several studies concur that cigarette smoking is
strongly associated wit.h t.he induction of aryl hydrocarbon hydrox-
ylase in the human placenta (18,38: 61,99? 109). This finding implies
that benzo( a) pyrene or other polycyclic hydrocarbons reach the
placenta. To date! evidence to support t,he passage of polycyclic hydro-
carbons t,hrough the placenta to t,he human fetus has not been
published.

Warnin B,, and Cyanide Detoxification

McGarry and Andrews (48) determined serum vitamin B,, levels
in 826 women at their first prenat.al clinic visit. They found that the
serum levels for smokers \vere significantly lower than for nonsmokers.
After adjustment for gestational age, parity, social class, hemoglobin
level, hypertension, and maternal weight, smokers still had signifi-
cantly lower levels of B,,. They also found a direct. statistically sig-
nificant dose-response relationship between cigarettes smoked and
serum vitamin B,, level. They again confirmed the relat.ionship be-
tween smoking and low birth \veight.. The authors suggested that. the
lowered vitamin B,, levels reflect a disorder of cyanide detoxification.
Cyanide is a demonstrable ingredient in cigarette smoke (39, 60, 6'2>
64,68,74 91).

Vitamin C

Venulet (105,106,107) has demonstrated that the vitamin C level
is significantly lower in the serum of women who smoke cigarettes
during pregnancy, compared to values for their nonsmoking counter-
parts.

Possible Mechanisms

The following mechanisms have been proposed for the production
of low birth weight and other unfavoralble outcomes of pregnancy
following exposure to cigarette smoke :

119


1. *4 direct toxic influence of constituents of cigarette smokeupon
the fetus (2, &5, 50, 51, 117).

2. Decreased placental perfusion (94).
3. Decreased maternal appetite and diminished maternal weight
gain \vith secondary effects upon the fetus (6, 33, 36, 65: 75, Qg.
117).

4. A direct effect upon the placenta (36: 57, 65,110).
5. An oxytocic effect on uterine activity (44).
6. A disturbance of vitamin B12 metabolism (&?).
`i. a disturbance of vitamin C metabolism (205,106,107).

Of the potential mechanisms, available evidence suggests that
neither decreased maternal appetite and decreased maternal weight
gain nor a direct effect upon the placenta are responsible for a sig-
nificant reduction in birth weight. Existing evidence does not permit
firm conclusions concerning the relative significance of the remaining
mechanisms.

Timing of the Influence of Cigarette Smoking on Birth Weight

Several investigators have published results which bear on the time
period during which exposure to cigaret*te smoke most affects fetal
growth. Lowe (46) and Zabriskie (118) have offered evidence which
suggests that cigarette smoking influences fetal growth most during
the second half of pregnancy. Butler, et al. (15) found that the birth
weights of infants of women n-ho did not smoke after the fourth
month of pregnancy were essentially the same as those of the infants of
nonsmokers. This implies that the influence is most probably exerted
after the fourth month of pregnancy. Herriott, et al. (35), however!
found that women in lower socioeconomic classes who gave up smoking
early in pregnancy tended to have intermediate weight babies as com-
pared with nonsmokers and persistent smokers, but his numbers of
women were small and the results were not statistically significant.
I'ndervood, et al. (100) found that cigarette smoking in any single
trimester was associated with a lower birth weight of the infant,
although the difference between the birth lveights of infants of
women who smoked only during a single trimester and infants of non-
smokers was not statistically significant because of small numbers.
Several investigators hare detected a nearly constant difference be-
tween the birth weights of the infants of smokers and nonsmokers.
delivered during the last month of pregnancy. following gestations
of comparable length [fig. 1, (12)-j. ,4lthough this observation is

120


compatible with the suggestion that the influence of cigarette smoking
upon the fetus occurs prior to the last month of pregnancy, it is based
upon data derived from cross-sectional rather than longitudinal
studies. The results of many human epidemiological studies suggest
that maternal smoking prior to pregnanq does not influence fetal
\reight gain (15, 25: 46, ~$9, 123).

Site of Action at the Tissue and Cellular Level

The use of labelled nicotine (98) and the preparations of autoradio-
grams have permitted the localization of nicotine within the tissues
of the fetus and mother. Tjalve, et al. (98) found high levels of nico-
t.ine in the respiratory tract, adrenal, kidney, and intestine of 16- to 18-
day mice fetuses. The use of other labelled constituents during various
parts of gestation might further the understanding of how certain
ingredients in cigarette smoke produce an impact upon birth weight.
Haworth and Ford ($3) have reported data which suggest that, the
reduction of birth Keight of rat fetuses caused by the action of the
ingredient (s) of tobacco smoke results from a. reduction in cell number,
but not in cell size.

Significance of the Association

Among all women in the United States, cigarette smokers are
nearly twice as likely to deliver low-birt,h-weight infants as are non-
smokers. Assuming that 20 percent of pregnant, women in the United
States smoked cigarettes ~through the entire pregnancy (extrapolated
from data on changes in smoking behavior during pregnancy collected
for the British Perinatal Mortality Study), taking into account the
apparently different risks of delivering a small-for-dates infant, for
Caucasian and non-Caucasian women who smoke during pregnancy,
and considering the number of infants with a birth weight less than
2,500 grams born to Caucasian and non-Caucasian women, an excess
of nearly 43,000 occurred in the 286,000 low-birth-weight infants
among the 3,500,OoO infants born in the I'nited States in 1968, because
of the increased risk among women who smoke of having smnll-for-
dates infant,s.
Since neonatal mortality is higher for low-birth-weigth infants.
with gest,ational ape held const,an#t, the escess of small-for-dates infants
among smoking mothers would implv a significant excess mortality
                               .,
risk as well.

121


A C3llS~Il association between cigarette smoking and fetal growth
retardation is supported by the following evidence :

1. The IXS& of all 42 studies in which the relationship between
smoking and birth weight was examined have demonstra+t& a
strong association between cigarette smoking and delivery of
small-for-dates infants. On the average, the smoker has nearly
twice the risk of delivering a low-birth-weight infant as that of
a nonsmoker.

2. This association has been confirmed by both retrospective and
prospective study designs.

3. A strong dose-response relationship has been established between
cigarette smoking and the incidence of low-birth-weight infants.
Available evidence suggests that the effect of smoking upon fetal
growth reflects the number of cigarettes smoked daily during a
pregnancy, and not t,he cumulative effect of cigarette smoking
which occurred before the pregnancy began.

4. When a variety of known or suspected factors which also exert
an influence upon birth rreight have been controlled for, cigarette
smoking has consistently been shown to be independently related
to low birth weight.

5. The association has been found in many different countries,
among different populations, and in a variety of geographical
settings.

6. Kew evidence suggests t,hat if a woman gives up smoking by t,he
fourth month of pregnancy, her risk of delivering a low-birth-
weight. infant is similar to that of a nonsmoker.
`7. The infants of smokers experience a transient acceleration of
growth rate during the first 6 months after delivery, compared
to infants of nonsmokers. This finding is compatible with viewing
birth as the removal of the smoker's infant. from a toxic influence.
8. The results of experiments in animals have shown that exposure
to tobacco smoke or some of its ingredients results in the delivery
of low-birth-weight offspring. New evidence demonstrates that
chronic exposure of rabbits to carbon monoxide during gestatioll
results in a dose-related reduction in the birth weight of their
off spring.

9. Data from studies in humans have demonstrated that smokers'
fet,uses are exposed directly to agents within tobacco smoke, such
as carbon monoxide, at levels comparable to those which haye
been shown to produce lore-birth-weight offspring in animals.

122


Cigarette Smoking and Fetal and Infant Mortality

Introduction

Several previous studies of the relationship between cigarette smok-
illg and higher fetal and infant mortality among the infants of smokers
have been reviewed in the 1971 and 1972 reports on the health con-
sequences of smoking (101, 102). In many of these studies, the authors
coinbined two or more categories of fet.al and infant mortality. Differ-
cjnt morta1it.y outcomes, such as spontaneous abortion. stillbirth, and
neonatal death, are influenced by different sets of factors. Among
other factors, the frequency of abort.ion is influenced by congenital
infections, hormonal deficiencies, and cervical incompete.ncy. In addi-
tion to other factors, the frequrncy of stillbirth is influenced by pre-
wuure separation of the placenta, utcrinc inertial and dystocia. Along
with other factors, the frequency of neonatal dcat,h is influenced by
,zestational maturity, birth injuries. and delivery room and nursery
~`~re. Separate analysis of the relationship of cigarette smoking to
each different mortality outcome, with control of the unique set of
factors which influences it, may facilitate understanding of the
relationship.

Spontaneous Abortion

Previous epidemiological and experimental studies of the relation-
ship between spontaneous abortion and cigarette smoking revielved in
the 1971 and 1972 reports on the hea.lth consequences of smoking (101,
I@%`) form the basis of the following statements :
The results of several studies, both retrospective and prospective,
have demonstrated a statistically significant association between ma-
ternal cigarette smoking and spontaneous abortion (43, 65. 70. 99,
118). Data from some of t.hese studies have documented a strong dose-
response. relationship between the number of cigarettes smoked and
the incidence of spontaneous abortions (70,%9,118). In general, rari-
ables other than cigarett,e smoking (e.g., maternal age, parity, health,
desire for the pregnanc,y, and use of medication) : whic,h may influence
the incidence of spontaneous abortions, have not been controlled. The
results of the one studv. in which adjustment for t.he woman's desire
for the pregnancy was `performed, indicated that after such adjust-
inent cigar& smoking during the pregnancy retained an association
aith spontaneous abortion of borderline significance (49). The time
Period during xvhich cigare.tt,e smoking might exert an influence on
the incidence of spontaneous abortions has not been determined. Abor-

123


tions have been produced in animals only with large doses of nicotine
($3, 96, 104) ; the relevance of these studies for humans is uncertain,

SPOSTAXEOKTS ABORTION; SUXMARY

Although several investigators have found a significantly higher,
dose-related incidence of spontaneous abortion among cigarette
smokers as compared to nonsmokers, t,he lack of control of significant
variables other than cigarette smoking does not permit a firm con-
clusion to be drawn about the nature of the relationship.

Epidemiological st.udies of the association between cigarette smok-
ing and stillbirth previously reviewed in the 1971 and 1972 reports on
the health consequences of smoking (102,10.$) form the basis for the
following statements :

In one group of ret'rospective and prospective studies, a higher still-
birth rate was found for the infants of smokers as compared to those
of nonsmoker-s (14, 25, 43'). I n another group of retrospective and
prospective studies, no significant difference was detected in the still-
birth rate among the infants of smokers and nonsmokers (16,20,&j, 99,
100). Differences in study size, numbers of cigarettes smoked, or the
presence or absence of control of variables, such as age and parity,
which may influence stillbirth rates, were probably not sufficient to
explain the differences in results obtained.

Several recent epidemiological studies have added to our under-
standing of the relationship between cigarette smoking and stillbirth.
Niswander and Gordon (63) have reported data from 39,215 preg-
nancies followed prospectively and collected between 1959 and 1966
at 12 university hospitals in the United States. A random sample of
women who presented to hospital prenatal clinics were enrolled in t,he
study. The authors reported no increase in st.illbirths among white
smokers as compared with white nonsmokers. A higher incidence of
stillbirths was found among black women who smoked than among
nonsmoking hla.ck women. and a. dose-response relationship Kith
cigarettes smoked was suggested, although the findings did not attain
statistical significance. The results mere not adjusted for other vari-
able. Rush and Kass (82) found, in a prospective study of 3,296
pregnancies at Boston Cit,y Hospital, a nonsignificant increase in

124


stillbirths among white women who smoked, but a st.at,istically signifi-
cant increase in stillbirths among black women who smoked (P<O.O2).
These findings are consistent with those previously outlined by
Frazier, et al. (26) and UnderwoodY et al. (99).
Rumeau-Roquette (81), in a prospective study of 4,824 pregnancies
in Paris, demonstrated that the risk of stillbirth was significantly
higher for cigarette smokers than for nonsmokers (P<O.OOl). The
authors also presented evidence that a woman with either a previous
stillbirth or at least one prior infant weighing less than 2,500 grams
at birth \ras significantly more likely to have a future stillborn infant
than a woman without such an obstetrical history. After previous
obste,trical history was controlled, smokers still retained a statist,ically
significant increased risk of subsequent stillbirth as compared to non-
smokers (P<O.Ol). Of further interest, was the finding t,hat among
women who previously had delivered only living infants, a-eighing
over 2,500 grams, cigarette smoking had no influence on the stillbirth
rate.

Previous experimental studies were reviewed in the 1971 and 1972
reports on the health consequences of smoking (101: 10~). The authors
demonstrated that exposure of pregnant rabbits to tobacco smoke and
pregnant rats tc large doses of injected nicotine resulted in a signifi-
cant increase in stillbirths (7: 8,23,87).

STILLBIRTH SL-XMSRY

1. The results of recent studies suggest that cigarett.e smoking is
most strongly associated with a higher stillbirth rate among
ITomen who possess less favorable socioeconomic surroundings or
an unfavorable previous obstetrical history. In the United States,
black women hare higher stillbirth rates than I\-bite women. The
finding that cigarette smoking is associated with an even greater
difference between the stillbirth rates of the t,wo groups merits
special attention. These findings may provide at least a partial
explanation for the lack of a significant difference in stillbirth
rates between smokers and nonsmokers, which some investigators
have found.

`2. The results of experiments in animals demonstrate that exposure
to tobacco smoke and some of its ingredients, such as nicotine,
can result in a significant increase in stillbirth rate.

125


Late Fetal nn.47 .Ileonatal Death8

Considerable variation has occurred in the definition of the study
population among the studies in which the relationship of cigarette
smoking to fetal mortality (other than abortion) and early infant
mort.ality was examined. The most commonly identified st,udy popula.
tions have been perinatal deaths, neonatal deat'hs, and late fetal phIs
ntwnat:~l deaths. Pcrinatal deaths are a combination of late fetal deaths
(i.e., stillborn infants) and deaths occurring within the first week of
life. Neonatal deaths include all deaths of liveborn infants wit,hin the
first 28 days of life.

EPIDEMIOLOGICAL STUDIES

Most, of the earlier epidemiological studies of the association between
cigarette smoking and late fetal plus neonatal mortality were revieffed
in the 1971 and 1972 reports on the health consequences of smoking
(101, Z&Y). h review of previously unreported studies (67? 763, as weI1
as reexamination of previously cited studies. forms the basis of the
following statements :

The results of several prospective and retrospective studies indicate
a statistically significant higher late fetal and/or neonatal mortality
for the infants of smokers compared to those of nonsmokers (14, li.
25, 43). The results of other prospective and retrospective studies iden-
tified no significant tliffcrmce in the mortality rates between the in-
fants of smokers and nonsmokers (20.6.5. 72.85, 1013. 115).

If mortality rates were compared for those infants of smokers and
nonsmokers weighing less than S..`,OO prams. the infants of nonsmokers
apparently had a consitlrrably !lipher risk than did those of smokers.
The results of recent studies, coupled with a critical review of thp
design and analysis of previous studies, and a reexamination of exist-
ing data, may provide at least a partial explanation of discrepancies
between the results of previous studies.

Comparisons of the 3Iortality Risks of r,o~v-Rii~ll-~T'eiF]lt Infants
          Born to Smokers and ;?;onsniokers

The perinatal mortality risk for infants weighing less than 2.5M
grams appears to bc lower for those infants born to women wlln
smoke during pregnancy than for those born to nonsmokers (tablr

126


3). I-Ton-ever, available evidenre shows that cigarette smokers' infants
tend t,o be small-for-gestat,iorlal age rather than gestationally pre-
mature. Hence, within a given birth w-eight group, the infants of
smokers are, on the average, gestationally more nlature than those of
nonsmokers. Data collected by the Kational Center for Health Sta-
tistics (IO./) demonstrate that within a given birth weight group? the
snore gestationally mature an infant, the lower is its mortality risk
(fig. 6). Thus, the difference in perinatal mortality risks experienced
Iy the infants of cigarette smokers and nonsmokers, within comparable
hirtll n-right classes, reflects the facts that the two sets of infants are
not of the same average gestational age, and that gestational age is
:I major factor influencing late fetal and neonatal mortality. An accu-
rate estimate of comparative mortality risks for the infants of cig-
arette smokers and nonsmokers requires adjustment for gestational
age.

For infants of comparable gestational age. lower birth weight is as-
sociated with higher mortality (fig. 6). Since infants of cigarette
smokers have, on the awrage, loner birth weights than the infants of
[lousmokers. within groups of comparable gestational age, cigarette
wakers' infants should experience higher mortality rates than non-
slnokers' infants of similar gestational ages. In a recent review, Meyer
nnd Comstock (51) provided a more extensive discussion of these
points.

TABLE 3.- Comparison qf the perinata.1 mortality -for infants u$eighing
   less than 2,500 grams, qf smokers and nonsmokers

Authcr, reference

Perinatal mortality rate (deaths per 1,CWJ
        live births)

   Smokers      Nonsmokers

rnderwood, et al. (l00)-~-_--_----_-_------.-
(`ntario Department of Health (67)------.-----
Kullander and Kiillen (4s)._----_-~-------_---
l~antdmio (76)__-.__--_-__-_-_----~~- ____ -_
YfmhaImy 1 (IIS) :
Blackwomen-_-_--__-_-_- __._ -__- .___ -.
White women---_----_-_--~--.---------~
Rrltlerand Alberman (14)------~-------------

187          269
232          300
129          139
288          344


114          202
114          218
269          284

' %"Xted neonatal mortality rates only.

127


In
ii   100

`E   80
f
.-   60


   40                      1,
rl

     JANUARY 1 TO MARCH 31, 1950
400                                  7
  .\
     \

Figure &-Neonatal mortalify rates amoyg single white births in h,ospitals (by
    detailed birth weight and speckfled gestation groups: United States),

28-31 weeks

BIRTH WEIGHT (in grams)

SOURCE: U.S. Public He&h Service, National Center for Health Statistics (103).

Recent Studies

The Ont.ario Perinat.al Mortality Study (66: 67) eras conduct4
among 10 teaching llospitals (Iuriug 1%X and 1961. In this retrospw
tivr study of 51.190 1"~~
          `~wi;~li(~irs. a statistically siguificant increa~c~
in the prinatal mortality rate was dcmonstratecl for sniokers' in-
fants as conipar~d with those of nonsmokers; the infants of sulolters
csperienwd an 0~crall relative risk of 1.27 (I'< 0.001). Moreover, tlw
inr-rstigators found a statistically significant (low-response relationsllip
b&Keen t.hc amount of cigarettes smoked and the prinatal mortality
rate (P<O.OOl) (fig. `i).

128


Figure 7.-Perinatal mortality rate per 1,000 total births by cigarette smoking
     category.

          Nonsmoker



Number of
Perinatal deaths:   659

Total births:    28,368

<I pack of
cigarettes     z,l pack of
           clga rettes
per day       per day



  425            220

15,328         6,581

(P <O.ool)

SOURCE: Ontario Department of Health (66).

Recently Butler, et al. (15) further analyzed the British Perinatal
IIortality Study. They found a highly significant association between
niaternal smoking after the fourth month of pregnancy and both
Iate fetal and neonatal deat,hs. Infants of smokers had an increase in
Ilie late fetal mortality rate of 30 percent, and an increase in the neo-
W%l mortality rate of 26 percent, compared to the infants of non-
smokers. The overall mortality ratio of late fetal plus neonatal deaths
`yas 1.28 (P<O.OOl). Given t,he large number of women in the study,
:llld the significant changes in smoking behavior which occurred,
nkcy found it possible to consider the effect. of a change in smoking

129


behavior bctxecn the beginning of pregnancy and the fourth month
on late fetal and neonatal mortality. ,I statist,ically significant alld
dose-related increase in mortality occurred among the infants et
mothers who continued to smoke after the fourth month of pregnanrY,
as compared wit,h the infants of nonsmokers and those of women I&,
smoked prior to the pregnancy but gave up smoking by the fourth
month of gestation.

Nislvandtr and Gordon (63) reported data from the prospectne
Collaborative Perinatal Study of the National Institute of Xeurologi.
cal Disease and Stroke. The :39,215 pregnancies registered at 12 uni-
versity hospitals in the I-nited States were almost equally divided
between black and white w-omen. They found a nonsignificant. increase
in perinatal mortality among t.he infants of white smokers as Compared
to those of white nonsmokers; the overall mortality ratio was 1.1:3
(P>O.l). The infants of black smokers, however, had a significant]!
higher mortality risk than did those of black nonsmokers; the mar-
tality ratio was 1.18 (P<O.O2). Moreover, a definite dose-response r-e-
lationship bet.ween cigarettes smoked by pregnant mothers and
mortality risk was shown for black infants. Black women were noted to
smoke significantly fewer cigarettes, on the average? than white
women.

Rush and Knss (83) found, in a prospective study of 3.2'76 preg-
nancies followed at Boston City Hospital. a nonsignificant increase
in late fe'tal plus neonatal mortality rate among the infants of white
n-omen who smoked as compared to those of white nonsmokers. Holy-
ever, the infants of black women who smoked had a statistically sig-
nificant increase in mortality rate compared to the infants of blacb
nonsmokers (P<O.Ol) . The overall mortality ratio for black women
who smoked was 1.86. The difference in frequency of stillbirth among
the infants of smokers and nonsmokers was the primary factor w-hick
contribrltcd to the signifcancc of the difference in mortality rates.

-1nalysis of Previously Re.ported Studies

Previously reported studies can be divided into two groups : A proq
in which the late fetal plus neonatal mortality rates for infants born
to cigarette Fmokers were significantly higher than those for thp
infants born to nonsmokers, and a group in which no significant
ditl'crrnces were detected in the mortality rates for the infants born
to smokers and nonsnrokers. The results of several studies (I.$. 17. ,OC
49, $3, 55, Sj. 92) yielded mortality ratios ranging from 1.38 to 1.X
The results of other studies ($0. 65/r: 76. X,5, I/XI. 215) yielded mortalit!
ratios ranging from 1.01 to 1.06. Roth groups contained retrospective
and prospective studies of comparable size. The two groups did differ

130


~~~iiificantly, however. with regard to control of wriables other t,han
,ig;wctte smoking which influence perinatal mortality.

Fwtors V7~ich Influence Pcrinatal Mortality Other Than Smoking

13utler and Mberman (I.)), on data from the British Perinatal
Ywtality Study, employed a logit tl.:~nuforlllatio~l analysis of vari:mceY
.1t1(1 demonstrated that nlaternal height, agr, l)aritJ? social class, and
wwre preeclampsia all had a dignificant indelwndent ctlect On late
itatal and neonatal mortality. Rumeau-Roquette (81) provided evi-
~lcwe that a 1)rerious stillbirth or low-birth-\vcight infant significantly
it~rrrnsc~d the risk of a future stillbirth. Meyer and C'omstock ~~51)
lwvided examples of 110~ the diflerrntial distribution of smoking and
1~t11rr factors which are related to perinntnl mortality, in a population
of women, can bias data (e.g., black w01ne~i have higher perinatal
lllortnlity rates than do white women, but black women smoke, less
t11an white women do. Hence. nonsmokers Iv-ill tend to include more
`~lwk women, and smokers more white women. This I\-ill tend to
r&ice any differences between the groups in mortality rates.) Meyer
~l1t1 Comstock conc~luded, Comparisons of mortality rates of smokers
~1 nonsmokers' babies Aould be made within subgroups according
to parity, socioeconomir status. and other appropriate risk factors:
M not separated by birth weight."
In three of the studies in which a significantly higher mortality risk
aas demonstrated for the infants of smokers, adjustment for other
rnriables was performed. The resu1t.s indicated that, after such ad-
jtistment, a significant independent association between cigaret,te
smoking and infant mortality persisted (13 and 15. 17, 81). Of the
studies which revealed no significant increase in mortality risks for
smokers' infants, one (11.5) cont,rolled for race alone. Hence, at least
l)art of the discrepancy in results between the two groups of studies
1iia.r be explained by a lack of control of variablw other than smoking.
-inother possible, at, least partial, explanation of the discrepancy
iii results obtained by the tn-o sets of studies is that cigaret'te smoke
may be more harmful to the fet,uses of certain women- than others.
Several developing lines of evidence suggest that. this may be the case:
1. Cigarette smoking and socioeconomic background.
Butler, et al. (15) noted t.hat when data from the British Perinatal
JIertality Study are grouped by social class of the mother's husband,
the late fetal plus neonatal moG.ality ratio for infants of smokers and
tiensrnokers in the upper social classes I and II is 1.10: t.he mortality
ratio for the entire sample was 1.28. Rush and Kass (82) reviewed the
%tish Perinatal JIortality Study, along with several other studies,
and noted that all have sho\rn the strongest, association betwwr excess
infant mortality and cigarette smoking among the infants of those

405-028 o--7B----Jo                                      131


mothers with lower socioeconomic status. Comstock and Lundin (16)
found excess mortality among smokers' infants almost entirely eon.
fined to those whose fathers had a grammar school education or 1%.
Several of the studies which revealed no significant difference in mopA
tality among the infants of smokers and nonsmokers were conducted
in predominately middle class populations ($0, 100,115).

2. Cigarette smoking and previous obstetrical experienc;e.
Peterson, et al. (72) had rigid criteria for entry into his stu$

population of 7,740 women, He*included only those women who pre.
viously had healthy infants with a birth weight greater than 2,500
grams. He found a significant decrease in birth weight among smokers,
infants, but no significant increase in mortality rates. Rumeau.
Roquette (81) found that among women who previously had delivered
only healthy infants weighing more than 2,500 grams, cigarette smok.
ing was not associated with an increased risk of stillbirth ; among those
women with a previous stillbirth, smoking was significantly associated
with increased risk of a future stillbirth.

3. Cigarette smoking and gBnetic differences.

The consistent finding that the mortality risk for the infants of black
smokers is higher than t,he risk for the infants of white smokers, even
when the socioeconomic background for both is ostensibly similar.
suggests that genetic factors also may interact with smoking to pro-
duce enhanced risk (82, 99, 115).

Availa,ble evidence suggests that. if those women, who are already
likely to have small infants for reasons other than smoking, smokp
during pregnancy, t.heir infants will be most unfavorably affected,
This means that the women in the United States Those infants will
be most affected by cigarette smoking are those who have an unfavor-
able socioeconomic sit,uation, have a history of previously unsuccessful
pregnancies, and are black.

Studies in Animals

Studies previously reviewed in the 1971 and 1972 reports on the
health consequences of smoking (101,102) demonstrate that exposure
of rabbits and rats to tobacco smoke and to injections of large doses
of nicotine resulted in significantly increased late fetal and neonatal
mortality. Astrup ($?) has recently studied the e.ffect of continuous
exposure of pregnant rabbits to carbon monoxide on stillbirth rates.
He found a significantly higher, dose-related incidence of stillbirtllF
and deaths within the first 21 hours of life among the offspring of the
experimental rabbits (table 4).

132


TABLE 4.-ELff~cf ?f carbon monoxide exposure of pwgnant rabbits on
        birth weight and neonad mortality

Group 1,     Group 2,      Oroup 3,
0 psrrnt   8 to 10 Percent  16 to 18 percent
COHb      COHb       COHb

(P<O.OOl)

' 1 percent.
? 10 percent.
$36 yerccnt.
Source: Astrue, I'. (a)

Studies in Humans

Some investigators have examined the causes of death among the
infants of smokers as compared nith those of nonsmokers. Comstock,
et al. (17) found that infants of smokers died more frequently of as-
])hyxia, atelectasis, and immaturity. Kullander and Kallen (.&!I) found
ilhruptio placentae significantly increased as a cause of death among
smokers' infants. Butler and Xlherman (14) found little difference in
the death rat.es for the infants of smokers and nonsmokers from iso-
immunization and malformations. but higher rates mere found for
smokers' infants in t.he groups in which death occurred before or dur-
ing labor, or in which death resulted from massive pulmonary hemor-
rhage, or pulmonary infection. As t,he authors noted. "The lat,ter three
are conditions knoLn to be associated 4t.h small-for-dates babies."
Tlley pointed out that distribution of causes of deat.11 in the smoking
~enp could be accounted for almost, entirely by the excess of low-birth-
~~~~ipht babies. This supports the conclusion that the mechanism which
Lltfects birth weight also influences mortalit,y.

$hGNIFICAXE OF TIIl? ~k3SOCIhTION

The following calculation is offered to piw some idea of the order of
r~9?nitude of increased late fetal and neonatal mortality associated
"yitll Cig:lty$ttl srljokill f (Illl.iIIg 1)1ygtl:lllc\-. If \voi11t~ii \\I10 snloked dltr-

133


inp pregnancy in the United States had an elevation in risk of 28 per.
cent for late fetal and neonatal mortality. as demonstrated by Butler.
ct, al. (l/j) for I3ritain, Srotlancl, and Wales, and if 20 percent ef
pregnant women smoked throughout the pregnancy,l the higher risk
of stillbirth and neonatal death for the infants of mothers who smoke
cigarettes during pregnancy would account, for approximately 4,606 of
the 87,263 stillbirth and neonatal deaths in the rnited States in 1Dfjfj.

LATE FETAL AND NEONATAL DEATH SUMMARY

A strong, probably causal association between cigarette smoking
and higher late fetal and infant mortality among smokers' infants is
supported by the following evidence :

1. Twelve retrospective and prospective studies have revealed a sh-
tistically significant relat.ionship between cigarette smoking ant1
an elevated mortality risk among the infants of smokers. In t,hree
of these studies, of sufficient size to permit adjustment for other
risk factors, a highly significant independent association betweet!
smokng and mortality was established. Part of the discrepancy in
results between these studies and those in which a sign&ant
association between smoking and infant mortality was not dem-
onstrated may be explained by a lack of adjustment for risk fac-
tors other than smoking.

2. Evidence is converging to suggest that cigarette smoking may be
more harmful to the infants of some women than others; this may
also, in part, explain the discrepancies between the results of the
studies in which a significantly higher mortality risk was shown
for the infants of smokers compared to those of nonsmokers and
the results of those studies in which significant differences in
mortality risk were not, found.

3. Within groups of similar birth weight, the infants of nonsmokers
appear to have a higher mortality risk t,han do the infants of ciga-
rette smokers. This results from the fact that the infants of non-
smokers within such similar birth weight groups are on the
average gestationally less mature than the infants of cigarette
smokers. Available evidence indicates that within groups of sim-
ilar gestational age, infant,s of lower birth weight experience a
higher mortality risk. Since the infants of cigarette smokers an

`Based on extrapolation of data on smoking behavior change during pregnancy from
the British Perinatal Mortality Studs. which probably Fields a conservatire estimnte.

134


small-for-gestational age, one. should expect, that if the infants of
cigarette smokers and nonsmokers are compared within similar
gestational age classes, the infants of cigarette smokers would
have the higher mortality rat,e.

4. The results of recent studies have documented a statist.ically sig-
nificant dose-response relationship between the number or amount
of cigarettes smoked and late fetal and neonatal mortality.
5. Kew data suggest that if a woman gives up smoking by the fourth
month of pregnancy, she will bnve the same risk of incurring a
fetal or neonatal loss as a nonsmoker.
6. Available evidence strongly supports cigarette smoking as one
cause of fetal growth retardation. The causes of excess deaths
among the infants of smokers are those associated with small-
for-dates babies.

i'. Data from experiments in animals ha1.e demonstrated that expo-
sure to tobacco smoke or some of its ingredients, such as nicotine
or cnrboii monoxide. rwults in it significant increase in late fetal
and or neonatal deaths.

8. The results of studies in humans have shown that the fetus of
a smoking mother may be directly csl~owtl to agents such as
carbon monoxitlc nitllin tobacco smoke, at ha\-els comparable to
those n-hicall llal-e heen shown to produce stillbirth in experimental
animals.

Sex Ratio

-4lthough a number of small studies have found a slight, usually
statistically nonsignificant. increase in tlic prot)ortion of female infants
born to smokers, the three lill'gest studies of Ivndrrwood. ct al. (48.505
pregnancies), Butler (15,791 l~regnancies)7 and NacMahon (12,155
pregnancies) have found similar infant sex ratios among bot.h smok-
ing and nonsmoking mothers. with tlw espwtetl slight excess of males
among each (table 5).

Available cviderlre strongly indicates thnt matt~rnnl c*igarette smok-
irlg does not influenc~e the sex ratio of ncwl~~rn infants.

135


TABLE 5.-Proportion qf male in,fants delivered to smoking and non-.
           smoking mothers

Author, reference

    Propo;;C$;f male
Pregnancies               Statistical

       Smokers    NOW   significance
              smokers

Underwood, et al. (IOO)-_. .--_-__--._-- 48, 505
Butler and Alherman (f.$- _ .__. _..___.. 15, `791
MacMahon, et al. (49)-_~--~-~-----~--- 12, 135
Kullander and Klillen (43)- __-_-_ . . . . . .  6,363
Reinke and Henderson `(78) - - _-. . _.. .__  3, 156
Frazier, et al.' @?b) -___. . _ _. _ _ _. . . . . . . - _  2, 915

518    519
,518    .516
513    .512
515    501
498    .517
472   505

502
492
501
532
513

493
. 517
,533
529
. 512

Kizer (@)-.- . . . . - ._.. ~_~ . .._ . . . . ..__  2,095
Herriott, et al. (35)..-- ._.... ~.----_---  2, 745
Ravenholt, et al (77) ____.-.__...__.____  2, 052
Lowe (46)-_-_..--..---_-~_..----~.--- 2,042
Russell, et al. (85) _._._ -. . .___-_..___ ._  2, 002

' Black women.

Congenital Malformations

Previous epidemiological studies which examined the relationship
between cigarette smoking and congenital malformations mere E-
viewed in the 1971 and 1972 reports on the health consequences of
smoking (101, 10.2). Recently, the authors of the Ontario Perinatal
Mortality Study (Ml 67): a retrospective study of 51,490 births, re-
ported no difference in malformation rate for the infants of smokers
and nonsmokers. The various studies of the. association b&aeen ciga-
rette smoking and congenital malformation have differed signific.antly
with regard to stud>- design. the type of population sampled. sample
size and number of infants with malformations, the definition of mal-
formation, and resu1t.s (table 6).

Previous experimental vork was reviewed in the 1971 and 1972
reports on the health consequences of smoking (102, 102). The chick
embryo has been employed in recent studies. The direct application of
nicotine to the embryo results in cephalic hematomas (26). malforma-
tions of the cervical vertebrae (99). and anomalies of the heart (27).
depending upon dose of nicotine and period of incubation in which
exposure occurs. Anomalies of the limbs of chicken embryos can also
be induced by exposure of the e gg to high levels of carbon monox-
                                   _
ide (4).

None.
Do.
Do.
Do.
Do.
(fl:od.OS)
None.
DO.
P<O.O5
None.
DO.

136


TABLE 6.-Relatire risk qf congenital ma(;formation .for in:fants of
cigarette smokers and nonsmokers, comparzng available studies with,
regard to study design, study population, sample size) number of
infants with malformaiions, and cl&ition qf malformation

Author.
reference

Study design

                 Infants Relative
Study population   Sample   with    risk    Definition of
             size   malfor-  SM/SS  malformations
                 mations

Cornstock, et al.
(17).
Yerushalmy (112)

Ontario Depart-
ment of Health
(i;Y).
htlur and hl-
berman C/4).

Gullender and
Gallen l&3).

Retrospective. Stillborn plus 24.hour
          deaths.

.__._ do __.__.... Neonatal deaths __.___

Prospective.. Infants less than
         2,500 g.
RetrGspectlve. Stillborn plus lst-
         week deaths plus
          surviving infants.
_..._ do _...... Stillborn plus neo-
          natal deaths.
   I (8) Stfllborn plus neo-
             natal deaths

rrospectise.. .

plus remainder
of deaths to age
1.

I (b) Surviving infants
   to age 1.
(4 ' Stillborn plus
   neonatal deaths 1
   and deaths to

Fedrick, et al.
(14).

Retrospective.

age 7.'sur-
vlvors 2 to age
7.

I (b) Neonatal deaths '
   (3-month
   study).

2,042

236

695


51,490



7,123

137

4,903

17,418

7,822

23

3i

59

1, 744

1.382

43

7cn

86







201

1.36 Jlajor.

.31 xajor, cause of
    death.
.6i Major.

.9?

1.19 JlRjOT, CallSB of

1.25



   8


1.06

death.

bfajor and minor
malfomlations.

1.55 (1).







1.07 (2).

' hutopsy-proron congenital cardiac malformation.
' Clinically determined congenital heart disease.

Given the considerable variation in study design, study population,
sample size, number of affected infants, definition of malformation,
and results, no conclusions can bc drawn about, any relationship
between maternal cigarette smoking and congenital malformation at
the present t,ime.

137


Lactation

Introduction

The following section is a review of available evidence which bears
upon any interaction bet.ween cigarette smoking and lactation. Emphn.
sis is placed upon the relationship of cigarette smoking to the quantity
of milk produced, to the presence of constituents of cigarette smoke
within the milk, and to effects upon the nursing infant mediated
through changes in either the quantity of milk available or the sub-
stances within the milk.

Epidem.ioZogica.Z Studies

Underwood, et. al. (99)? in a study of 2,000 women from various
social and economic strata, observed a definite but statistically insig
nificant trend toward more frequent inadequacy of breast milk pro-
duction among those smoking mothers who attempted to nurs,e
compared to nonsmokers.

Mills (5a), in a study of 520 women, found that among women who
indicated either a desire to nurse or no desire to nurse yet continued
to nurse beyond 10 days, and who had delivered their first live-born
infant, the average period of nursing for mothers who smoked was
significantly shorter than for nonsmokers. Moreover, among t.he 24
mothers who had given up smoking during at least the final 3 months
of their pregnancies, the average length of nursing was identical to
t,hat, of the nonsmokers. There was no significant difference between
smokers and nonsmokers with regard to complete inability to nurse
their offspring. This study is difficult to interpret because the author
did not determine the reason(s) for the discontinuation of nursing
among the women.

Experimental Studies

STEDIES IS ~~IAI,S

Nicotine

         Influence on the Lac.tation Process
BIake and Sawyer (11) studied the influence of subcutaneousl!
injected nic,otine (4 mg. total over a 5-minute period) upon lactatioll
in the rat,. They found that nicotine inhibited the suckling-inducrll

138


rise in prolact,in. So effect, of injected nicotine was demonstrated for
qtocin secretion since milk release was not' blocked.
1vilson (110) examined the effects of nicotine supplied through
,lrinking water (0.5, 1.0, and 2.0 mg. daily) on the weight gain of
nrirsing rats. Apparently. the nicotine had been available throughout
gestation as well. because the author commented on a reduction in litter
size among the experimental groups. more, or less proportionate to t.he
close of nicotine; hence, a prenatal effect could not have been dis-
tinguished from a postnatal one. Average birt,h weight was similar for
rspcrimental and control groups. So difference in weight. gain was seen
for any of the, groups. The lack of impact on birth \veight suggests
that close was lower t,han that used in other studies.

Presence of Nicotine in the Milk

Hatcher and Crosby (3.2): using a frog bioassay, reported traces of
nicotine in cow's milk 24 hours after the intramuscular injection of
5.0 mg./kg. and 5 hours aft,er the injection of 0.5 mg./kg.

Evidence for an Effect Upon the Nursing Offspring

Hatcher and Crosby (3.2). found that 0.5 mg./kg. nicotine injected
into nursing cats had no apparent harmful effect upon the kit,tens.
dpparently 4.0 mg./kg. suppressed lactation. Kittens fed the milk
from the cow which had been injected with 5.0 mg./kg. nicotine were
also apparently unaffected.

Kitrosamines

Bohr (53) found that diethylnitrosamine and dibutylnitrosamine,
Then administered to lactating hamsters? lvere associat,ed with the
(ierelopment of typical tracheal papillary tumors in the young? sug-
gesting passage of these compounds in.the milk. Although diet,hyl-
aitrosamine and dibutylnitrosamine have not been identified in ciga-
rette smoke,, many N-nitrosamines are potent carcinogens, and some
of them are present in cigarette smoke (37, 79).

STUDIES IX HCMANS

Nicotine and/or Tobacco Smoke

        Influence on the Lactation Process
Emanuel (~2') noted no reduction in milk production among 10 wet
nurse who were encouraged to smoke seven to 15 cigarettes daily ;

139


some were observed to inhale the smoke. Hatcher and Crosby (32)
noted that after a mother smoked seven cigarettes within 2 hours, it
was difficult to obtain a specimen of breast milk. Perlman, et al. (71)
found that of 55 women smokers wit.h an adequate milk supply at the
beginning of his st,udy, 11 (20 percent) of the women had an inade-
quate supply at the time of discharge from the hospital. No relat,iou-
ship was reported between the number of cigarettes smoked and the
likelihood of developing an inadequate milk supply. The authors' im-
pression was that there was no greater proportion with an inadequate
milk supply among smokers than among nonsmokers, but no car-
roborat.ing data were supplied.

Presence of Nicotine in the Milk

Hatcher and Crosby (32) f ound, using a frog bioassay, that the
milk of a woman collected after she had smoked seven cigarettes in 2
hours contained approximately 0.6 mg./liter nicotine. Emanuel (.ss),
using a leech bioassay, studied excretion of nicotine in the milk of wet
nurses who were encouraged to smoke for the experiment. After the
subjects had smoked six to 15 cigarettes over a l- to e-hour period, the
author found nicotine in their milk 4 to 5 hours after smoking, with a
maximum concentration of 0.03 mg./liter. Bisdom (10) demonstrated
nicotine in t,he milk of a mother who smoked 20 cigarettes a day.
Thompson (97) found approximately 0.1 mg./liter of nicotine in the
milk of a mother who smoked nine cigarettes a day (plus three pipe-
fuls). Perlman, et al. (71)) using a Daphnia bioassay, demonstrated
nicotine in the milk of all women who smoked in their study. Moreover,
they found a direct dose-relat.ionship between concentration of nicotine
and the number of cigarettes smoked. No comment is made by the
authors on the possible inaccuracy introduced by examining only the
residual milk following nursing, but it, is well known that the composi-
tion of the fore milk and hind milk is different and perhaps the
concentration of nicotine also differs.

Evidence for a Clinical Effect Upon the Offspring

Emanuel (22) noted that among t,he infants in his study, loose stools
were observed only in the one whose wet nurse had smoked 20 c&a-
rettes in the previous 4 hours. Bisdom (10) observed a case of "nico-
tine poisoning" in a 6-meek-old infant whose mother smoked 20 cig:l-
rettes a day. The symptoms included : restlessness. vomit,ing, diarrh~~:l.
and tachycardia. Nicotine was demonstrated in the milk, and tl~
symptoms abated when smoking was stopped. Greiner (JO) also &-
scribed a case of possible nicot,ine poisoning in a 3-week-old nurslil+'

140


~llose mother smoked 33 to 10 cigarettes a day. The symptoms included
vomiting and loose stools. Following the curtailment of smoking. the
+wptoms gradually abated over a 3-day period. I'erlman2 et. al. (71)
noted no effect of smoking on the weight gain of the infants of the
smokers in their study. Furthermore, no untoward symptoms were
observed. They therefore doubted an effect of smoking on lactat,ion.
Thy noted that, the dose received by the infants was beneath the toxic
level as computed from adult experience, and this accorded wi-ith their
clinical observations. The fact that they admit.ted to the study only
\vomen with an apparently adequate milk supply may have affected
tlteir results. The authors suggested that perhaps t.he lack of effect of
smoking upon lactation might represent the development of tolerance
to nicot,ine! as both the mother and the oRspring had been exposed
throughout the pregnancy.

VITAMIN C

Venulet (105, 106, 107). in a series of studies, demonstrated that
the level of vitamin C was reduced in the milk of smoking mothers as
compared with nonsmokers. The clinical significance of this observit-
tlon has not been evaluated.

Lzctndion Xu.mmary

1. The two pertinent epidemiological studies suggest. a possible in-
fluence of smoking upon the adequacy of milk sul~ply However,
with only limited numbers of women and without control of other
potentially significant variables, no conclusions can be drawn.
2. Studies in rats have clrmonstrxted that nicotine can interfere with
suckling-induced rise in prolac~tin. The rele\-ancc for humans
is uncertain.

3. Evidence csists that nicotine passes into breast milk. Xo clear
evidence for an acute efTect upon the nursing infant is arailable.
Potential chronic effects Ilaw not been studied.
4. Sew eviticncc froni c~slwrinwilts with niicc suggests that nitros-
amines. lillO\V11 cnrcino,~ws, 1~ass tllrorlgtl tlle milk to suckling
yonnp.

141


Preeclampsia

Previous epidemiological studies of the relationship between ci,g.
arette smokimg and preeclampsia were revierved in the 1971 and 197~
reports on the health consequences of smoking (101,102) and form the
basis of the follo\ving statements :

The results of several large prospective and retrospective studies
indicate a statistically significant lower incidence of preeclampsia
among smoking women (1& 43,100). The results of one large retre.
spective study demonstrated a significant inverse relationship betlreen
the incidence of preeclampsia and the number of cigarettes smoked
(100). When other risk fact,ors, such as parity, social class, maternal
weight before the pregnancy, and maternal weight gain during the
pregnancy were controlled, smoking women retained a significanth
decreased risk of preeclampsia (22). The lower risk of preeclam&
for cigarette smoking women has been demonstrated in Britain and
Scotland (14. 21. 46, 83)) The IJnited States (100, 118)? Venezu&
(@), and Sweden (43). If a maternal smoker does develop preeclamp.
sia, however, available data suggest that her infant has a higher mar.
tality risk than does the infant of a nonsmoker with preeclampsi~
(.21,83).

1. Available evidence indicates that maternal cigarette srnok?b
have a significantly lower risk of developing preeclampsia a>
compared to nonsmokers.

2. If a woman who smokes cigarettes during pregnancy does derelnl,
preeclampsia, her infant has a higher mortality risk than the
infant of a nonsmoker with preeclampsia.

Pregnancy References

(1) ABERNATHY, .J. R., GREENBERG, B. G.. VELLG, H. B., Frwzzsa, T. 11
   Smoking as an independent variable in a multiple regression anal+.
   upon birth weight and gestation. American Journal of Public Health an!
   the ration's Health 56 (4) : 626633, April 1966.
(2) ASTBUP, P. Pathologische Wirkungen mirssiger Kohlenmonoxid-Rome!.
   trationen. (Pathological effects of moderate carbon monoxide concenlK1
  Cons.) St.aub-Reinhaltung der Luft 32 (4) : 146-150,1972.
(3) BAILEY, R. R. The effect of maternal smoking on the infant birth wei@
   New Zealand Medical Journal i'l(456) : 293-294, May 1970.

142


14) BAKER, F. D., TUMASONIS, C. F. Carbon monoxide and avian embryc-
  genesis. Archives of Enrironmental Health 24(l) : 5361, January 1972.
1.j) BAFXBAUD, L., YACOUB, M., FAURE, J., JIALIXAS, Y., CAU, G. L'oxyacar-
  bonemie de l'enfant nP de mere fumeuse. (Presence of carbon monoxide
  in the blood of a child born of a smoking mother.) AIedecine Legale et
  Dommage Corporel 3 (3) : 272-274, July-August-September 1970.
iG) BEBL, V. A. Nutritional studies during pregnancy. Journal of the Ameri-
  can Dietetic Association 58(4) : 821-326, April 1971.
/: ) BECKER, R. F., KING, J. E. Studies on nicotine absorption during preg-
  nancr. II. The effects of acute heavr doses on mother and neonates.
  American Journal of Obstetrics and Gynecology 95 (3) : 515522, June
  15,1!%6.

18) BECKER, R. F., LITTLE, C. R D., KINO, J. E. Experimental studies on
  nicotine absorption in rats during pregnancy. III. Effect of subcutaneous
  injection of small chronic doses upon mother, fetus, and neonate. Ameri-
  can Journal of Obstetrics and Gynecology lOO(7) : 057-968, Apr. 1. 1968.
(9) BECKER. R. F., MARTIX, J. C. Vital effects of chronic nicotine absorption
  and chronic h.rpoxic stress during pregnancy and the nursing period.
  American Journal of Obstetrics and Gynecology llO(4) : 5L"2-333, June
  15, 1971.

10) BIRDOM, C. J. W. Alcohol and nicotine poisoning in infants (sucklings),
   Maandschrift voor Kindergeneeskunde 6 : 332-341, 1937.
1111 BLAKE, C. A., SAWYER, c`. H. Nicotine blocks the suckling-induced rise
  in circulating prolactin in lactating rats. Science 177(4049) : G1!3-621,
   Aug. 18, 1972.

112) BUNCKER, C. R. Cigarette smoking and duration of pregnancy. American
   Journal of Obstetrics and Gynecology 103(7) : 942-946. Apr. 1, 1969.
`1.3) BUTLEB, N. R, ALBEBMAN, E. D. (Editors), Perinatal Problems. The Sec-
   ond Report of the 1958 British Perinatal Jlortalits Survey. London, E.
   and S. Livingstone, Ltd., lS69,395 pp.

'I$) BUTLER, N. R., ALBERMAN, E. D. (Editors). The effects of smoking in
   nregnancy. Chapter 5. In: Perinatal Problems. Edinburgh, E. and S.
   Livingstone, Ltd., 1969, pp. 72-84.

`1.5) BUTLER, K. R., GOLDSTEIN, H., Ross, E. M. Cigarette smoking in preg-
  nancy: Its influence on birth weight and perinatal mortality. British
   Medical Journal 2: 127-130, Apr. 15, 1972.

`I(;) COMGTOCK, G. W., LUNDIN, F. E., Jr. Parental smoking and perinatal
   mortality. American Journal of Obstetrics and G~ncologr S8(5) : 70s
   718, July 1,1967.

"7) ~MSTOCK, G. W., SHAH, F. K., MEYER, M. B., ABBEY, H. Low-birth weight
   and neonatal mortality rate related to maternal smoking and socio-
   economic status.  American Journal of Obstetrics and Gynecology
  111(l) : 53-59, Sept. 1,197l.

`18) COX~JEY, A. H., WELCH, R., KUXTZMAX, R., CHANQ, R., JACORSOX, M.,
  %IUXROFAURE, A. D., PECK, ,4. W., BYE, A., POLAND, A., POPPERS, P. J.,
   FIYSTER, N., WOLFF, J. A. Effects of environmental chemicals on the
   metabolism of drugs, carcinogens, and normal body constituents in
   man. Annals of the Sew York Academy of Sciences 170: 335-172. July
   6.1971.

`I$) D~MAQALA, J., DO~I~~GALA, L. Zachowanie sie wagi urodzeniowej oraz
   r7MtOsc wv.rstepowania nczesniactwa I wad \yrodzonych u noworodkow
  kobiet palacych tyton. (Rirth weight and incidence of prematurity and
   Congenital anomalies in newborns of mothers smoking tobacco.) Pedi-
  atria Polska T. 47 ( 6) :73;5%73'i, 1972.

143


(20) DOWNING, G. C., CHAPMAN, W. E. Smoking and pregnancy. A statistical
   study of 5,659 patients. California Medicine 194(3) : 187, March 19%.
(21) DUFFUS, 0. M., MACGLLLIVEAY, I. The incidence of preeclamptic toxaemh
   in smokers and nonsmokers. Lancet l(7556) : 994995, May 11, 19~.
(22) EVANUEL, W. fiber das Vorkommen von Nicotin in der Frauenmilck
   nach Zigarettengenuss. (On the presence of nicotine in breast milk fol.
   lowing the use of cigarettes.) Zeiischrift fiir Kinderheilkunde 52: 41-
    46, 1931.

(23) ESSENBERG, J. M., SCHWIND, J. V., PATRAS, A. R. The effects of nicotine
   and cigarette smoke on pregnant female albino rats and their offspring,;,
   Journal of Laboratory and Clinical Medicine 25: 708717, 1940.
(24) FEDRICK, J., Ammbim, E. D., GOLDSTEIN, H. Possible teratogenic e&t
   of cigarette smoking. Sature 231: 5299530, June 25, 1971.
(25) FRAZIER, T. M., DAVIS, G. H., GOLDSTEIN, H., GOLDBEBO, I. D. Cigarette
   smoking and prematurity : A prospective study. American Journal 0t
   Obstetrics and Gynecology 81(5) : 988-996, May 1961.
(26) GATLING, R. R. Effect of nicotine on chick embryo. Archives of PathoioQ
    `78 : 652-657, December 1964.

(27) GILANI, S. H. Nicotine and cardiogenesis. An experimental study. Patho].
   ogia et Microbiologia 37(5) : 383-392,197l.
(28) GOLDSTEIN, H., GOLDBERG, I. D., FRAZIEE, T. M., DAVIS, 6. E. Cigarette
   smoking and prematurity. Journal of the American Osteopathic &jse
    ciation 64 : 541-549, *January 1965.

(29) GO~YJ~RD, J., ETIENNE, C., E~RARD, F. Caracteristiques materneiles et poi&
   de naissanee. (Maternal characteristics and birth weight.) Revue du
   Praticien 19(28, Supplement) : 54, 59-62. 65, Sov. 1, 1969.
(SO) GREINEB, I. Nikotinvergiftung, beobachtet bei einem Siiugling. (Nicotiie
   poisoning observed in a breast feeding infant.) Jahrbuch fur Kinder.
    heilkunde 146 : 131-132,1936.

(31) HADDON, W., Jr., NEGBIT, R. E. L., GARCIA, R. Smoking and pregnancy
   Carbon monoxide in blood during gestation and at ,term. Obstetrics anti
   Gynecology 18(3) : 262-267, September 1961.
(32) HATCIIEB, R. A., CROSBY, H. The elimination of nicotin in the milk. Joumai
   of Pharmaceutical and Experimental Therapy 32(l) : l-6, 1927.
(33) HAWORTH, J. C.. FORD, J. D. Comparison of the effects of maternal under-
   nutrition and exposure to cigarette smoke on the cellular growth of thu
   rat fetus. American .Journal of Obstetrics and Gynecology 112(5) : 653.
    656, Mar. 1, 1972.

(34) HERON, H. J. The effects of smoking during pregnancy: A review with 2
   preview. Sew Zealand Medical Journal 61 : 545548, Sorrmber 196?.
(%) HERRIOTT, A., BILLEWICZ, W. Z., HYTTEN, F. E. Cigarette smoking in prer
   nanry. Lancet 1 : 771-7i3. Apr. 14. 1962.
(36) JAR~IXES. P. A., OGTERLUND, K. Effect of smoking during pregnancy nr.
   the fetus, placenta and delivery. Annales Paediatriae Fenniae 9: IP-3
    1963.

(97) JOHRSOS, D. E., RHOADES, J. W. N-nitrosamines in smoke condense!r
    from several varieties of tobacco. Journal of the National Cancer I!.
    stitute 48( 6) : 1845-18-17, June 1972.

(38) .Jr,c~ar:, JI. R. Human placental hydroxylation of 3,4benzpyrene dunnr
   early gestation and at term. Toxicology and Applied Pharrnacnl~~c
    18(3) : 665675, March 1971.

(39) KEITH. C. H., TESH, P. G. Measurement of the total smoke issuing fmc
   a burning cigarette. Tobacco 16011.5) : 26-29, Apr. 9, 1965.

144


(40) KIXG, J. E., BECKER, R. F. Studies on nicotine absorption during pregnancy.
   I. LDMI for pregnant and nonpregnant rats. American Journal of Ob-
   stetrics and Gynecology Q5 (4 ) : 50%>14, Juno 15, lQ66.
,$I) KIRWIIBAUX. T. H., DILTS, P. V., Jr., BRINKNAN, C. R., III. Some acute
   effects of smoking in sheep and their fetuses. Obstetrics and Gynecology
   35 (4) : 5327-536, April 1970.

( $2) KIZEX, S. Intiuencia de1 habit0 de fumar sobre el embarazo, parto y recien
   nacido. (Effect of the smoking habit on ltiregnancy, delivery, and the
   newborn.) Rerista de Obstetricia y Ginecologia de Venezuela 2'7(4) :
   59X%43,1967.

143) KULLANDER, S., K;~LLEN, B. A prospective study of smoking and pregnancy.
   Acta Obstetrlcia et Gynr~ologica Scandinavica 50(l) : 8%Q4, 1971.
($4~ KCMAR, D., ZOIXLAG, P. A. Studies on human premature births. II. In
   riro effect of smoking and in vitro effect of nicotine on human uterine
   contractility. American Journal of Obstetrics and Gynecology Si'(3) :
   413-417, Oct. l.lQ63.

c&Y) Loruco, L. D. Carbon monoxide in the pregnant mother and fetus, and
   its exchange across the placenta. Annals of the Sew York Academy of
   Sciences 174 ( 1) : 313-341. Oct. 5. 1970.
($6) LOWE, C. R. Effect of mothers' smoking habits on birth weight of their
   children. British JIedic,al Journ#al 2 : 673676, Oct. IO. lQ5Q.
W) MCDONALD, R. L., LANFORD, C. F. Effects of smoking on selected clinical
   obstetric factors. Obstetrics and Gynecology 26 (4j : 470-175, October
    1965.

148) MCGARRY, J. M., ANDREWB, J. Smoking in pregnancy and vitamin Bu
   metabolism. British Medical Journal 2: 7+77. Apr. 8, 1972.
149) ~IACMAHON, B., ALPERT, 121., SALBE.R, E. J. Infant weight and parental
   smoking habits. American Journal of Epidemiology 82(3) : 247-261,
    November 1965.

($0) MANTELL, C. D. Smoking in pregnancy : The role played by carbonic anhy-
   drase. Sew Zealand Jledical Journal 6.3: 601-603, September 1964.
(51) MEYER, M. B., COMSTOCK, G. W. Maternal cigarette smoking and perinatal
   mortality. American Journal of Epidemiology 96(l) : l-10, July 1952.
(52) AXILLS, C. A. Tobacco smoking: Some hints of its biologic hazards. Ohio
   State Medical Journal 46( 12) : 1165-1170, December 1950.
`*%y) Mona, U., ALTHOFF, J. Carcinogenic activity of aliphatic nitrocamines via
   the mother's milk in the offspring of Syrian Golden hamsters. Proceed-
   ings of the Society for Experimental Biology and Medicine 136(3) :
   1007-1609, March 1971.

`j4) ~~UXHERJEE, S., MUKHERJEE, E. N. A study of premature births. Indian
   Journal of Pediatrics 38(285) : 38Q392, October 1971.
(jj) ~IULCAHY, R., Knaccs, J. F. Effect of age. parity, and cigarette smoking
   on outcome of prrgancy. American Journal of Obstetrics and Gynecology
   lOl(6) : 814-S40, July 15, 1968.

rag) -\IuLCAHY, R., MURPHY, J. Maternal smoking and the timing of delivery.
   Journal of the Irish Nedical Association t%(i) : 175157. Apr. 1. 1972.
"') >fT-LCAHY, R.. MURPHY, J., MARTIX, F. Placental changes and maternal
   weight in smoking and nonsmoking mothers. American Journal of Ob-
   stetrirs and Gynecology 106 (*5) : 703-704. Mar. 1,197O.
""I ~~~?RDocI~, D. E. Birth weight and smoking. Nebraska State Medical Jour-
   nal 48 (11) : 604-606. Sovember lQ63.
"`) -\IVRPIIY, J. F  \IT:LCAHT. R. The effect of age, parity, and cigarette smok-
            ., .
   lng on baby weight. American Journal of Obstetrics and Gynecology
   111(l) : 2Z2.5, Sept. 1,1971.

145


(60)

(61)

(62)

(63)

(64)



(65)

(66)

(67)

(68)


(69)


(70)

(71)



(72)



(73)

(74)



( 7-s )


(76)

NALL, J. F. Complexed cyanide in collected cigarette smoke. Abstracts ot
20th Tobacco Chemists' Research Conference, NOV. l-3, 1966, Winston.
Salem, S.C., 1966, pp. 26-27.

NEBERT, D. W., WINKER, J., GELBOIN, H. V. Aryl hydrocarbon hydroxylaw
activity in human placenta from cigarette smoking and nOnSmoking
women. Cancer Research 29(10) : 1763-1769, October 1969.
NEW~OME, J. R., NORMAN, V., KEITH, C. H. Vapor phase analysis of tobac.
co smoke. Tobacco Science 9: 102-110, July 23, 1965.
SISWAX~ER, K. R., GORDOX, 11. Section 1. Demographic characteristics,
Cigarette smoking. In: The Women and Their Pregnancies. The co\.
laborative Perinatal Study of the National Institute of Neurological Dls.
eases and Stroke. Philadelphia, IV\`. R. Saunders CO., 1972, PP. 72-80.
NORMAS v,, SEWSOME, J. R.. KEITH, C. H. Smoking machines for the
analysis of the vapor phase of cigarette smoke. Tobacco Science 12:
216221,196s.

O'LANE, J. M. Some fetal effects of maternal cigarette smoking. Obstetrja
and Gynecology 22 (2) : 181-U!+& August lQ63.
OXTARIO DEPARTMEXT OF HEALTH. Second Report of the Perinatal 110~.
tality Study in Ten University Teaching Hospitals. Toronto, Canada,
Ontario Department of Health, Ontario Perinatal Mortality Study Corn.
mittee, vol. I., lQ67, 255 pp.

ONTARIO DEPARTMEST OF HEALTH. Supplement to the Second Report of thP
Perinatal Mortality Study in Ten rniversitg Teaching Hospitals. Toran.
to, Canada, Ontario Department of Health, Ontario Perinatal Nortalltr
Studs Committee, vol. II, 1967, pp. 95-275.
OSRORNE, J. S., ADAMEK, S., HOBBS, M. E. Some Components of gas phase of
cigarette smoke. Analytical Chemistry 28(2) : 211-215, February 195f,
OUXSTED. JI. Maternal constraint of foetal growth in man. Develrpmental
Medicine and Child Seurology 7: 459-191, October 1965.
PALMGREN, B.. WALLASDER, R. Cigarettriikning och abort. Konsekutir ~roc
pektiv undersKkning ar 4312 graviditeter. (Cigarette smoking and abnr.
tion. Consecutive prospective study of 4,312 pregnancies.) Liikarrtid-
ningen AR(22) : 2611-2616. Jlay 26, 1971.
PERLMAN. H. H., DAXNENBERG, A. M., SOKOLOFF, N. The excretion of nicotine
in breast milk and urine from cigarette smoking. Journal of the Amrrimr
Medical Association 12IJ (13) : 1003-1009, Nov. 28,1942.
PETERSOX. W. F.. MORESE, K. PC., KALTREIDER, D. F. Smoking and ilrr-
maturity. A preliminary report based on study of 7,740 Caucasian>
Obstetrics and Gynecology 26((i) : 775759, December 1965.
PFZERSSOS, F. Medicinska skadeverkningar av r8kning. RGkning orh 1bF
neknlogisk-obstetriska tillstand. (Harmful clinical effects of smoking
Smoking  and gynecologiral-obstetrical condition.)  Social-JIedici~iGi
Tidskrift 2 ( Special R'o. `j : `78-82, February 1971.
PHILIPPE. R. J., HOBBS. II. E. Some romponents of the gas phase I,!
cigarette smoke. Analytical Chemistry 28(12) : 2002-200.5, Decrnllwr
1956.

PRIXROSE. T.. Hrcc~ss. A. A study in human antepartum Imtritilr
Journal of Reproductive Medicine 7 (6) : 2X'-2W, December 1971.
RAsTAKAI.I.IO. P. Groups at Risk in Low Birth WPigbt Infants and IkiwI
tal Mortality. A 1,rospertirr study of the biological characteristics HII~!
socioeronnmir rirmlmrtnnces of mothers in 12,000 deliveries in Sort!.
Finland 1966. A disrriminant fnnrtion analysis. Acta Paedintn
Srandinavira (Supplcmcant 193) : 1969, 71 pp.

146


IV) RSVENUOLT, R. T., LEVIX~KI, h1. J., CELLIST, D. J., TAKEYAGA, 31. Effects
   of wiolcirig 1111~111 rcqlrotlnction. ,\nlr~rican Journ; of Oljstetrics and
   G~-ncTlrlnpy !K;(:!) : L'Gi-%I, Stxl't. 1.3. l!m.
IX') RCISVKE. \I-. X.. IIESDERSOS. 31. Smoking and 1)rematurity in the presence
   of other variables Archives of Environmental Health 12 (S) : 600--606,
   Jh>- l!Mx.

13) RIIOADES, J. W., JOIISSOS, D. E. Xethod for the determination of S-nitro-
    samines iu tol,ac~cl-~~111,lit' colttlt~uwte. Journal IIf the Sational (`ancer
    lustitllte 4S (G 1 : 1\41-lS43. 511nv 1972.
I ,F/) ROBIXSOS. 1'. `\-sl~\\-n w11ym Ii\\ rmmy\\--t vzmn hhry\vn whshp'tw `1 h'm
   h'wt)r w-h>-lw-cl. ( $:luol;iug II> I<urnr~~xr n'omen dariug l~rr~na~~c~ and its
   influence on the mother, the fetus and the ncxborn.) Harefuah
    1~1 ( 2 ) : xi-3!). l!G.

~8.1) RL-SSELI.. c'. S.. TAYLOIZ, R.. I,.\w. C. E. Smoking in pregnancy, maternal
   blood pressure. ljregnancy outcome, bah~ weight and growth. and other
   related fa<*tors. A l)rc~slwc'tirt~ stlldy. British .Journal of Preventive and
   Social 1Iedicint~ 22 (3 1 : 11%1%. July 196%
1')) RI-SSELI.. C`. S., T.4~1.01~. R.. ~IADDISOS. R, S. Some effects of smoking in
   pregnancy. Journal cbf Olwtetrics and (:yuecology of the British Common-
   wealth 73 : 742-746, October 1,966.

1851 SAVEL, I<. E., ROTII. E. Effects of smoking in pregnancy: h continuing
   retrospective study. Ol)sCetrics nut1 Gynecology 20(3 1 : 313-316. Septem-
   her 1962.

186) SCHLEDE, E., MERKER, H.-J. Effect of benzo(a)pyrene treatment on the
   henzo (a) pyrerre hytlms~lnre activity in maternal liver. placenta. and
   fetus of the rat during day 13 to day 18 of gestation. Saun;rn-Schmiede-
   berg's Archires of I'liarmacc~log~ 172 (1 ) : SQ-100, Dec. 21, 1071.
Icr':i PCII~EXECK, F. J. Cigarette smoking in pregnsncy. Sew York State
   Journal of Medicine 41 : l!M.k1945, Oct. 1, 1CMl.
'r*Q) %OPPETT.I. V. Sul contenuto di ossido di carhonio nel sanpue CirCOIante
   di gestnnti fumatrici. (Carlwn monoxide rontcnt in the blond circulating
   in pregnant smokers. ) .\rchirio di Oatetricia e Ginecologia `i3(3) : 369-
   3i5, MapJune 196s.

"9) SIELIER, S. 31.. Fa~xo. S. Identification of drugs in the lweimplantation
   blastoc.vst and in the plasma, uterine secretion and urine of the pregnant
   rahhit. dournal nf I'harmacology and Experimental Therapeutics 176(l) :
   65-X. 3971.

`!r0i SIMPSOS, W. .J. ,k lnv?liminary report on cigarette smoking and the
  incidence of prematurity. American Journal of Obstetrics and Gyne-
   wlo~ X (4) : MLS1.X .ipril l%i.
In1 1 SPEARS  k. IV. ROT-TX. I\`. B. A romlliued approach to the qunntitatire
        IA .
   analysis of tht, riolatilta c~clmllonents of cigarette smoke. I?aper presented
   at the 18th Tnl,ncrn (`llemists Research Conft~renre, Raleigh. N.C.,
   1864.

QS-026 o--73-11

147


(91) STEELE, R., LAXGWOKTH, J. T. The relationship of antenatal and post.
   IMtal factors to Sll~ldt'll lulrsl~t~ctf~tl dt%th ill infancy. Canadian JIedical
    &soriation .J~n~rn;rl !)4 : IlOT,-1171. May 2S, l!)W
(93) STRUIIEI.. G. Action tcrntogc,nr tlu sulfate tlr nicotine sur l'embryon de
   poulet. (Trrntoprnic action of nicotine sulphntr on chick embr;po,)
   Comptes Rendus IIt~ll~lolll:~daires ties Seances de 1'Acadamie des Sciences:
    1) : Sciences Satnrelles 2i2t-1) : 8i3-676, Jan. 2.i. 1971.
(94) SUZLTKI. IL, HORIGLTXI. T., C'o~ras-17rmuTIa. A. C., MUELLER-HEuBA~H, E,.
   ~IORISHIMA. il. Cl., hDA%CSOSS. K. ~harr~lncolod~ effWtS of nirotine
    upon the fetus and mother in the Rhesus monkq. American aournal of
    Obstetrics and Gynecology Ill(R) : 1092-1101, Dec. 13.1971.
(95) TERRIS, M., Gor.n. E. JI. An epidemiolngiic study of prematurity. I. Relation
    to smoking. heart volume, employment. and physique. American Journal
    of Obstetrics and Gynecology 103 (3) : 35ls-370. Feb. 1, 1969.
(96) THIEXES, C. H., I,OMRARD, C. F., FIEI~DISG. F. .J., T,ESS~R, A. J., ELI.ES.
    IIORN. M. J. Alterations in reproductive functions of white rats ass~.
    &ted with daily exposure to nicotine, Journal of Pharmacology and
    Experimental Therapeutics 87 : l-10, 1946.
(97) THOMPSON, W. B. Nicotine in breast milk. American Journal of Obstetrics
    and Gynecology 26 : 66%667,1933.
(98) TJXLYE, H., Haxsso~, E., SCHMITERLW, C. G. Passage of I'C-nicotine and
    its metabolites into mice foetuses and placentae. Acta Pharmacologica et
    Toxicologica 26 (6) : 53%556. 1968.
(99) UNDERWOOD, P. B.. HESTER, L. I,., LAFITTE. T., Jr., GREGG, K. V. The relation.
    ship of smoking to the outcome of pregnancy. Smerican Journal of
    Obstetrics and Gynecology 91(2) : 270-276, Jan. 35, 1965.
(100) UNDERWOOD, P. B.. KESLEB. K. F., O'LAXE, J. >I., CALLAGAN, D. A. Parental
    smoking empirical& related to pregnancy outcome. Obstetrics and
    G.vnecolo-7 29(l) : I-8, dannary 1967.
(101) T.S. PCBLIC HEALTH SERVICE. The Health Consequences of Smoking, A
    Report of the Surgeon General : 1971. Washington, U.S. Department of
    Health, Education, and Welfare,  DHEW Publication So. (IISM)
    71-7513, 1971, 458 pp.
(102) T'.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking, A
    Report of the Surgeon General: 19i2. Washington, U.S. Department of
    Health, Education, and Welfare, DHEW Publication Xo. (HSMi
    72-7516, 1972, 158 pp.
(109) U.S. PYBLIC HEALTH SERTICE. S~TIOSAL (TESTER FOR HEAI.TH STATISTICS,
    Weight at hirth and survival of the newborn--United States. early 1950.
    Washington. U.S. Department of Health, Education, and Welfare, Public
    Health Service Publication No. 1000, Series 21, No. 3. .Tuly 1965, 33 pp,
(104) VAFCA, P., KINNUNES, 0. The effect of nicotine on the female rabbit and
    developing foetus. An experimental study. Annals Aiedicinae Esperi-
    mentalis et Biologica Fenniae 29 : 202-231, 1951.
(105) ~7~~~~~~. F. SaStPpStwa niedoboru xvitnminy c u paIaCZy. (~OIW?qU+?nW?
    of vitamin C deficiency in smokers.) Polskie Archiwum Medyc.rny
    Wetvnetrznej 26 : 393402, 1956.
(106) VEXXET, F.. I,avsz. II. U'hytek nitaminy c w narzadach zab poddanyh
    dzialaniu dFmu tytonion-ego. (Influence of tobacco smoke on ascorM,
    acid content in mothers milk.) Acta Physiologica Polo&a 4(4) : 3%
    356, 1954.
(107) VESYL~, F.. D.4susz. A. TVplyw palenia tytnniu na poziom witaminy c n
    mleku Kobiecym. (The influence of tobacco smoking on the level (if
    vitamin C in human milk.) Pediatria Polska 3019) : 811-817, 1955.


1ln8) WELCH. R. JI., Go~r-\rr. B.. ALVAHES. A. P.. COTSEY, A. H. Effect of enzyme
   induction on the metabolism of henzo (a)pyrene and 3-methyl-4-
    mo~~o~net1~~lan~inonzol~e~ize~~e in the pregnant and fetal rat. Cancer Re-
   warch 32(S) : 973-978;. May lOi?.

IO!)) TELCII, R. 11.. HMIRISOX. T. E.. GOMJII. IL TV., POPPERS, P. J., FISSTER, M.,
   COXSEY, A. H. Stimulat#)r~ effect of cigarette smoking on the hydrosyla-
    tion of 3.4-l wnq~yrenr and the X-drmeth.rlstion of 3-methyil-4-mono-
    mrtl~~luniinonzol~c~~izrt~e 1,~. cnz~mes in hnmxn placenta. Clinical Phar-
   macology am1 Therapeutics 10(l) : lWlO9, JannarF-February 1969.
, 110) WILSOX. E. IV. The &ect of smoking in l'rcynnncy on the ~~lncental coeffi-
    cient, Sew Zealand Medical Jnurnnl i4 (li.5) : 384-385, 1972.
I 111) TTrr~rn. E. I,., HOFFx4Sx. II. Tnl~ncro and Tobacco Smoke. Ptndies in
    Exl,erimentnl Cnrcin~)grrtesis. Scxv York. Academic Prtw, 1967, 730 pp.
( Il?j TERI-~HALXI-. J. Infants wit11 low-birth vright born before their mothers
   started to smoke cigarettes. American Journal of Obstetriw and GFne-
    colo,l2\` 132(2i : Yi-`1s-i. Jan. 35, 1973.

1 1l.j) YER~-SIT,~I.XY, J. Mother's cignrrttte smoking: and surviral of infant. Ameri-
   van .Jwrnal of (hIMetric< and Gynecol~gv SS ( 4 1 : 50~-51>;, Fell. 15, 1964.
I II j) YERT`STI.~T XI-, ,T. Statistical ron~iderations and ernlnatinn of rpidemiologi-
    cnl ex-idence. lir : .Iamcx G.. Rosentlial. T. (Editors). Tol~cco and Health.
   P~wlncfirld. Chnrlcs V. Thomns. 196L'. *qx 2OM30.
lll.il TERI-SII~LMY, .J. The relntiowhi~~ of parents' cigarette smoking to outcome
   of I,re.~rlnnc~-ilrl~11icnti~,lls a$ tcj the prolrlem of inferring causation from
    observed associations. American Journal of El)idemiolog.r 93 (6) : 443-
    4.56. June 1971.

1 Ilfi YOI-SOSZAI. >I. K., KSCIC. A.. H~WORTII. .J. C. Cigarette smoking during
   pregnancr : The effect npon the hc~m:~tocrit and arid-lease balance of
    the newlwrx infant. (`nnatlian JIedical Association Journal 99(5) :
   197-200, Aug. 3, 1068.

`II;) Yo~:soszar, >I. hr.. I'EI.OSO. J.. I-Iawon~~. J. C. Fetal gron`th retardation
   in rats rs~~oscd to cigarette slllolte tlnrilrg ~~rr,qnnncy. American Journal
   of Olwtetrics and GynwoloC'y 104 (fi) : 30T-1213, Ang. 15, 1969.
"18) ZABRISKIE, .J. R. Effect of cigarette smoking during pregnancy. Study of
   2.000 cases. Obstetrics and Gynecology `71(4) : 405111, April 1963.

149


CHAPTER 5

Peptic Ulcer Disease


Contents

Page

Introduction-_-.._- _____ --___-__--__---___--_____________   155
E:pidemiological and Clinical Studies-- _ - - _ _ - - - - _ - _ _ - _ - -_ _ _ _   155
Experimental Studies

Gnslri~ Secretion_-- _______ - ____ -__- ____ -__-___--_--__   157
Pancreatic Secretion---- ____ ---- __..- --____--_-_-__--_-   159
summary of Recent Peptic Ulcer Disease Findings- - _ - _ _ - _ _ _   162
References_---_-- ____ -___-_____ ______ - ___________-_____   163

List of Figures

Figure I.-Gastric ulcer mortality ratios of Japanese (men and
women combined) by age at initiation of cigarette smoking
(1966-70)-----e--e- -__- -_-- ___-_-_ _- __--_-_-__------_   156
Figure 2.-Effect of cigarette smoking on volume of secretin-
stimulated pancreatic secretion in humans-_ --_ __-_ __--_-_   160
Figure 3.-Effect of cigarette smoking on secretin-stimulated
pancreatic bicarbonate output in humans_--- __ _ _ -_ _ - -_ _ - _   161

153


Introduction

Previous epidemiological and csperimental st.udies of the reMion-
ship bctn-ren cigarette smoking and peptic ulcer disease were reviewed
in the 1071 and 1072 reports ou the hea1t.h c,onseqnences of smoking
(17, 18) nnd form the basis of the following summary :
The results of epidemiological studies indicate t.hnt cigarette smok-
ing males hare ml increased prevalence of pept.ic ulcer disease and a
(venter mortality from peptic ulcer as compared to nonsmoking males.
t
.1niong ~nalcs. the association between cigarette smoking and peptic
ulcer disease is stronger for gastric than for duodenal ulcer, but sig-
Axnt for both. For males, cigarette smoking appears to reduce the
ctfectiveness of standard 1)eptic ulcer treatment and to slow the rate of
lqtic ulcer healing. The relationship between cigarette smoking and
the prevalence of and mortality from pept,ic ulcer disease is less clear
for females than for males.

Experimental studies of t.he effect of cigarette smoking in man, and
Of the effect of injection and infusion of nicotine in animals, on gastric
secret,ion and motility have producecl conflicting results. In dogs, an
infusion of nicotine has been found to inhibit. pancreatic and hepatic
l~icnrbouate secretion, t,hus demonstrating a possible link bet.ween
cigarrtte smoking and duodenal ulcer.

Kecemly, additional epidemiological, clinical, autopsy, and esperi-
lllental studies have confirmed the associat.ion bet.we.en cigarette smok-
ing and gastric ulcer mortality and have clarified a mechanism through
nhich cigarette smoking might be linked to duodenal ulcer.

Epidemiological and Clinical Studies

Previous studie.s of the relationship between peptic ulcer disease and
"ixarette smoking have been conducted in predominantl;y IT-hi&, West-
(`1~ populations. X large prospective. epiden~iological studS is current,Iy
t)eing conducted in ,Tapan. From this study, Hiraynma. (6) reported
s;-~ear followup data on 265,118 men and women, aged 46 years and
()lh, representing 91 to 99 percent of the t.otal 1)opnlation in the area
(If the 29 llcalth clistricts in which the study n-as conducted. ISot,h male

155


Figure l.-Gastric ulcer mortality ratios of Japanese (men and women Combined)
     by age at initiation of cigarette smoking (1966-1970).

4.00




3.00




2.00




1.00





0

         Nonsmoker





SOURCE: Hlrayama, T. 16).

:>25        <24        <19
Age at initiation of cigarette smoking (years)

156


Alp, et al. (1) conducted a retrospective survey of 638 pat,ients,
~tlmittecl to two ,Iustralian teaching hospitals between 1954 and 1963,
with chronic gastric ulcer confirmed by roelltgcnogrraphic, cndoscopic,
or swgical examination. The findings in the patients were compared
wit.11 information available about the South Australian population
obtained at census in 1954 and 1961, and with a control group of 233
subjects matched for age and sex with the ulcer patients. Cigarette
use, a family history of peptic ulcer. domestic stress. and aspirin and
:~lcohol intake, occurred significantly ~IOIY~ fruquentl~ among ulcer
patients. Alp, et al. (2) found that after surgical trcatmrnt, recurrence
of the ulcer was significantly more likely to recur amoug those patients
~110 continued to smoke, drink, and use aspirin (P<O.OOl).

Fingerland, et al. (5) compared the autopsy findings from `i65 males
with their smoking history. The atltopsies were performed without
selection during 1965 and 1966 at the I-nivcrsity of Hradec Kr;ilovk:
Czechoslorakia. Peptic ulcer was significantly more frequent among
de es-smokers and male lifelong smokers than among male non-
smokers (P<O.O2). Among males. a close-response relationship was
found between estimated total cigarette consumption and the presence
of peptic ulcer at autopsy.

Cooper and Tolins (4) rrportcd results from a retrospective st,udy
of the relationship between cigarette smoking and postoperative com-
plications among 2,988 males? admitted to 19 Veterans Administration
hospitals, for the surgical treatment of duodenal ulcer. Smoking his-
tory was obtained for 1,441 of the men, and of these 273 were non-
SITlOkers, 1,018 smoked cigarettes only, and 93 smoked cigarettes plus
a pipe and/or cigars. The authors fouud no evidence of an association
between either the number of cigarettes smoked per clay> or the number
of years of cigarette smoking, ant1 postoperative complications, opera-
tire mortality, or length of hospital stay. They emphasized that their
results must be viewed wit11 considerable caution ant1 listecl several
potential sources of bias. In addition. they noted, U* * * that these.
results apply only to the immediate 1)ostopcrativc findings and do not
:lpply to the long-rnugr ctiects of smokiug upon the patient after
surgery for duodenal ulcer disease."

Experimental Studies

IIorales, et al. (10, II) studied the effect of cigarette smoking on
gastric secretion in a group of 312 patients. The patients included 138

157


with duodenal ulcer, 93 with gastric ulcer, and 81 with other gastro.
intestinal disorders, who served as controls. Cigarette smoking was
significant,lv more frequent among the patients with peptic ulcer than
         "
among the controls.

The chronic effect of smoking on gastric secretion was quit.e variable.
Male smokers among the controls and in the group with duodenal
lllcers had a significantly increased baseline acid output as Compared
mit,h nonsmokers in the same groups (P<O.OS). After a subcutaneous
injecbion of histamine, only the group of male smokers with gastric
ulcers had a significant increase in acid output over the values obtained
for nonsmokers in the same group (P<O.OS). Among the smokers in
the control group, the relationship between gastric acid output and the
number of cigarettes smoked daily was dose dependent. pu'o such rela-
tionship was obtained for either of the two groups with peptic ulcers,

In these experiments, the acute effect of smoking on gastric secre-
tion was slight. In one set of experiments, a group of eight smokers
served as its own control. The smoking of two cigarettes prior to
collection of gastric juice had no significant effect on acid output as
compared to baseline value's After smoking two cigarettes and also
receiving a subcutaneous injec,tion of histamine, the patients experi-
enced no significant change in gastric acid output as compared to
baseline values. , 21 male patients, including members from the groups
with ulcers and controls, smoked one cigarette 1 hour after an intra-
venous infusion of histamine. A transient depression of gastric acid
output was noted as compared with the values obtained from nine
patients who did not smoke.

Kontllrek, et al. (8) studied the effect of intravenous infusion of
nicotine on the formation of acute, experimental duodenal ulcers in
cats. The authors infused nicol-ine intravenouslyv in doses comparable
to the smoking of four, eight. and 16 cigarettes per hour into cats in
whom near maximal gastric acid output had been stimulated with
intravenous pcntagastrin. The jnvrstigators found that nicotine in the
two lowr doses had no effect upon the gastric acid output stimulated
by pentagastrin. bllt that thr highest dose produced a significant. de-
crease in wspo~me. due to a fall in both \-olume and acid concentration.
Sicotine nlonc failed to alter :t negligible basal gastric secretion. In
control animals ( pcntagastrin alone), duodenal ulcers were found in
eight of 10 animals. Sicotine at the two lower doses, in rombination
with pentagastrin, prodnccd ulcers in all 26 animals. .1t the inter-
mediate dose of nicotine, the mean ulcer area was twice that found in

156


the control group. ,1t the highest dose of nicotine. peptic ulcers ap-
pearecl in only two of six animals and the area of ulcer was reduced
compared to controls.

Shaikh, et al. (14) studied the acute and chronic effects of sub-
cutaneously injected nicotine on gastric secretion in rats. I-r&r basal
conditions, the volume of gastric sccrrtion x-as initinllx depressed,
then stimulatrd, and deprcsstvl again as the dose of nicotine was
increased. A4cid output KM dccrcnsctl over the entire range of nicotine
dosage. Pepsin output rrflrctrtl a similar triphasic response to in-
creasing nicot.ine doses as did gastric secretory volume. In the absence
of nicotine. pentngastrin stimulated gastric volume, acid, and pepsin
output. The injection of nicotinr. in increasing doses. administered
simultaneously with pentngastl~iii. resulted in a pradual decrease in
response for all parameters. I-olunw of gastric juice, acid output, and
pepsin output x-rre all increased sipiificantly by chronic exposure to
nicotine alone. Based 011 an a\-ernqe smoking dose of nicotine. the dose
of nicotine rmploycd in the chronic csprrinwnts corresponded to the
smoking of three to five cigarettes lwr. day.

Thoml)son. et al. (16) extended the study of rats clcscribed above
by studying the effects of chronic nicotine injections in wgotomized
rats and rats with cliscr.etcJ lesions in the hypothalanlus. In sham-
operated animals, chronic, nicotine injections significantly increased
baseline volume of gastric juice? acid output, aud pepsin output. Fol-
lowing vagotonry, tlw nicotine reslm~w was completely suppressed.
Caudal hypothalamic lesions did not influence the response to nicotine
in the preseilce of intact vagus nerves . -Interior hypothalamic lesions,
ranging from the anterior hypothalamic area to the ventromedial
hypoth&amus, blocked the nicotine-induced gastric secretory stimula-
tion in the presence of intact vagi. The authors concluded that chronic
nicotine-induced gastric secretory stimulation is mediated via anterior
hypothalamic activation and intact vagus nerves. `I% imp0rtanc.e of
local effects remained uncertain.

ByJIUI~, et al. (3) studied the effect of cigarette smoking upon pan-
rreatic secretion in 23 ltealthy JYN~~ males and females. Five control
nlale nonsmokers were compare"d with seven male and tv;o female light
snlokrrs (less than one pack of cigarettes per day for less than 3 years)
UKYI eight male and one female heart qnlokers (more than one pack of

159


cigarettes per day for more than 3 years). Pancreatic secretion was
n~rasur~d by the double secretin test, using Boots secretin. The experi.
ment was divided into two 1)arts for the smokers: A basal collection
period and an experimental period during which the subject,s smoked
seven nonfiltered cigarettes at the rate of four per hour. Light smokers
had basal values for pancreatic secretory volume and bicarbonate out-
put in response to secretin wllich were not significantly different from
controls. After the subjects had smoked, s&r&cant depression of both
pancreatic volume and bicarbonate output was noted (P<.OOl).
Heavy smokers ha.d basal values that \vere significantly less than in the
control subjects (P<O.Ol). Smoking, however! did not further depress
the response to sccretin (figs. i! and 3).

Solomon and ,Jacobsen (15) reviewed some possible mechanisms
whereby the increased prevalence and mortality from duodenal ulcer
among cigarette smokers might be produced. They concluded that
evidence from studies in animals, coupled with the findings of Bynum.
et al. (.3), supported the hypothesis that the mechanism active in
humans involves impaired neutraliza.tion of acid secondary to tIlc
inhibition of pancreatic bicarbonat'e secretion.

Figure 2.- Effect of cigarette smoking on volume of secretin-stimulated pancre.
       atic secretion in humans.

MeanDvp'ume
pancreatic
fluid in
milliliters
per kilogram
body weight

3.0

2.5


2.0

1.5


1.0

0.5

a

1 Significantly different from nonsmoking test within group of light smokers (P <O.oOl)
3 Significantly different from nonsmoking controls (P <O.Ol).

SOURCE: Bynum. et al. Qb

160


Figure 3. -Effect of cigarette smoking on secretin-stimulated pancreatic bicar.
     bonate output in humans.

Mean hourly 8
output of
bicarbonate 6

   in
milliequiva. 4
lents per hour

J

`Significantly different from nonsmoking test within group of light smokers (P <O.OOl).
`Significantly different from nonsmoking controls (P 10.01).

SOURCE: Bynum. et al. (3).

STUDIES IN bUMALS

Konturek, et al. (7) extended his research on the mechanism of
nicotine-induced inhibition of pancreatic secretion in the dog, using
the design previously employed (9). Infused secretin alone led to a
sustained increase in pancreatic bicarbonate output. Intravenous nico-
Cne, at all four doses of infused secretin, produced a significant in-
llibition of pancreatic. volume and bicarbonate out.put (P <0.05).
Infused nicotine appeared to inhibit compet.itively the effect of secre-
tin on pancreatic secretion of fluid and bicarbonate. Topical (intSraduo-
denal) nicotine failed to affect significantly the response to infused
secretin. Stimulation of endogenous secretin by an acid infusion into
the duodenum produced the expected pancreatic secretory response.
Nicotine either applied to the duodenal mucosa or injected intra-
venously significantly inhibit.ed the pancreatic secretory response to
%dogenous secret.in. n'icotine had no significant effect, on total pancrea-
tic protein output. Nicotine did not alter the cholecystokinin-induced
3timulation of pancreatic secretion. The authors concluded that nico-
&le may inhibit pancreatic secretion of fluid and bicarbonate both

161


by a direct effects on pancreatic secretory mechanisms, acting as a corn-
petit ive inhibitor of secretiq and by a secondary effect on the duodenal
mucosa. depressing the endopenous release of secretin by acid.

Robert (I,?) studied the Ilotentiation of active duodenal ulcers by
nicaotine administration in the rat. Subcutaneous infusion of pentagas-
trin and ca.rbachol resulted in the dose-dependent formation of duo-
denal ulcers within 24 hours. Nicotine alone produced no ulcers.
Increasing closes of subcut.aneously infused nicotine, in combination
with the other two agents, resulted in a steadily increasil:gdose-related
incidence and severity of the duodenal ulcers. Robert noted that
Roaturek, et al. (9) found that nicotine inhibited pancreatic and
biliary bicn&onate secretion in dogs, and that Thompson, et al. (16)
found that acute doses of nicotine in rats either depressed or did not
alter gastric secretion. He concluded that the most probable mechanism
11y which nicotine potentiated acute duodenal ulcer formation in t.he
rat, w-as via a sui)pression of pancreatic secretion.

Robert, ct al. (I.?) further tested this hypothesis by infusing acid
via the esophagus of rats in doses found to cause duodenal ulcers in
one-third of the experimental animals. One group of rats also received
a sulwutallcous infusion of nicotine. Another received nicotine, but
only l\.:ltcr was infused via the esophagus; 31 percent of the animals
rcwit-ing :lvitl but no nicotine had duodenal ulcers; 93 percent of the
[kicutiw-wit1 group had duodenal ulcers, rvhile none of the nicotine-
\v:ltt'r c~`oult Ilad ulcers. The. ulcers in the nicotine-acid group were
n1ow I~~~~WL'OIIJ, extensive, and deeper than those in the animals which
wwivcd acrid alt~nt'.

Sunmn~y of Recent Peptic I-leer Disease Findings

TIL :t~l~lition to the findings wlnting cigarette smoking to peptic ulcer
,li -I~:I;c . slullnlarize~l in previotla reports on the health consequences of
.51il,,f~i1l:, ( I;. IR) :in~l cited in the introduction to this chapter, recent
at Il'liC'i LA;-c cwlltrilrlitetl fri1thcr to our understanding of the
:I,s.,cr~~iatii)l~:

1. `1 11t\ tillililq of n 5ignitic:illt dose-related escess mortality from
,2:1-t I ii, t11~~rs ;1111011g Imth 1na1c and female Japanese cigarette
>III~J~`I 5'. in a large proqwtiw stud-, ant1 in the context of the
~t,llc~t ic, :IIII~ c\lltur:ll tlitf~lrenccs be.t\veen the Japanese and pre-
l-ilJ:~-lF in\-& igated IVesi-cm l)opulations, confirms and extends
t 11~ association Iwtv.ecn cigarette smoking and gastric ulcer
m0rtalit.y.

162


2. Data from experiments in several different animal species sug-
gest t.hat nicotine potentiates acute duodqlal ulcer formation by
means of inhibition of pancreatic bicarbonate output.
8. Cigarette smoking has been demonstrated to inhibit pancreatic
bicarbonate secretion in healt.hy young men and women.

Peptic Ulcer Disease References

(1) BLP, 31. H., HISLOP, I. G., GRAST, A. K. Gastric ulcer in South Australia,
  1954-63. 1. Epidemiological factors, Medical Journal of Australia 2(24) :
  1128-1132, Dec. 12,197o.

12) ALP, %I. H., HISLOP, I. G., GRAST, A. K. Gastric ulcer in South Australia,
  195463. 2. Symptomatology and resljonse to treatment. Medical Journal
  of Australia 1 (i ) : 3712-374, Feb. 13, 1971.
(S) BYKUM, T. E., SOLOJLON, T. E., JOHSSON, L. R., JACOBSOX, E. D. Inhibition
  of pancreatic secretion in man by cigarette smoking. Gut 13(5) : 361-365,
   May 1972.

(4, COOPER, P'., TOLISS, S. H. Relationship between smoking histor)- and compli-
  cations immediately following surgery for duodenal ulcer. JIount Sinai
   Journal of Medicine 3Q t 3) : ?87-2QL', May-June lQi2.
(5) FIXGE~LAXD, A., HUSAIC, T., BEXDLOVA, J. Contribution to the investigation
  of the effect of cigarette smoking. Sbornik VedeckFch Praci Lekarske
  Fakulty Karlovy University v Hradci Kralove l+i(2) : 22'1-234, 1971.
(6) HIRAYANA, T. Smoking in relation to the death rates of 265,118 men and
  women in Japan. A report of 5 years of followup. Presented at the Amer-
  ican Cancer Society's 14th Science Writers' Seminar, Clearwater Beach,
  Fla., Mar. 27, 1972, 15 pp.

(1) KOXTUREK, Y. J., DALE, J., JACVBSON, E. D., JOHNBON, I.. R. Mechanisms of
  nicotine-induced inhibition of pancreatic secretion of bicarbonate in the
  dog. Gastroenterology 62 (3) : 42%429, 1972.
(8) KOXTUREK, 8. J., RADECKI, T., THOB, P., DEMBISSKI, a., JACOBSON, E. D.
  Effects of nicotine on gastric secretion and ulcer formation in cats. Pro-
  ceedings of the Society for Experimental Biology and Xedicine 138(2) :
   6i4-67 4, November 1971.

!9) KOSTOBEK, 8. J., SOLOS~ON, T. E., &CRUeH'r, W. G., Joassox, L. R.,
   JACOBSOX, E. D. Elfects of nicotine on gastrointestinal secretions. Gastro-
   enterology W(6) : lOW-1103, June 1971.
(1s) MOBALES, a., HILVA, S., -~LCALIJE, J., WAISSBLUTII, J., RAWX, J., BEY, H.,
   SASZ, R. Cigarrillo y secretion gastrica. I. Analisis de la swrecidn
   gtistrka en I)acientes digestives fumadores y no fumadores. (Cigarettes
   and gastric secretion. I. Analysis of gastric secretion in smoking and non-
   smoking ulcer patients. J Rerista Nedicu de Chile W(4) : Z'l-274, April
    1971.

(11) &~OR.~LES, A., SILvA, S., OSORIO, G., QLC.ILDE, a., U'AISSBLUTII, J. Cigarrillo y
   secretion gastrica. II. Efecto de1 cigarrillo sobre la secreci6n gastrica.
   (Cigarettes and gastric secretion. II. I%&& of cigarettes on gastric secre-
   tion.) Rerista Xedica de Chile QQ(4) : Zi%2i9, Agril 19il.

4!KGcl"b o--73--12

163


(12) ROBERT, A. Potentiation, h.v nicotine, of duodenal ulcers in the rat. Pro-
   ceedings of the Society for Experimental Biology and Medicine 139( 1) :
   319-322, January 1972.
(13) ROBERT, A., STOWE. D. F., NEZAMIS, J. E. Possible relationship between
    smoking and peptic ulcer. Nature 233(5X0) : 497-498, Oct. 16, 1971.
(14) SHAIKH, M. I., TBOMPSON, J. H., AUBES, D. Acute and chronic effects of
    nicotine on rat gastric secretion. Proceedings of the Western Pharma-
    cology Society 13 : 178-184, 1970.
(15) Solomon, T. E., JACOBSOK, E. D. Cigarette smoking and duodenal-ulcer dis-
    ease. New England Journal of >Iedicine 286(2'1) : 1212-1213, June 1, lQ72.
(16) T~rou~som, J. II., GEORGE, R., ANGULO, M. Some effects of nicotine on gastric
   secretion in rats. Proceedings of the Western Pharmacology Society
    14 : li3-177, 1971.
(17) U.S. PUBLIC HEALTH SEIKICE. The Health Consequences of Smoking. A Re
   port of the Surgeon General : 19'71. U.S. Department of Health, Education,
   and Welfare. \Vashington, DHEW Publication No. (HSM) 71-7513,
    1971, 458 pp.
(18) U.S. PUBLIC HEALTH SERVICE:. The Health Consequences of Smoking. A
   Report of the Surgeon General : 1972. U.S. Department of Health, Educa-
   tion, and Welfare. Washinglon, DHEW Publication No. (HSM) 72-6516,
    1972, 158 pp.


CHAPTER 6

Pipes and Cigars


Contents

Introduction ___-____-__ --- _____ --_-_-- _____ -_-_--- _-_--_-
The Prevalence of Pipe, Cigar, and Cigarette Usage-----__---
The Definition and Processing of Cigars, Cigarettes, and Pipe
Tobaccos___-___-___------------------~---------------
Chemical Bnalysis of Cigar Smoke----_ _ _ _ ___- _ _ _ _ __ ____ ___
Mortality

List of Figures

Figure I.--Inhalation among pipe smokers by age- ~- - --~ - -- -
Figure Z.-Inhalation among cigar smokers by- age--I&m-
mond_-___-----__--~~--____________________~~------~
Figure S.-Depth of inhalation among cigarette smokers by
age-IIamrnond-___________________________-----------
Figure J.-Percent distribution of 130 brands of cigarettes and
25 brands of little cigars by tar content- _ - - _ _ _ - _ _ - _ _ _ _

Page
171
173

175
177

179

180
183
189
189
190
191
193
197
203
210
210
215
216
222
222
229
230

184

185


185

225

167


Fig~rc 5.--Percent distriblttion of 130 brands of cigarettes and
25 brands of little cigars by nicotine content,-- - _ - - - - - - - _ _ _

List of Tables

Table I.-Percent, distribution of U.S. males aged 21 and older
by type of tobacco used for the years 1964, 1966, and 1970--
Table 2.-Percent distribution of U.S. males b>- type of tobacco
wed and agefor 1970_--.._-----_--_-----~-~------~- ____
Table S.-Percent distribution of British males aged 2.5 and
older by tJ.pe of tobacco used for the J-ears 1965, 196S, and
1971---_-_-._--_--_---.------~-----------------~~-~-~
Table 4.-Amounts of several components of 1 gram of par-
ticulate material from mainstream smoke of tobacco prod-
ucts ---_- --~--~---_~--~- -__. -----_---_------_-_-_____
Table 5.-A compariqon of Iseveral chemical compounds found
in the mainstream smoke of cigars;, pipes, and cigarettes--_-
Table 6.--AIortalit)- ratios for total denth~ b>- type of smoking
(males onl~-)~_-~_-_.~__-_--_--~--~-------~.~--~- ___.__
Table T.--bIortality ratios for total deaths of cigar and pil)e
smokers by amount smoked-~~~arutnontl and IEorn- _ - _ - -- _
Table S.--;\Iortalit\- ratios for total deaths of cigar and pipe
smokers by amount smoked---Best--_- - - - - - - - _ - - _ - - - - _ _
Table 9.-Jlortality ratios for total deaths of cigar and pipe
smokers by age and amoltnt smoked-Kahn- - - - _ - - _ - _ - - _ -
Table IO.-IIortnlit>- ratios for total deaths of cigar and pipe
smokers by amount smokt~d-~Iammond- - _ - - - - - - _ - - - - _ -
Table 11 .-The extent of inhaling pipes, cigars, and cigarettes
by British males aged 16 and over in 1968 and 1971_ - - - _ _ _
Table 12.--Inhalation among cigar, pip, and cigarette smokers
b\- age--Doll and )Iill---~-.--~-.._-_~-_~-_--_-__-.--_-. -
Table 15.-1lortalit.v ratios for total deaths of cigar and pipe
smokcr~ by- ape and inhnla tion-~ItlmIllond-~ _ - _ - _ _ _. - _ _ -
Table l-2..-Prrcrntage of British mnlc cigar smokers who rc-
ported inhaling a lot or a fair amount b)- type of product
rrnoked__~______~__-~_-._-~--_--~--_-~--------_----_~
Table lj.p-Percentagc of ir~divitluals reporting inhalation of
"almost every p~iff" of tobacco smoke by current and pre-
Gous tobacco usapc and t:+-pc of tobacco used - - - - - - _ _ _
Table 16.-Percentage of British males I\-ho reported inhaling a
lot or fair amount of cigar smoke by current and previous
tobacco usage and tylw of tobacco previously smoked
(196S)--_~_~__~-_~ ____ -._-__-_--_--_-_--_--~--~------

226

173


174

li4

177


17s


is0


1Sl


181


182


152


1%


IS6


1s;

1Pi

IS8

1%


Page

Table 17.-Extent of reported inhalation of cigar smoke by
British male cigar smokers who jvere es-cigarette smokers in
1968, analyzed by extent of reported inhalation of cigarette
smoke when lxcrioud?- smoking cigarettes_-_- _ - - - - - _ - - _ - - -
Table lrj.-Jlortality ratios for total cancer deaths in cigar and
pipe smokers. A summary of prospective epidemiological
~tuclies---_--_-__-~~-~~-~~-~-----~----~------------~--
Table lg.-Relative risk of lip cancer for men, comparing cigar,
pipe, and cigarette smokers vith nonsmokers. A summary of
retrospectivest~~dies---_--__--__--~-----~-----~-~--~---
Table 20.--1\Iortality ratios for oral cancer in cigar and pipe
smokers. A summary of prosl)ectivc epidemiological studies- _
Table 21.-Relative risk of oral cancer for men, comparing
cigar, pipe, and cigarette smokers n-ith nonsmokers. A sum-
mar). of retrospective studies- - - - - _ - - _ - - - - - _ - - _ - - _ - - _ - - _
Table 22.--?\lortality ratios for cancer of the larynx in cigar
and l)ipe smokers . A summary of prospective epidemiological
studies__-__-__-__-_____________________--------------
Table 2X.-Relative risk of cancer of the laq-ns for men, com-
paring cigar, pipe, and cigarette smokers with nonsmokers.
A summary of retrospective studies-_- _ _ - _ -_ _ _ - _ - - _ _- _ __ _
Table 24.--?\lortality ratios for cancer of the esophapu; in
cigar and pipe smokers. A summary of prospective epidernio-
logical studies-_- ____________ -------------_------------
Table 25.-Relative risk of cancer of the esophagus for men,
comparing cigar, pipe, and cigarette smokers with non-
smokers. A summary of retrospective studies..- _ _ - _ _ _- _ - -_ -
Table 26.-Mortality ratios for lung cancer deaths in male
cigar and pipe smokers. A summary of prospective studies__--
Table 27.-Lung cancer death rates for cigar and pipe smokers
by amount smoked-Doll and Hill__----- ____ -__--_--_--
Table 28.-Lung cancer mortality ratios for cigar and pipe
smokers by amount smoked-Kahn ____ _ _ - _ _ _ - _ _ _ _ - _ _ - _ _ -
Table 29.-Relative risk of lung cancer for men, comparing
cigar, pipe, and cigarette smokers with nonsmokers. A
summary of retrospective studies__----_--_-_-___________
Table :30.--Changes in bronchial epithelium of male cigar,
pipe, and cigarette smokers as compared to nonsmokers- _ - -
Table 31.-Tumorigenic activity of cigar, pipe, and cigarette
smoke condensates in skin painting experiments on animals-
Table 32.--Mortality ratios for cardiovascular deaths in male
cigar and pipe smokers. A summary of prosI>ective epi-
demiological studies-------_-_-_----------~------------

189

189

192


193

194

196

198

200

201

204


204

205

206

209

213

216

169


TabIf, :3:3.-Ilortality ratios for chronic obstructive pulmonary
tlfv~ths in male cigar and pil)c smokers. A summary of pros-
pectirc c~~itlcmiologica1 studies- - _ - - _ - _ - _ - _ _ - _ _ _ - _ - _ - _ - _ _
Table :H-Preralrncc of respiratory symptoms and illness by
type of smoking-..--------.-------_-__--__-___-_-__--__
Table 35.-Pulmonnr>- function values for cigar and pipe
smokers as compared to nonsmokers - - - - . - _ _ - _ - _ - _ _ _ _ - - _ _
Table 36.--?\lortality ratios for peptic ulcer disease in male
cigar and pipe smokers. Summary of prospective studies- _ _
Table 37.~Shipment of small and large cigars destined for
domestic consuml)tion (1970, 1971, 1972)-----.. -____--____
Table :%.--Sclcctetl (*otnl)ounds in mainstream smoke_-- _ - _ - _
Table :39.-The 1111 of the mainstream smoke of selected
tobacco products---~-_----_-_____________________--~--

219

220


221


2?!


227
221


22x

170


Introduction

This chapter is a review of the epidemiologic,al, pathological, and
~spcrimental data on the health consequences of smoking cigars and
pipes, alone, together, and in rarious combinations with cigarettes.
Prel-ious rerie& on the health consequences of smoking have dealt
primarily with cigarette smoking. hlthouph some of the material on
pipes and cigar-s presented in this chapter has been presented in preri-
DUS reports of the Surgeon General. this is the first attempt to summa-
rize what is known about, the health effects of pipe and cigar smoking.
since the use of pipes and cigars is limited almost exclusively to men
in the United States! only data on men are included in this review.
The influence of pipe and cigar smoking on health is determined
11~ examining the overall and specific mortality and morbidity ex-
perienced by users of these forms of tobacco compared to nonsmokers.
Epidemilogical eridcnce suggests that individuals who limit their
smoking to only pipes or cigars have overall mortality rates that are
Flightly higher"than nonsmokers. For certnin specific causes of death,
i~owever, pipe and cigar smokers experience mortalitv rates that are
as great as or exceed those experienced by cigarette smokers. This
analysis becomes more complex when combinations of smoking forms
we examined. The overall mortality rates of those ~1~9 smoke pipes,
$jars, or both in combination with cigarettes appear to be inter-
IMiate between the high mortality rat& of cigarette smokers and
the lower rates of those who smoke only pipes or cigars. This might
Qeln to suggest, that smoking pipes or cigars in combination with ciga-
rettes diminishes the harmful effects of cigarette smoking. However,
an analysis of mortalitv associated with smdking combinations of ciga-
rettes, pipes, and cigars should be standardized for the level of con-
sumption of each of the products smoked in terms of the amount
B"loked, duration of smoking, and the depth and degree of inhalation.
For example, cigar smokers ITho also smoke a pack of cigwettes a day
might. be expected to have mortality rates some\\-hat higher than those
Iho smoke onlr cigarettes at the level of a pack a day, assuming that
both groups smoke their cigarettes in the same may. Mixed smokers
Rho inhale pipe or cigar smoke in a mannrr similar to the gag they
"make cigarettes might be expected to halye higher mortality rates
than mixdd smokers \vho do not inhale their cigars and pipes and also

171


resist inhaling their c.igarett'es. I-nfortunately, little of the published
material on mixed cigarette, pipe, and cigar smoking contains these
types of analyses or controls.

A paradox seems to exist b,etween the mortality rates of ex-smokers
of pipes and cigars and es-sntokers of cigarettes. Ex-cigarette smokers
experience a relative decline in overall and certain specific causes of
mortality following cessation. This decline is important but indirect
evidence that cigarette smoking is a major cause of the elevated mor-
tality rates experienced by current cigarette smokers. In contrast to
this finding! several prospective epidemiological investigations,
Hammond and Horn (40)) Best (9), Kahn (50)) and Hammond (38))
have reported higher death rates for ex-pipe and ex-cigar smokers
than for current pipe and cigar smokers. This phenomenon was ana-
lyzed by Hammond and Garfi.nkel (39). The development of ill health
often results in a cigarette smoker giving up the habit, reducing his
daily tobacco consumption, switching to pipes or cigars, or choosing
a cigarette low in tar and nicotine. In many instances, a smoking-
related disease is the cause of ill health. Thus, the group of ex-smokers
includes some people who.are ill from smoking-related diseases, and
death rates are high among persons in ill health.

As a result', ex-cigarette smokers initially have higher overall and
specific mortality rates than continuing cigarette smokers, but be-
cause of the relative decrease in mortality that occurs in those who
quit smoking for reasons other than ill health, and because of the
dwindling number of ill ex-smokers, a relative decrease in mortality
is observed (w-ithin a few years) following cessation of cigarette
smoking. The beneficial effects of cessation would be obvious sooner
were it not for the high mortality rates of those who quit smoking
for reasons of illness. A similar principle operates for ex-pipe and cx-
cigar smokers, but because of the lower initial risk of smoking these
forms and therefore the smaller margin of benefit following cessation,
t,he effect produced by the ill ex-smokers creates a larger and more
persistent, impact on the mortality rates than is seen in cigarette
smoking.

For the above reasons a bias is introduced into the mortality rates
of current smokers and ex-smokers of pipes and cigars, so that a more
accurate picture of mortality might be obtained by combining the
ex-smokers with the current smokers and looking at the resultant
mortality experience.

Because of a lack of data that would allow a prec.ise analysis of
mortality among ex-pipe and ex-cigar smokers, a detailed analysis
of these groups could not be undertaken in this review.
For each specific, cause of death, tables have been prepared which
summarize the mortality and relative risk ratios reported in the major

172


prospective and ret,rospective studies \Thich contained information
:lbout pipe and cigar smokers. The smoking categories used include:
\-igur only, pipe only, total pipe and cigar, cigarette only, and mixed.
The total pipe and cigar category includes: those who smoke pipes
only, cigars only, and pipes and cigars. The mixed category includes:
tllose who smoke cigarettes and cigars; cigarettes and pipes; and
cigarettes, pipes, and cigars. Mortality and relative risk ratios were
calculated relative to nonsmokers.

The Prevalence of Pipe, Cigar, and Cigarette Usage

The prevalence of pipe, cigar, and cigarette smoking in the United
States was estimated by the National Clearinghouse for Smoking and
Health from population surveys conducted in 1964,1966, and 1970 (98,
39, 200). In each survey, about 2,500 interviews were conducted on a
l\ational probability sample stratified by type of population and
geographic area. The use of these products among adults aged 21 and
older is summarized in tables 1 and 2. The prevalence of pipe, cigar,
and cigarette smoking in Great Britain for the years 1965, 1968, and
1971 is presented in table: 3.

TABLE I.-Percent distribution qf U.S. male smokers aged 21 and older
  by type of tobacco used for the years 1964, 1966, and 19YO

Forms used

1970
(percent)

6. 8      5. 5       5. 6
1. 7      3. 0       3. 6
3. 9      4. 9       4. 4
28. 6     31. 2     25. 9
11. 3      9. 9       6. 6
5. 3      4. 9       5. 3
7. 7      6. 3       4. 6
34. 7     34. 3      44. 0

   Total-_--_-__-____-________________    100. 0    100. 0     100. 0

Number of persons in sample- - _ _ _ __-_ -. - _. _   2, 389    2, 679    2,861
Total pipe users (2+3+6$7) ___._ - ____..___    18. 7     19. 2     17. 9
Total cigar users (1+3+5+7)------ .___.___     29. 9     26. 7      21. 2
Total cigarette users (4+5+6+7) ___.__.-_--     52. 9     52. 4      42. 3

Source: U.S. Department of Health, Education, and Welfare (98, 99,100).

173


TABLE 2.-Percent distribution of C.S. male smokers by type qf tabwe
         co wsed and age for 1.970

21 to 34    35 to 44   45 to 54   55 to 64  65 to 75  _

1. Cigar only ___. -__-_-------_     3. 7    6. 5     4. 7    6. 7     9.
2. Pipeonl3.__-_~----_-_-----~       3                          :j
                            4.      3. 5     3. 0    3. 2     3.
3. Pipe and cigar-_              3.                           6
              _-.- _. - .____       8    3. 3     5. 2     4. 4     6. 0
4. Cigarette onl~---~------~~     28. s    29. 0    27. 1    24. 3    13.
5. Cigarette and cigar_-__                                      6
                   - _. _ . _      6. 8    10. 4     5. 5     5. 2     4.
6. Cigarette and pipe-_-------_                                2
                           6. 6    4. 4    5. 6    4. 0     3. h
7. Cigarette, pipe, and cigar- - - _     .5. 8     4. 8    5. 0    4. 0     1. 4
&  Nonsmoker-__-__-_--.- _.___    40. 2    38. 1    43. 9    48. 2    57. L'

   Total-_-_--_-_-__-_.--~    100. 0   100. 0   100.0   100.0   100. 0
                       ---__--___
                       -------------En=_
                                                    -
Number of persons in sample- _ _   1,009     528     ,523    405     35%
                        :---
Total pipeusers___---_-___~_-.     20. 5    16. 0    18. 8    15. 6    1.5. 7
Total cigar users_--_-------_-_     20. 1    25. 0    20. 4    20. 3    21. F-
Total cigarette  users- - _ - _ - - _ - _    4P. 1    48. 6    43. 3   37. 5    23. r,

Source: U.S. LIepartment of Health, Education, and Welfare (IW)

TABLE S.----Percent distrib?ltion of British male smokers aged % anI/
older by type of tobacco used for the years 1965, 1968, and 1971

Forms used

               --
1965       1968      1971

1. Cigarsonl~~--.--~--~--~--~--~--.-~~-~~~      1. 9      2. 8       3. 3
2. Pipeonly __.__. -..-._-_~-_--_--~-__-_.-     5. 1      5. 6       5. 9
3. Cigarettesonls.-_~-.---~-.--.--.-~-~~.-     46. 8      45. 7      40. h
4. Cigarettesalldpipe---_-_.-_.-_.-__-~_-_     8. 0      7. 0       6. 1
5. ~lixedsmokers-~~-~-~.--.-~~--.-~~--~-~     7. 5      9. 1       8. 4
6. Nonsmokers.-~--~--~~-.~-~--.~-.-..  ___     30. 7     29. 9      35. 4

   Total__.-_---~-~--.~-.~- ~~-.- __._._    100. 0     100. 0     100.0
                                                        -.
Number of persons in sample_--_ .--------~-   3, 576    3, 566    3, !594

Totalpipeusers~...~~.~~-~---.-- .--~-_.~_~-     13. 9     14. 3      13. 3
Totalcigar-~~-.~~..~.-~.--~-~~.---------..     9. 0     11. 7      11. 3
Totalcigarette-.._-_~-.--_--~~..~-.~ _.._._    67. 6     67. 6      61. 6

Source: Todd, Cr. F. (9:)

174


The Definition and Processing of Cigars, Cigarettes, and
          Pipe Tobaccos

Cigarettes

The U.S. Government has defined tobacco products for tax pur-
poses. Cigarettes are defined as " (1) Any roll of tobacco wrapped in
paper or in any substance not containing tobacco, and (`2) any roll of
tobacco wrapped in any substance containing tobacco which, because
of its appearance, the type of tobacco used in the filler, or its packaging
and labeling, is likely to be offered to, or purchased by, consumers as
a cigarette described in subparagraph (1) ." Cigarettes are further
classified by size, but virtually all cigarettes sold in the I-nited States
are "small cigarettes" which by definition weigh "not more than 3
pounds per thousand" which is not more than 1.361 grams per
cigarette (96).
American brands of cigarettes contain blends of different grades of
Virginia, Burley, Maryland, and oriental tobaccos. Several varieties
of cigarette tobaccos are flue-cured. In this process, tobacco leaves are
(wed in closed barns where the temperature is progressively raised
over a period of several days. This results in "color setting," fixing,
und drying of the leaf. The most conspicuous change is the conversion
of starch into simpler sugars and suppression of osidatix-e reactions.
Flue-cured tobaccos produce an acidic smoke of light aroma (35,112).

cigars

Cigars have been defined for tax purposes as: "Any roll of tobacco
`Qapped in leaf tobacco or in any substance containing tobacco (other
than any roll of tobacco which is a cigarette within the meaning of
Qhparagraph (2) of the definition for cigarette)" (112). In order to
Elarify the meaning of %ubstance containing tobacco" the Treasury
`k'par&nent has stated that, "The wrapper must (1) contain a signifi-
(`ant proportion of natural tobacco; (2) be within the range of colors
normally found in natural leaf tobacco; (3) have some of the other
characteristics of the tobaccos from which produced; e.g., nicotine
"`Jnter& pH, taste, and aroma: and (4) not be so changed in the
!`censtitution process that it loses all the tobacco characteristics"
' I@). Further, L`To be a cig ar the filler must be substantially of
                          ,
rohaccos unlike those in ordinary cigarettes and must not have any
"`lded flavoring which would cause the product to hare the taste or
drema genera 11. attributed to cigarettes. The fact that a product does
          y

175


not rcs,~nllll~ a cigarette (slwh as many large cigars do not) and has a
                                               .
tlistillctivp cigar taste and aroma IS of consulerahle srgmficance in
rrrakinp this determination" (202).

Cigars arc also classified by size. "Small cigars'! weigh not more
than 2 ponnds pw thousand and Y nrpe cigars" weigh more than 2
pom~ds per thousand. "Large cigars" are further divided into seven
classes for tax purposes based on the retail price intended by the
manufacturer for such cigars (96).

Cigars are made of filler, binder. and -x-rapper tobaccos. Most cigar
tobaccos are air-cured and then fermented. More recently, reconsti.
tuted cigar tobaccos have been used as wrapper. binder. or both. Cigars
are either hand-rolled or machine made. Some brands of small cigars
are manufactured on regular cigarette making machines. The aging
2nd fermentation processes xed in cigar tobacco production producp
chemical catalytic, enzymatic. or bacterial transformations as eri-
den& by increased tempcmtnrc. oxygen utilization, and carbon
dioxide generation within fermenting cigar tobaccos. In this comples
process. up to 20 percent of xhe dry weight of the leaf is lost through
decreases in the concentration of the most readily fermentable ma-
terials such as carbohydrates, proteins, ~1~1 alkaloids. The flavor and
aroma of cigar tobaccos are in large measure the results of precisely
controlled treatment during the fermentation process (35.36,112).

P'ipe Tobnccos

The definition of pipe tobacco used by the 1'S Government was
repealed in 1966 and therr is no Federal tax on pipe tobaccos. The
most popular pipe tobaccos are made of Burley : however. many pipe
tobaccos are blends of different types of tobacco. A fen- contain a
significant proportion of midrib parts that arc crrrshed between rollers.
"S aucing" material. or casings containing licorice. sweetening agents.
slyars. and other flavorinK nntrrinls are added to improve the flavor.
aroma. and s~nolcc taste. These ndtlitives modifyv the characteristics
of smoke components (112).

Because of the nniqur curing and processing methods used in the
production of cigar and pipe tobaccos. significant physical and chrmi-
cal differences esist betn-cm pipe and cigar tobaccos and those used iI1

176


cigarettes. The extent to which these changes may alter the health
ronsequcnces of smoking pipes and cigars can best be estimated by an
analysis of the potentially harmful chemical constitutents found in
tile smoke of these tobaccos. the tumorigenic activity of smoke conden-
sates in experimental animals, and a review of the epidemiological
data which has acclm~ulatcd on the health etfects of pipe and cigar
smoking.

Chemical Analysis of Cigar Smoke

Only a few studies have been conducted that compare the chemical
constituents of cigar smoke with those found in cigarette smoke.
Hoffmann, et al. (&I) compared the yields of several chemical com-
ponents in the smoke from a plain 85 mm. cigarette, two types of
cigars, and a pipe. The particulate matter. nicotine. benzo( a) pyrene!
and phenols were determined quantitatirely in the smoke of these
tobacco products. One cigar tested was a 135-mm.-long, 7.8-g.> U.S.-
made cigar. The other was a handmade TIavana cigar 147 mm. long
aeighing 8.6 g. The relative content of nicotine in the particulate
matter produced b;v the cigars was similar to that of the cigarette
tars. The benzo(a)pyrene and phenol concentrations in the cigar
rondensate was two to three times greater than in cigarette "tar" (t,able
4). Kuhn (58) compared the alkaloid and phenol content in conden-
sates from an BO-mm. Bright-blend cigarette sold commercially in
hustria with that obtained' from 103-mm. cigars. These were tested

TABLE 4.--,qmou,nts ?f set'erar! components qf 1 g. ?f particulate material
     from mainstream smoke of tobacco products

Compound

U.S.    IIavans
cigar A   cigar II
(b)      (b)

Stsndatd
Piw
tobacco
in pipe
(h)

       65 mm.   85 mm.
Cigarette plain U.S. plaiu U.S.
tobacco   cigarette  cigarette
in pipe     (8)      (h)

Nicotine (mg.) _ _ _ - - . _ _ _.   46. 2    63. 6    56. 1    61. 0    65. 9    77. 4
Benzo(a)pyrene (pg.) - - _ -    3. 9    3. 6    6. 0    3. 6     1. 2     1. 3
Phenol (mg.) ____ --- _____    8. 2     6. 7    15. 0    7. 3    2. 9     4. 1
O-Cresol (mg.) _ _ _ _ _ _ - _ _ -    1. 6    1. 7     1. 9    1.4 .6 .8
mtp-Cresol (mg.).-----.    4. 8    3. 8    5. 6     3. 4     1. 4     1. 9
mtp-Ethylphenol (mg.)--    1. 1     1. 5     1. 1    1.3 .7 .7

' smoking condition%:

b) 1 puff pw minut?, duration 2 SK., puff rolume 35 ml.
(b) 2 puffs prr minute, duration 2 sec., puff volume 35 ml.
Smw: IIoffnlaIm, et al. ($5).

177


wit11 and without the USC of a cellulose acetate filter. The concentr,.
tions of total alkaloids and phenol in the cigar smoke condensate tverp
essentially the same as in the cigarette condensate: bnt pyridine valu&
were about 2?,/2 times higher in the cigar condensate.

Campbell and Lindsey (17) measured the polycyclic hydrocarbon
levels in the. smoke of a small popnlnr-type cigar 8.8 cm. long, weighi%
1.9 g. Significant, quantities of ant.hracene, pyrene, fluoranthene, and
benzo (a) pprene were detected in the unsmoked cigar tobacco, in con.
centrat.ions much greater than those found in Virginia cigarettes but
of the same order as those folmd in some pipe tobaccos. The smoking
process contribntcd considerably to t,he hydrocarbon content of the
smoke. Table 5 compares the concentrations in the mainstream sm&
of cigarettes, cigars, and pipes of four hydrocarbons frequently found
in condensates. The authors reported that the mainstream smoke from
a popular brand of small cigar contained the pol.ycyclic aromat.ic
hydrocarbons : acenapht.h;v-lene, phenanthrene, anthracene, pyrene,
ilnoranthene, and benzo(a) pyrene. The concentrations of these hydr".
carbons in the mainstream smoke mere greater than those found in
Virginia cigarette smoke..

Osman, et al. (69) analyzed the rolat,ile phenol conte.nt of cibr
smoke collectcld from a 7-g. American-made cigar with domestic filler,
After quantitative analysis of phenol. cresols? xylenols, and met.a and
para ethyl phenol, the, ant,hors concluded that the levels of these corn..
pounds were generally similar to those reported for cigarette smoke.
Osman and Barson (68) also analyzed cigar smoke for benzene,
tolnene. ethyl benzene, m-, p-, and o-xylene, m- and p-ethyltoluene,
1,"+trimethylbcnzene, and dipentene, and generally found levels
wit,hin the range of those previously reported for cigarette condensates.

In summary, available evidence suggests that cigar smoke contains
many of the same chemical Sconstit.urnts, including nicotine and other
alkaloids. phenols, and polycyclic aromatic. hydrocarbons as are found

TABLE 5.-L4 comparison qf seaerai chemical compounds found in thf
    mainstream smoke qf cigars, pipes, and cigarettes

1 This is a liglu pipe toharco.
Sourre: Camph4, J. 11.. Lindsey, A. J. ($7).

178


in cigarette smoke. Most of these compounds are found in concentra-
tions which equal or exceed levels found in cigarette "tar." A more
complete pict,ure of the carcinogenic potential of c.igar "tars" is ob-
tained from experimental data in animals.

Mortality

Overall Mortality

Several large prospective studies have examined the health conse-
quences of various forms of smoking. The results of these investiga-
tions have been reviewed in previous reports of the Surgeon General
in which the major emphasis has been on c.igarette smoking and its
efl'ect on overall and specific mortality and morbidity. The following
pages present a current review of the health consequences of smoking
pipes and cigars. Data from the prospective investigations of Dunn,
et al. (31), Rue& et al. (16), Hirayama (Q), and Weir and Dunn
(105) are not cite.d, because in these studies a separate category for
pipe and cigar smokers was not established.

The smoking habits and mortality experience of 187,783 white men
between t.he ages of 50 and 69 who were followed for 44 months were
reported by Hammond and Horn (41). The overall mortalit,y rates of
men who smoked pipes or cigars were slightly higher than the rates
of men who never smoked. The overall mortality rate of cigar smokers
was slight.ly higher than that of pipe smokers.
In a study of 41,000 British physicians, Doll and Hill (%`, 27) re-
ported the overall mortality of pipe and cigar smokers as being only
1 percent greater than that among nonsmokers. Be& (9)) in a study of
78,000 Canadian vet~erans, reported overall mortality rates of pipe and
cigar smokers slightly above those of nonsmokers. Kahn (50) exam-
ined the death rates and smoking habits of more than 293,000 U.S.
veterans and Hammond (38) examined the smoking habits of and
mortality E&S experienced by 440,559 men. In these studies, pipe
smokers experienced mortality rates similar to those of men who never
smoked regularly, whereas cigar smokers had death rates somewhat
higher than men who never smoked regularly. Table 6 summarizes the
results of these five studies.

Thus, data from the major prospective epidemiological studies
demonstrate that the use of pipes and cigars results in a small but defi-
nita increase in overall mortality. Cigar smokers have somewhat
higher death rates than pipe smokers, and mixed smokers who use
cigarettes in addition to pipes and cigars appear to experience an inter-
mediate level of mortality that approaches the mortality experience
of cigarette smokers.

495-028 -73-13                                      179


TABLE 6.--Mortality ratios for total deaths by type of smoking (1~~~
              0 nW

                          Smoking type

Author, reference   NiXI-   Cigar   Pipe   Cigar  Cigarette  Ciparette   Mixed     -

           smoker  only   Only   snd
                         pipe  and cigar and pipe (cigarette  %amtts
                                            and other)   0llly

Hammond and
Horn 1 (40)---  1. 00  1. 22  1. 12  1. 10    1. 36    1. 50    1. 43    1. 68
Doll and Hill
(d6)-v-----  1.00  --_-   --_-  1.01  -_-___   -______   1. 11    1. 28
Best (9).------  1.00  1. 06  1. 05    98
Kahn (&I---__  1. 00  1. 10  1. 07 1108    1. 22    1. 26    1. 13    1. 54
                                 -_--__   -- _____   1. 51     1. 84
Hammond 4
(38)-------_-  1.00  1.25  1.19  1.01   ______   _______   1. 57    1. 86

                                                      ~-
1 Only mortality ratios for ages 50 to 69 rue pwrented.
1 Only mortality ratios for ages 55 to 64 BE prerented.

Aforta7ity and Dose-Response Relationships

A consistent association exists between overall mortality and the
total dose of smoke a cigarette smoker receives. The methods most
frequently used to measure dosage of tobacco products are: Amount
smoked, degree of inhalation, duration of smoking experience, a@
at initiation, and the amount of tar in a given tobacco product. For
cigarette smokers, the higher the dose as measured by any of these
parameters, the greater the mortality. The significance of the small
increase in overall mortality t,ha.t occurs for the entire group of pipe
and cigar smokers can be anal;yzed by examining the mortality of
subgroups defined by similar measures of dosage as used in the study
of cigarette smokers.

AMOUNT SMOKED

Hammond and Horn (&I) reported an increase in the overall mor-
ta.lity of pipe and cigar smokers with an increase in the amount
smoked. Individuals who smoked more than four cigars a day or more
th,an 10 pipefuls a day had death rates significantly higher than men
who ne.ver smoked (PCO.05 for cigar smokers and PCO.05 for pipe
smokers) (table `7). Cigar and pipe users who smoked less than this
amount experienced an overall mortality similar to men who never

180


smoked. The study of Canadian veterans (.9) also contained evidence
of a dose-response in mortality bg anlonnt smoked for cigar smokers.
No dose.-response relationship was observed among pipe smokers (table
8). Kahn (50) reported a consistent, increase in overall morta.lity
wit,11 an increase in the amount smoked for both pipe and cigar smokers
(table 9). Hammond (38) f ound no consistent relationship between
overall mortality and t.he number of cigars or pipefuls smoked
(table 10).

TABLE T.-Mortality ratios for total deaths of cigar and pipe smokers by
        amount smoked-Hammond and Horn

Amount smoked

-

Number of deaths

Observed   Expected   Mortality ratio

Nonsmoker_.___.___-.__________________   1, 664    1, 664       1. 00
Cigar only :
  Total..._- ._____ - __.___.____ _--_---_     653      598       1. 09
  1 to 4 cigars ____ -_- ___________ -_----     410      400       1. 03
  >4 cigars---~--- .___._.___ -__-_----     229      185       1. 24
Pipe only:
  Total ________._ - _____ -.--_-_-__-__-     609      560       1. 09
  1 to lOpipefuls__-_-___-__-----------     391      374       1. 05
  > 10 pipefuls ____ _ -. _ _ _. _. . . ____ _ _ _ _ _     204      172       1. 19

Source: Hammond, E. C., Horn, D. (40).

TABLE 8.-Mortality ratios for total deaths of cigar and pipe smokers
         by amount smoked--Best

Amount smoked

          Number of deaths
__--
  Observed     Expected   Mortality ratio

Nonsmoker- _ _ _ _ _ _ _ _ . _ - _ _ - _ _ _ _ _ _ _ _ _ _   _ _ _ _ _
Cigar only :

1. 00

  Total----- ____ -_-___--_- _______
  1 to2cigars--- ________________ -
  3 to 10 cigars- __.___ -___ ________
  >10 cigars _____________________
Pipe only:

90      82. 07       1. 10
64     56.05       1. 14
23      19. 40       1. 19
1       1. 59       .63

Total ____ -__-_-_-___--_---_-___       570     566. 99        1. 00
1 to 10 pipefuls ______ -_-_- _______       374     370. 09       1. 01
10 t,o 20 pipefuls- - _ _ _ _ _ _ - __ __ _ _ _      141     140.84       1. 00
> 20 pipefuls- _ _ _ _ _ _ _ _ _ _ _ _ _ _ - _ _ _       36     35.90       1. 00

Source: Best, E. W. R. (9).


The above evidence suggests that a dose-response relationship may
exist between t.he number of cigars and pipefuls smoked and overall
mortality. However, because of the high-mortality rate of ex-smokers
of cigars and pipes, it is difficult to interpret the data presented wit,h-
out including this group with the continuing smokers. Without data
which examines patterns of both daily rate of smoking and inhalation
at various age levels, no firm conclusions can be drawn `as to the nature
of this dosage relationship.

TABLE 9.-Mortality ratios j'or total deaths of cigar and pipe smokers
        by age and amount smoked-Kahn

-

Amount smoked

Mortality ratio, age

56 to 6-i       65 to 74

Nonsmoker_-_---___--________.__ _______ - _______
Cigar only :

  Total-_--__--____-_.____-_______________~--
  lto4cigarsperday _._____._______ - _____ -___
  5toScigsrsperday---- ___. ---__--__- _____ --
  >Scigarsperday--- .___ - _._______ - _____ -___
Pipe only:

Total ______ --___---__---___-- ____ -___- _____
1 to 4 pipefuls per day----_.-- _____ - _____ -___
5 to 19 pipefuls per day- _ - _. ____ ____ __-_ _- __ _
>19 pipefuls per day_---__.---___--_________

1. 00

1. 01       1. 08
89
1: 14       1. 00
        1. 23
1. 65       1. 28

1. 08
1. 16
1. 04

1. 00

1. 06
91
1: 10
1. 18

Source: Kahn, H. A. (50).

TABLE lo.-Mortality ratios -for total deaths of cigar and pipe smokers
        by amount smoked-Hammond

Amount smoked    MO&t/p

Amount smoked

Mortality
rat10

Nonsmoker--- .___ -.._-- ___.   1. 00 Current pipe smokers:
Current cigar smokers:              Total- _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ . _    1. 04
Total_--_._---___--------    1. 09   1 to 9 pipefuls per day- _ _ _.    1. 08
1 to 4 cigars per day--._---    1. 03   >9 pipefuls per day---_-_-    .92
>4 cigars per day---------    1. 18

Source: Hammond. E. C. (93).

182


Inhalation of tobacco smoke directly exposes the bronchi and the
lungs to smoke and results in the absorption of the. soluble constituents
of the gas and particulate phases. Without inhalation tobacco smoke
only reaches the oral cavity and the upper digestive and respiratory
tracts and does not reach the lungs where further direct effects and
systemic absorption of various chemical compounds can m.ur.
Although the smoker has some voluntary control over the inhalation
of smoke, the physical and chemical properties of tobacco smoke to a
degree determine its acceptability and "inhalability.!'
The condensate of pipe and cigar smoke is generally found to be
alkaline when the pH is measured by suspending a. Cambridge filter
in CO,-free water. Cigarette condensate is slightly acidic as measured
by this method. Since alkaline smoke is more irritating to the respira-
tory tract? it has been assumed that, the more alkaline smoke of pipes
and cigars mas in part responsible for the lower levels of inhalation
reported by pipe and cigar smokers. Brunnemann and Hoffmann (15)
have analyzed the pH of whole, mainstream smoke of cigar&es and
cigars on a puff-by-puff basis using a pH electrode suspended in main-
stream smoke. Smoke from several U.S. brands of cigaret,tes was found
to be acidic throughout the entire length of the cigarette. Of interest
was the finding that cigar smoke also had an acidic pH for the first
tao-thirds of t.he cigar and became alkaline only in the last 20 to 40
percent of the puffs from t.he cigar. Available epidemiological evidence
indicates that most cigar smokers do not inhale the smoke and most
cigarette smokers do. The fact that smoke from the first. half or more
of a cigar is acidic, near the range of pH values commonly found in
cigarette smoke, and becomes alkaline only toward the end of the
cigar might suggest that the pH of the smoke of a tobacco product
may not be the only factor that influences inhalation patterns. Per-
haps "tar" and nicot.ine levels as well as the concentration of ot,her
"irritating'? chemicals also affect the degree to which a tobacco smoke
Rill be inhaled.
Nicotine is rapidly absorbed into the blood stream from the lungs
when tobacco smoke is inhaled. The amount of nicotine absorbed from
the lungs is primarily a function of the nicot.ine concentrat.ion in the
smoke and the depth of inhalation. Some nicotine may also be ab-
wrbed t.hrough the mucous membranes of the mouth. This is more
likely to occur under alkaline conditions when nicotine is unprot,onated
(3, 15, 79). Th' 1s suggests that cigar smokers may be able to absorb
SOme nicotine through the oral cavity without having to inhale, par-
ticularly during the time that the smoke from the cigar is alkaline.


\{Tith the development, of sensitive measures of serum nicotine levels
(~8) the extent, to which nicotine is absorbed through the membranes
of the mouth in pipe and cigar smokers can be more accurately
determined.

Inhalation patterns of smokers were determined in several of the
large prospective and some of the retrospective epidemiologioa.1 studies.
Inhalation was usually determined by the administration of a que.
tionnaire that required a subjective evaluation of one's own patterns
of inhalat.ion. Although the accuracy of t.hese questionnaires has not
been confirmed by an objective measure of inhalation, such as carbosS.
hemoglobin or serum nicotine levels, their reliability is supported by
mortality data, whi& demonstrate higher overall and specific death
rates with self-reported increases in the depth of inhalation.

Doll and Hill (26) and Hammond (38) presented information on
inhalation patterns of pipe, cigar? and cigarette smokers (figs. 1,2,3!
and t,able 12). Some 80 to 90 percent, of cigarette smokers reported
inhaling, with the majority of individuals inhaling moderately cr
deeply, whereas most pipe and cigar smokers denied inhaling at all.
Pipe smokers reported slightly more inhalation than cigar smokem
For each type of smoking, less inhalation was reported by older
smokers. This change may represent less awareness of inhalation,
differences in smoking habits of successive cohorts of smokers, or it
may reflect t,he operation of selective factors which favor survival of
noninhalers.

The Tobacco Research Council of the TTnited Kingdom has, since
1957, periodically reported the use of tobacco products by the British.

Figure 1 .-Inhalation among pipe smokers by age.

  No
inhalation

Some
inhalation

34.8      31.2      26.2      23.9       25.5

     I                                  1
   Age     40       50        60        70        80
SOURCE: Hammond, E. C. (38).

184


Figure 2.- Inhalation among cigar smokers by age-Hammond.

  No
inhalation

Some
inhalation

26.4      22.9      17.1       13.7       18.5

    Age  40        50       60        70       80
SOURCE: Hammond, E. C. (38).

Figure 3 .-Depth of inhalation among cigarette smokers by age.-Hammond,

Slight
inhalatir

.._. --3n

Moderate
inhalation

DeeP
inhalation

None

        I                                          J
     Age 40       50       60       70      80

SOURCE: Hammond, E. C. (38).

Recent reports edited by Todd have contained data on the inhalation
pattern of cigar, pipe, and cigarette smokers (92, 93, 94). Table 11
shows that most, cigarette smokers inhale a "lot" of "fair amount"
lrhereas most pipe and cigar smokers do not inhale at all or "just a
little.`Y Little change is observed in t,he inhalation patterns of a given
product since 1968.

Best (9) reported inhalation data among male cigarette smokers by
smoking intensity and age group, but, did not report, the inhalation
             s

185


patterns of pipe and cigar smokers. The overall mortality rates of
current pipe smokers who inhaled at, least slightly were reported by
Hammond (38) as being somewhat higher than for men who never
smoked regularly. The overall mortality rates of current cigar smokers
who reported inhaling at least slightly were a.ppreciably higher than
for men who never smoked regularly (table 13).

,4vailable evidence indicates that cigarette smokers inhale smoke
to a greater degree than smokers of cigars or pipes. Once a smoker has
learned to inhale cigarettes, hovvever, there appears to be a tendency
to also inhale the smoke of other tobacco products. For cigars, this is
evident.ly true whether one smokes both cigarettes and cigars or
switches from cigarettes to cigars (tables 14,X, 16).

Bross and Tidings (14) examined the inhalation patterns of
smokers of large cigars, cigarettes, and those who switched from one
tobacco product to another (table 15). Nearly 75 percent of those who
Kere currently smoking only cigarettes reported inhaling "almost every
puff" and only 7 percent never inhaled. The opposite was true for per-
sons who had always smoked only cigars among whom 4 percent re-

TABLE 11 .-The extent of inhaling pipes, cigars, and cigarettes by
     British males aged 16 and over in 1968 and 1971

Amount of inhalation

                -

Tobacco product

Cigars       Pip3      Cigarrttes
                   ----__
1963   1971 1968   1971   19%   1971

Inhale a lot-. .________________ .____   23    19    8     8    47    47
Inhale a fair amount----------- _____   16    19    10    8    31    30
Inhale just a little _____________ .____   27    27    24    26    13    15
Do not inhale at all- ____. - _____ ._--_   34    35    59    58    9     6

Total------- ______ -- ___. .____  100   100   100   100   100   100

Source: Todd, 0. F. (93, 94)

TABLE 12.--Inhalation among cigar, pipe, and cigarette smokers by
           age--DoU and Hill

Smoking type

        Percentage of inhalers, age
.25 to 34  35 to 44  45 to 54  55 to 64  wit074 >i4

Cigar and pipe-- ___._. --___---  12. 00  10. 00   7. 00   5. 00   4. 00   4. 00
Mixed (cigarette and other)_-- _
                      -  74. 00  60. 00  47. 00  36. 00  30. 00   26. 00
Cigarette only-----.----___-_-  90. 00  85. 00  75. 00  66. 00  58. 00   41.00

Source: Doll, R., Hill, A. B. (?6)

186


ported inhaling almost every puff a.nd 89 percent said they never
inhaled. Cigar smokers who also smoked cigarettes reported inter-
mediate levels of inhalation between the cigar only and cigarette only
categories. Inhalation patterns were similar whether the individual
continued to smoke both products, stopped smoking cigarett,es but
continued smoking cigars, or stopped smoking cigaret,tes and
s\v-itche,d to cigars. In all three groups. about 20 percent reported
inhaling "almost every puff." This suggests that once an individual's
inhalation patterns are established on cigarettes, he may be more likely
to inhale cigar smoke if he switches to cigars, or uses both cigars and
cigarettes, than the cigar smoker who has not smoked cigarettes.

Todd (93) reported similar data for a sample of smokers in the
ITnited Kingdom (table 16). The prevalence of inhaling a "lot!' or
`(fair amount" of smoke was highest among cigarette smokers who were
currently smoking cigarettes (77 percent) and lowest among current
cigar smokers who had previously smoked only cigars or pipes (18
percent). Individuals who switched from cigarettes to cigars main-

TABLE 13.--Mortality ratios -for total deaths of cigar and pipe smokers
        by age and inhalation-Hammond

Inhalation

Mortality ratio. age

45 to 64     6.5 to 84

Nonsmoker___-_____-_____-__-______________________    1. 00      1. 00
Cigar only :
  Total__-_____-__-__-____________________------~     1. 09       . 98
  Noinhalation-_-- _____ - _____ - ___.___.___________     1. 02       91
  Some inhalation ___F_.______ -__-___-_-___-___-__-     1. 28   1: 37
Pipe only:
  Totsl_-_--_____-________________________-------    1. 04       . 95
  No inhalation-_- ____________ - _____ - _.___________     98       87
  Some inhalation ___________ --__--__-___- _____ -___     1. 21   1: 11

Source: Hammond, E. C. ($8)

TABLE IJ.--Percentage of British male cigar smokers who reported
   inhaling a lot or a fair am0un.t by type of product smoked

Type of product

     1968             1971

Number of   Percent   Number of   Percent
individuals         individuals

Cigars only- __ _ __ __ _ _ _ __ _ ___. __ _ _ _ _ _
C' lgars and cigarettes-._-. . _ . ~. - - ~. . -
cigars and pipes.__ _ _ _ _ - _ - - _ _ . _. _. _ . _
Cigars, cigarettes, and pipes- _ _ _ - -. - - -

706   23. 0     111    27. 0
1, 193    42. 0      277     44. 0
596    35. 0      109     32. 0
  26    52. 0       15    32. 0

Source: Todd, C. F. (93, 91).

187


tained somewhat higher levels of cigar smoke inhalation than those
cigar smokers who had never smoked cigarettes (30 percent).

Todd (93) examined further the relationship between the inhalation
of cigarette and cigar smoke. In general, cigarette smokers who
switched to cigars mere much less likely to report inhaling cigar
smoke than cigarette smoke ; how-ever, those who in the past reported
inhaling cigarette smoke a "lot" or "fair amount" were much more
likely to report inhaling cigar smoke to the same degree than those ex-
cigarette smokers who in the past did not inhale the smoke of their
cigarettes (table 17).

TABLE IS.-Percentage of inAn%u& reporting inhalation of "almost
every puf of tobacco smoke by current and previous tobacco usage and
type of tobacco used

      Type of tobacco smoked         Number            PBICBll- "Opd&C
-                        __ of    Type inhaled
   Current usage       Previous lEa@     p.3tiMltS       %r
                                     inh ed Lower Upper

Cigarettes only ____ Cigarettes on1.y ____ 2, 359  Cigarette--- 74. 8  73. 1  76. 6
Cigars only- _ -__-_ Cigars only- - ---- -   649  Cigars-----  4.5   3. 0   6. 0
Cigarettes and    Cigarettes and      520 -----do _____ 20.4  10.5  28.6
cigars.        cigars.
Cigan- _ _ _ _ - - _ _ _ _ Cigarettes and      93 _____ do _____  18. 3   9. 0  30. 0
            cigars.
None ______ -----_ Cigarettes and      186 -----do _____  21.5  17.8  24.2
            cigars.
Cigars- _ _ _ - - - - _ _ _ Cigarettes only -.--    64 _----do_----  17. 2  16. 0  28.6

Source: Bras, I. D. J., Tidings, J. (14).

TABLE 16.-Percentage of British males who reported inhaling a lot or
fair amount of cigar smoke by curren.t and previous tobacco usage and
type of tobacco previously smoked (1968)

        Type of tobacco smoked           Number of            Percentage
-                                 individuals  Type inhaled    inhaled
    Current usage          Prev ous usage

Cigarettes only.-_ _ _ _ . _ Cigarettes only- -- - - -  2, 586  Cigarette.- _ _ _    77. 7
Cigars only-. _. _ _ _ _ _ __  Nonsmoker- - - - _ - __ _   306 Cigars..----    18. 0
Cigars only.. - _____.___ Cigarett,es only _____._    321 -~_~-do--_-__-    30. 0

Source: Todd, 0. F. (94).

188


TABLE 17.-Extent of reported inhalation of ciga.r smoke by British
male cigar smokers who were es-cigarette smokers in 1968, analyzed
by extent of reported inhalation of cigarette smoke when previously
smoking cigarettes

Extent of inhaling cigars

Extent of inhaling cigarettes

Inhale a lot    Inhale a little
or fair amount   or not at all

                                            PerCell       Pl?rCent
Inhalealotorfairamount-_---- ______ -_-__-_--_-      44. 0        5. 0
InhalealittleornotatalI~-._-_-- ____. -_-__-__-_-      56. 0       95. 0

Source: Todd, G. F. (97).

Specific Causes of Mortality

Cancer

Several prospective epidemiological studies have shown a signifi-
cantly higher overall cancer mortality among pipe and cigar smokers
compared to the cancer mortaljty of nonsmokers (table 18).
Pipe and cigar smokers have much higher rates of cancer at certain
sites than at others. The upper airway and upper digestive tracts
appear to be the most likely target organs. The relationship of pipe
and cigar smoking to the development of specific cancers is detailed
in the following sections.

TABLE 18.-Mortality ratios for totd cancer deaths in cigar and pipe
  smokers. A summary of prospective epidemiological studies

Author, reference

            Type of smoking
Nonsmoker Cigar only  Pipe only  Total pipe
                      and cigar  Cirp.~tte

Hammond and Horn (40)----    1. 00    1. 34    1.44  ---- ----     1. 97
Best (9)-- _____ - _______-_-_    1. 00     1. 13     1. 38  _ _ _ - _ _
                                               _   _     2. 06
Hammond (38)---- _ _ _ _ ___ _ _    1.00   -------   -------    1. 21      1. 76
Kahn (60)_-----_._________    1. 00    1. 22    1. 25    1. 25     2. 21

189


Cancer of the Lip

Approximately 1,500 new cases of cancer of the lip are reported
each year. Because of the possibility of early detection and surgical
accessibility of cancers in this area, there are less than 200 deaths from
cancer of the lip each year in the United States. Some of the earliest
scientific investigations exploring the association between tobacco use
and disease examined the smoking patterns of individuals with cancer
of the lip.

Broders (13) in 1920 examined the smoking habits of patients in
a retrospective study of 526 cases of epithelioma of the lip and 5~
controls. Of the cancer cases, 59 percent smoked pipes, whereas this
was true for only 28 percent of the controls. No association was found
between cigar or cigarette smoking and cancer of the lip.

In a restrospective study of 439 clinic patients with cancer of the
lip and 300 controls conducted in Sweden, Ebenius (32) reported 8
significant association bettveen pipe smoking and cancer of the lip.
A total of 61.8 percent of the lip cancer cases smoked pipes, while
only 22.9 percent of the controls smoked pipes. NO association ITas
found between the use of cigarettes, cigars, or chewing tobacco and
cancer of the lip.

In other retrospective studies, Levin, et al. (60) reviewed a series
of 143 cases of cancer of the lip, and Sadowsky, et al. (77) reviewed
5'71 cases of cancer of the lip. 1.n both studies, a strong association ras
found between pipe smoking and cancer of the lip. No significant
association was found between the use of tobacco in other forms and
cancer at this site.

In a study of environmental factors in cancer of the upper alimen-
tary tract, Wynder, et al. (11'S) found an association between pipe
smoking, cigarette smoking, and cancer of the lip. There were only 15
cases of cancer of the lip in this study.

Staszewski (87) examined the smoking habits of 394 men with
carcinoma or precancerous lesions of the lips. An association lvas
found between the smoking of pipes and cigars and cancer of the lip*
but this was only of doubtful significance. A significant association
was found between the use of cigarettes and cancer of the lip.

Keller (51) conducted a study of lip cancers in which he considered
a number of factors including histologic types, survival, race, occupa-
tions, habits, and associnted diseases. A total of 304 patients with
primary basal cell or squamous cell carcinoma of the lip and :W
controls from the same hospital matched for age and race were con-
sidered in this series. A significant association was found between
smoking in all forms and combinations and carcinoma of the lip. lt
\f'as also found that increasing age and outdoor occupations with
exposure to the sun were equally significant factors in the etiology of
lip cancer.

190


In summary, it appears that there are several factors involved in
the etiology of cancer of the lip. -4mong the various forms of tobacco
use, pipe smoking either alone or in combinat,ion with other forms of
smoking seems to be a cause of cancer of the lip. Table 19 summarizes
the results of these retrospective studies.

Oral Cancer

The lips, oral cavity, and pharynx are the first tissues exposed to
tobacco smoke drawn in through the mouth. Variations in inhalation
during the smoking of various tobacco products result in different pat-
terns of distribution of smoke throughout, t.he respiratory tree. How-
eve,r, the oral cavity and adjacent tissues are the sites most. consistently
exposed to tobacco smoke. For this reason, differences in inhalation
should result in less variation in exposure to tobacco smoke for these
sites than for t,he lower t,rachea and the lung. The, inherent carcinogen-
icity of pipe, cigar, and cigarette smoke is most reliably compared at
t.hose tissue sites where dosage and exposure to tobacco smoke are most
nearly equal. Data from the epidemiological studies suggest that little
difference exists between the smoking of cigarett'es, pipes, or cigars and
the risk of developing oral cancer.
Hammond and Horn (JO) examined the association between smok-
ing in various forms and cancer of the combined sites of lip, mouth,
pharynx, larynx, and esophagus. The mortality ra.tios were 5.00 for
cigar smokers, 3.50 for pipe smokers? and 5.06 for cigarette smokers
compared to nonsmokers. All the deaths from cancer of the lip, oral cav-
ity, and pharynx reported by Doll and Hill (Z'(3) occurred in smokers.
The death rates from cancer at these sites were 0.04 per 1,000 for pipe
and cigar smokers, 0.10 per 1,000 for mixed smokers? and 0.05 per 1,000
for cigarette smokers. A fairly detailed analysis of oral cancer was pre-
sented by Kahn (50) who differentiat.ed between cancer of the oral
cavity and cancer of the pharynx. The mortality ratios for oral cancers
were 1.00 for those who never smoked, 3.89 for all pipe and cigar
smoke.rs, and 4.09 for cigarette smokers. A further breakdown of the
pipe and cigar smokers demonstrated a mortality rat.io of 4.11 for
cigar smokers, 3.12 for pipe smokers, and 4.20 for smokers of pipes and
cigars. For cancer of the pharynx, the mortality ratios were 1.00 for
those who never smoked, 3.06 for all pipe and cigar smokers, and 12.5
for cigarette smokers. No deaths occurred among those who smoked
only ciga.rs. The mortality ratio was 1.98 for pipe smokers and 7.76
for smokers of pipes and cigars. Hammond (58) combined cancers of
the lip, oral cavity, and pharynx. The pipe and cigar smokers had a
mortality ratio of 4.94 and the cigarette smokers a mortality ratio of
9.90 compared to nonsmokers.

191


TABLE lg.---Relative risk of lip cancer for men, comparing cigar, pipe, and cigarette smokers with nonsmokers. A summary

qf retrospective studies

        Arlrllor rt~f?rt.rlrt~                      Helatiw risk ratio and percentage of ctlses and cmtrols by type of smoking
                          Nulr,ber -----~- ~.---.-------------_~-                 ----- ------__
                                             Nonsmoker Cigar only  Pipe only  Total pipe  Cigarette    Mired
                                                                      and cigar    only
--  __ .-~                                   -

Broders (15) :                      Relative risk ______ --_-.-
  Cases-m.mm--_-m. __-.--. ~_- 537    Percent cases-_-------m-
  Controlsmm ~--_--~..---_-~~-~- 600    Percent controls----_-_.-

Relative risk-m------_.--_
Percent cases-----.-m---
Percent controls-.._-__

Levin, et al. (CO):
   f--o-n.                      
   YU.?Ci)_ ---__--~-~--_-_~---__ 146
  Controls --__-.----___~----_ 554

Relative risk_--_m-m--_-_
Percent cases-----m__---
Percent controls_--._----

Relative risk ____ -_--__-_
Percent cafes- _ _ _ _ . _ - _ - -
Percent controls--. - ___

Wynder,' et al. (Ifs) :
  Cases-.__----_-___-_-~--~--~ 14
  Controls--_-__---_-_________ 115

Relative risk--__--_--_--
Percent cases- _ -. _ _____ -
Percent controls. _______

Staszewski (87) :

  Cases-____~__-._-_.__-----~~ 394
  Controls __--_. _. _ _ -. --_-_ _ --_  912

Keller: (61) :

Relativerisk-_-_---- ____
Percent cases--_--..------
Percent controls_ _ _ _ _ _ _ -

Cases-.-m--- _____ -__-_----_ 301
CoIltrols--~-- .__. ~_-- _____ --_  265

Relativerisk-_-_--..-.__
Percent cases- ___. -_-___
Percentcontrols-__-----

1. 0     0. 8     4. 3  - _ -. _ _ _ _ _    0   .____-__ -
7      19      41   -__---___     1   _____ -__
4      16       6   -____-_--    26   _ _ _ _ _ _ _ _ _

1. 0   6' 7     4. 1     0.5  -- _.___  ^.  _- _-__
49             41       4
65      12      13      10    ----__- -~- -___ -_

1. 0     1. 9
15      27
22      20

1. 0     1. 1
8       2
13       3

0        8
0    7'
24      9

1.0  - ________
5   _--_- ____
13   _ _ - _ _ _ __ _

1. 0     1. 4
7       2
17       4

4. 3     2. 6
18       6
7      4

1.8  ___---___
29   .______ ~_
16   _ _ _ _ _ _ _ _ _

       2. 1
        12

- _ . _ - - _      11

  4. 0
  6       1
  3       0

I. 1  ___-_ -___
45   ___-__. -_
46   _____ -_-_

1. 4      0. 4
44       22
53       19

1. 0      2. 2
36       29
36       13

2.4  -_-_--_--
73  ______--_
61  _________

2. 6
60       6
53        0


These studies are summarized in table 20. They demonstrate that
smokers experience a large. and significant risk of developing cancer
of the oral cavity compared to nonsmokers. This risk seems to be about
the same for all smokers whethe.r an individual uses a pipe., cigar, or
rigare&.

A number of retrospective studies have examined the relat,ionship
betwwn smoking in various forms and cancer of t.he oral cavity. The
results of these studies are presented in table 21. Some of the variations
in relative risk of developing oral cancer observed in the retrospect,ire
studies is probably due to the lack of a uniform definition of oral cancer
by anatomical site and the variolls means used in selecting and defin-
ing cases and controls. It appears, however, t,hat a significant risk of
developing oral cancer exists for smokers compared to nonsmokers
and t.his risk is similar for smokers of pipes, cigars, and cigarettes.

Several epidemiologic.al investigations have demonst,rated an asso-
ciation between the combined use of alcohol and tobacco and the
development of oral cancet . A few of these studies ($2. 62, 6.7. 10.9)
ront.ain data on pipe and cigar smokers. Heavy smoking and heavy
drinking are associated with higher rates of oral cancer than are seen
with either habit alone.

TABLE 20.-Mortality ratios for oral cancer in cigar and pipe smokers.
     A summary of prospective epidemiological studies

Author, reference

            smoking type
      ----__ --      ---__-
Non-    Ci ar    Pi e
SlllOker   d P    Total pipe Cigarette   Mixed
       0 Y     on Y   and cigar   OdY

Hammond and Horn'(@) _   1. 00   5. 00    3.50  --__----   5.06  -- .--__-
Doll and Hill 2 (16, 97) - - .   0.00  -__--_--   - _-.- -   0. 80    1. 00    2. 00
Hammond (98)---_--_---   1. 00  - _ _. _
                            - -  -   _ - -. . _   4. 94   39.90  __-.--- -
Kahn (60):
  Oral 4.. ___---_--__--   1. 00    4. 11    3. 12    3. 89    4.09  --__--_-
  Pharynx----_---_--_   1. 00  _ _ _ - - _ _ -   1. 98    3. 06   12.54  -___--_-

* Combines data for oral, larynx, and esophagus.
2 Ratios: relative to cigarette smokers.
3 Mortality ratios for 45 to 64
           ages     only are presented.
' Excludes pharynx.

          Cancer of the Larynx
The larynx is situated at. the upper end of the trachea. Because of
its proximity to t,he oral cavity, the larynx probably has a similar
exposure to smoke dra#wn through the mouth as the buccal cavity and
pharynx. Tobacco smoke that is not inhaled may still reach as far as
the larynx and upl)er trachea. Pipe and cigar smokers develop cancer
of the larynx at rates comparable to those of cigarette smokers. These

193


P

TAJILK 21.--Relative risk of oral cancer for men, comparing cigar, pipe, and cigarette smokers uith nonsmokers. A summary of retrospective
                                      studies

Author, rekwncr

              Relative risk ratio and percentsge of cases and controls by type of smoking
Number ---_----------__-----
                        Nonsmoker Cigar only  Pipe only  Total pipe  Cigarette
                                             and cigar    OdY

Mixed

dadowsky, et ai. (iii:
  CaseS------_._______--~-----
  Controls-~_._---------- __.___

Schwartz, et al. (83) :
  Cases--_-_._-- -------__~--
  Controls-----._~_~.--.- __.._

Wynder, et al. (209):
  Cases--_----_-- _________.___
  Controls~~....----_- _______ -_

1, 136
615

332
608

543
207

Relative risk--- - - _ _ _. _ _ _.
Percent cases- _ _ _ __ _. _ _ __
Percent controls-- - _ _ _ _ _ __

iieiative risk-~._~__--_---
Percent cases-_--------_-
Percent controls-. - _ _ . _ _ _ _

Relative risk----~-__-_--_
Percent cases-----_--_---
Percent controls-- - - _ _. _ _

1.0  --____---  -_-_--~-     7. 0
10   -_---___-  --._._..    55
38   _.__~_.__  ____--._    30


1. u
8
13


    ___
    ___

1. 0
16
23

Relative risk _____________     1. 0
Percent cases_- _____ -_--_    3
Percent controls-- ________    10

Relative risk_--- - _ _ _ _ _ _ _ _     1. 0
Percent cases----___-----    23
Percent controls-----__---    26

2. u     4.4  --_---___
4      18   --_. --___
3      7   _____~_._

        1.6  ___---___
__----    3   _____ -_-_
77       3   -- _______

3. 6     6. 1  - ________
20      11   ~-_-- ___-
13      6   ___-_-___

1.7      . 9  -_-_-____
13      12   -----_--_
9      16   _____---_

1. 4      2. 1
42      28
53       23

1.5  - -_____ --
63   _______ -_
58   __ -_--._

3. 0      3. 3
57        8
63        8

1. 2      1. 4
37       16
36       13


k Staszewski (87):
    Cases __._ ._____ -__-~--___--
    Controls- _.______ -__--_~--___

Martinez (69) :

178
220

1,400
713

383
912

408
408

170
510

346
346

Relative risk_---~_.-~---.
Percent cases--_----~----
Percent controls_-- _ _ ___ _ _

Relative risk-_--~---_----
Percent cases---.--- .____
Percent controls--_-_----_

Relative risk----.--_~----
Percent cases_- ____ -___--
Percent controls----_-- .-_

Relative risk_-- ._____ ---_
Percent cases- - ___-___-__
Percent controls---- _ _ ____

Relative risk---~--~_-_--_
Percent cases---U------_-
Percent controls--- _ - _ _ - -_

Relative risk_--- ____ -_~-_
Percent cases- _ - _______ --
Percent controls__ _ _ _ _ - - - _

1. 0     6. 0
4      33
16      22


1.0  _------_
21   _--_-_-_
39   ---_-_-_


1.0  ~_.__.~.
6   ---___-_
17   ---___--


1. 0     3. 1
5       7
11       6


1. 0     1. 7
8      10
14      10


1. 0     2. 0
12      10
22      9

3.6 -~ -_____
10 _---_--_

5

_---_-
_____-
_____-

3. 8
4
3

1. 3
1
2

2. 8

  3. 5
  13
  11


  2. 2
10
  13




___-___-




.___-_--

15 __--_--_
1    ___-----

4.0  ___-_ -._--
45   --___-_-.
45   ~_.._____

2. 2      2. 9
59       11
50       7


3. 6  -_~-___--
72   _--_-____
61   __-__--__


3.4  ___-- ---_
69   -___----_
56   ~-___--_.


1. 5      2. 3
39       34
44      25


1. 7      2. 5
34       34
36      25

' This study combines data for oral CmCeI and mncer of the esophagus.


rates are several times the rates of nonsmokers. The similarity of the
mortality ratios of cancer of the laqwx for smoking in various forms
suppcsts that, the carcinogenic potentials of the smoke from cigars,
pipes. and cigarettes are quite alike at this site.

Sewral of the prospective epidemiological studies include data on
deaths from cancer of the larynx for pipe and cigar smokers as \T-ell
as for cigarette snlokers. Hammond and Horn (.&I) combined data for
cancer of the larynx with cancer of the esophagus and oral cavity.
The mortalit,y ratios compared to nonsmokers were 5.00 for cigu
smokers, 3.50 for pipe smokers, and 5.06 for cigarette smokers. There
were no deaths from carcinoma of larynx among nonsmokers in
the study of British physici;ms by Doll and Hill (%%) ; however, the
de&h rate for cancer of the larynx among pipe and cigar smokers was
0.10 per 1,000 while the death rate for cigarette smokers was 0.05 pe1
1,000. Kahn (50) reported mortality ratios for c.ancer of the larynx of
10.33 for cigar smokers, 9.44 for pipe and cigar smokers, 7.28 for all
pipe and cigar categories combined, and 9.95 for cigarette smokers. No
deaths from cancer of t.he lar,ynx occurred in pipe smokers. Hammond
(.?a) reported a mortality ratio of 3.37 for all pipe and cigar smokers
and a mortality rat.io of 6.09 for cigarette smokers in the age category
45 to 64. These studies are, summarized in table 22.

Several retrospective studies have examined the smoking habits of
patients with cancer of the larynx and appropriately matched controls.
The small number of pipe and cigar smokers in each study results in
relative risk ratios that are quite unstable; however, it appears that
pipe and cigar smokers experience a risk of developing cancer of the
larynx that is similar to the risk observed among cigarette smokers
(table 18).

TABLE 22.-Mortality ratios,for cancer qf the larynx in cigar and pipe
   smokers. A summary qj' prospective epidemiological studies

Author. reference

              Smoking type

Non-  Cigar only Pipe only Total pipe Cifrpe   Mixed
smoker                and cigar

Hammond and Horn 1
(~o)--------~------~-~   1. 00    5. 00    3.50  --------   5. of3  . . . . ..~.
Doll and Hill * 126, 27) ~.   0.00  -- -----   ~-----   2. 00    1. 00    0. 60
Hammond (381.----...   1.00  ~._~~~_~   ~_~~~~   3. 37   3 6.09  ~.~~~~.~
Kahn iSO)----------..--   1. 00   10. 33   ~-~~~~   7.28    9.95  ~.....~.

1 Combines data for oral, larynx. and esop~gus.
1 Ratios: relative to cigaretle smokers.
3 Only mortality ratios for ages 4.5 to 64 BTG presented

!96


Wynder, et al. (108, 113) distinguished between intrinsic and ex-
trinsic larynx cancers. For smokers the relative risk of developing
cancer of the intrinsic larynx was similar to the relative risk of lung
cancer whereas the relative risk of developing extrinsic larynx cancer
was more like the relative risk of cancer of the upper digestive tract.

Histologic changes of the larynx in relation to smoking in various
forms were described by Auerbach, et al. (5). Microscopic sections of
the larynx from 042 subjects were examined for the presence of
atypical nuclei and proliferation of cell rows. Sections we.re taken
from four separate areas of the larynx in each CXCX. ,imong t,hose who
smoked cigars and pipes but not cigarettes. only 1 percent, had no
atypical c.ells and more than 75 percent of t.he subjects had lesions
wit,h 50 to 69 percent, atypical cells. Four of the cigar and pipe smokers
had carcinoma in sit.u and in one of t.hese four cases early invasion
was seen in three of the sections. Of those n-ho never smoked re,gu-
larly, 75 percent had no at,vpical cells. The cigar and pipe smokers had
a similsr percentage of cells with at.ypic.al nuclei as cigarette smokers
\r-ho smoked one to t.wo packs per day. With respect to the prolifera-
tion of cell rows in the basal layer of the true vocal cord, the least
proportion of cases with eight or more cell rows was found in men
who never smoked, and the greatest proportion was found in heavy
cigarette smokers. Pipe and cigar smokers had a distribution of cell
POWS that, was comparable to that of cigarette smokers who consumed
about a pack a day.

Several ret.rospective studies have, reported an associat,ion between
the combined use of tobacco and alcohol and cancer of the la.rynx. A
study by Wynder, et al. (108) included some informat.ion on pipe and
cigar smoking in relation to drinking habits and the development, of
cancer of t,he larynx, but because of t.he limited number of pipe and
cigar smoking subjects this relationship could not be adequately
determined.

Cancer of the Esophagus

The esophagus is not directly exposed to tobacco smoke drawn into
the mout,h; however, the esophagus does have contact with t.hat portion
of tobacco smoke that is condensed on the mucous membranes of the
mout.h and pharynx and then swallowed. The esophagus is also ex-
posed to a portion of tobacco smoke that, is deposited in t.he mucus
cleared from t.he lung by the ciliav mechanism or by coughing. Varia-
tions in inhalation of a tobacco p&duct may not appreciably alter the
exposure the esophagus receives from smoke dissolved in mucus and
saliva. This suggest.ion receives support from the prospective and
rebrospect.ive epidemiological studies which demonstrate similar mor-
tality rates for cancer of the esophagus in smoke,rs of cigars, pipes, and
cigarettes.

197


Relative risk ratio and prrcentwe of CBS~S and controls by type of smoking
         --~.-~__--
        Nonsmoker (`ignr only  Pipe only  Total pipe
                             and cigar   cigarettr
                                     OIllY

Mixed

TABLE %.-Relative risk qf can,cer qf the larynx .for men, comparing cigar, pipe, and cigarette smokers with nonsmokers.
                   A summary qf retrospective studies

Author. rrlwrnc,


     ___-..

Number

Relativerisk--- -----_--
Percent casts-

1. 0     0       1.1  _.___._~_
14       0      ?   -------__
24      10      11   __-------

Percent controb-_m_--__-

2.3 -_-- _____
so -----____
59 ~.~__.___

Sadowsky, et al. (77) :
  Cases---- ~~~----___--~.~--- 273
  Controls _.__ ~~-~---._-_-_~_~- 615

Relative risk----_-~ -~_-_
Percent cases- _ _ _ _ _ _ - -
Percent controls-----_.-.

1. 0     2. 2     2.3  ______- --
4       2       5   _ -
                   _ _ _ _ _  - _
13       3       7   _ _ _ _ _ _ _ _ _

3. 7      4. 1
60       29
53       23

Relative risk---_-_--m_--
Percent cases--- ____ --._
Percent controls__-__-_--

1. 0    15. 5    27. 7     11. 1
.5     8       5       1
11      10       4       2

24.6 _____ -__-
86   ___._ -- ._
74   _ _ - - - _ _ _ -

Wynder, et al. (ZfS):
  Casese--m------ ____ -._~---  60
  Controls---_.~_-___-_--.~ -._ 271

Relative risk_---_--.._-_-
Percent cases----_---__-
Percent controls__--___-_

1. 0     9. 7     4.5  _-_----__
5      17      15   --_____ -_
24       9      16   _______ -_

6. 3     6. 3
47       17
36       13

Wynder, et al. (116) :                Relative risk- _ _ - - _ _ - _ _ _
  Cases_----~-~_---_~--______ 142    Percent cases- _ _ - _______
  Controls-..~~ ._~--__-~-._~._. 220    Percent controls-------_-

1. 0     14. 5    16.0  ___._ -___
1      20       1   _-__ --___
16      22       1   _--~-__-_

22. 0     16. 0
62       16
45       16


Pernu (75) :                       Relative risk__------_--_     1.0  --. --._-_     4.5  -_--___--     8. 7      3. 2
  Cases.~~~------___-_-----_~~  546    Percent cases _______. --_    7   ___..__ ~_     4   - _______ -    78       4
  Controls------___- __________ -  713    Percent controls---------    39   ___- ___._    5    _ r _ _
                                                                           . . _.      50       7

Staszewski (87) :                    Relative risk-.---..----     1.0 -- _-_-___   ___---_    5. 9    50.2  ___-_-___
  Cases-..._~-~-._~------_____ 207    Percent cases _________ -_     .5  --_-----_   ___----     2      88   -----__ -_
  Controls_-----.._--- _._._.___  912    Percent controls--------_    17   .__-_-___   _______    11      61   ___-----_

Svoboda (!/O) :                     Relative risk_------     1.0 --_---_-_    2.6 ___---___    10.0 -________
  Cases_._._____-___~-----~~_- 205    Percent cases------ ___._    3 .__---___    3   _ _ _ _ _ _ - - -    95   - - - - _ _ _ _ _
  Controls--- ____.__ --~~~ . . . .._ 320    Percent controls__-m--_-- 22 _____ -___ 7 -- _______ 71 -- _______

Stell (88) :                       Relative risk___----- _...     1.0  -- _______   --__--_     1. 3     2.4  -_-- _____
  Cases--.  .~~~---._____----~_    190  Percent cases..-------_-_    11   .__-- ____   ___--__    8      79   --~-_-_--
  Controlsmm_-  -_~.--- _____._. -    190  Percent controls ________ -    17   --_._-.--   _____ --    10      50   __-----~-


In t,he prospective epidemiological studies, cigar, pipe, and cigarette
smokers all had similar mortality ratios from cancer of the esophagus.
Hammond and Horn (40) combined the categories of carcinoma of
the e.sophagus, larynx, pharynx, oral cavity, and lip and described
mortality ratios of 5.00 for cigar smokers, 3.50 for pipe smokers, and
5.06 for cigarette smokers. Doll and Hill ($6) reported an esophageal
ancer mortality ratio of 2.0 for pipe and cigar smokers, 4.8 for mixed
smokers, and 1.5 for cigarette smokers. Kahn (60) reported the fol-
lowing mortality ratios for smoking in various forms compared to non-
smokers: cigar only, 5.33: pipe only, 1.99; pipe and cigar, 4.17; all
pipes and cigars combined, 4.05; a.nd cigarettes only, 6.17. The results
of these prospective st.udies are summarized in table 24.

Several retrospective inrestigat,ions have also examined the associa-
tion between smoking in various forms and cancer of the esophagus.
These studies have been summarized in table 25. The evidence sug-
gests that cigar, pipe, and cigarette smokers develop cancer of the
esophagus at rates substantially higher than those Seen in nonsmokers,
and that lit.tle difference exists between these rates observed in smokers
of pipes and cigars and cigarettes.

Histologic c.hanges in the esophagus in relation to smoking in vari-
ous forms were investigated by Auerbach, et al. (`r), who looked for
atypical nuclei. disintegrating nuclei? hyperplasia, and hyperactive
esophageal glands. A total of 12.598 sections were made from tissues
obtained from 1,268 subjects. For each of the parameters investigated,
pipe and cigar smokers tlenlonstrated significantly more abnormal
histologic changes than nonsmokers J however, these changes were not
as severe or as frequent as those seen in cigarette smokers.
Several retrospective studies conducted in the United States and
other countries have examined t.he synergistic roles of tobacco use and
heavy alcohol intake on the development of cancer of the esophagus.
Four of these invest.igations contain data on pipe and cigar smoking
(12. 6,". @. 107). It appears that smoking in any form in combination
with heavy drinking results in especially high rates of cancer of the
esophagus.

TABLE 24.--,&fortali.ty ratios jbr cancer of the esophagus in, cigar and
pipe smokers. A summa y qf prospective epidemiological studies
                        -
                                Smoking type

Author, reference

NOW    Cigar
smoker    only

     ------____--
Pi e    Total
3          Cigarette
0 Y    pipe and    CdY    Mixed
      cigar

Hammond and Horn I(@)    1. 00    .i. 00    3.50  -----_--   5.06  ----_..r
Doll and Hill (86, 87).---   1.00  _--~----   _..~_.   2. 00    1. 50    4. 80
Hammond (S8).------_--   1.00                       2
                         _.--._-.   _---_-   3. 97    4. 17  --..---.
Kahn (60)-~~--..-..~-.~   1. 00    5. 33    1. 99    4. 05    6. 17  ._- _..._

1 Combines data for oral. larynx, and esophaqu
2 Mortality ratio for ages 45 to 64.

200


TABLE 25.-Relative risk of cancer of the esophagus for men, comparing cigar, pipe, and cigarette smokers with nonsmokers.
                  A summary of retrospective studies

Author, reference

              Relative risk ratlo and percentage of cases and controls by type of smoking
Number I---__---               ____~-        ----_-_
                       Nonsmoker Cigar only  Pipe only  Total pipe  cigarette    Mixed
                                           and cigar    OIllY

Ssdowsky, et al. (77):                Relative risk _______ ___ __
  Cases__-__________-______.._- 104    Percent cases- - _ _ ___ _ ___
  Controls--__------ ___________ 615   Percent controls ____ _ _ _ _ _

Wynder, et al. (213):
  Cases______________________- 39
  Controls _____ ____ ____________  115

Pernu (73) :
  Cases- - _ - _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ __ _  202
  Controls _____________________ 713

Relative risk _____ __ ____ _
Percent cases- - _ ______ -_
Percent controls _____ _ __ _

Relative risk ______ ____. _
Percent cases- _ _ _ _ _ _ _ _ _ _
Percent controls _________

Schwartz, et al. (84) :
  csses_______________________ 249
  Controls ________ - ____________ 249

Relative risk ____ _ _ _ _ _ _ _ _
Percent cases- _ _ _ _ _ _ _ _ __
Percent controls _________

Wynder and Bross (107):
  Cases___-__________--------- 150
  Controls _____ _ _ _ _ __ __ ________  150

Relative risk __________ __
Percent cases.. _ _ ________
Percent controls _________

1. 0     4. 8
4       5
13      3


1. 0     3. 1
13      15
24      9


1.0  _________
17   _ _ _ _ _ _ _ _ _
39   _ _ _ _ _ _ _ _ _


1.0  -__---__-
2   .`________
18   _ - _ _ _ _ _ __


1. 0     3. 6
5      19
15      16

3. 8     5. 1     3. 8      3. 3
8       6      60       18
7      4      53       19

2. 1  _ _ _ _ _ - - _ _
18   _ _ _ _ _ _ _ _ _
16   _ _ _ _ _ _ _ _ _

2. 6
51
36

3' 4


13

3.0 _________
7   - _ _ _ _ _ _ _ _
5   _ _ _ _ _ _ _ _ _

2. 7
59
50

5. 9
18
7

2.6 _________
2   _ _ _ _ _ _ - _ _
7   _ - - _ _ - - _ _

11. 7      8. 6
38       7
67       7

9. 0     6. 0     2. 8     3. 7
9       4      51       11
3       2      55       9


TABLE 25--l!elative risk of cancer of the esophagus for men, comparing cigar, pipe, and cigarette smokers with nonsmokers.
               A summary of retrospective studies.-Continued

Relative risk ratio and percentage of cases and controls by type of smoking
      Nonsmoker Cigar only  Pipe only  Total pipe   Cigarette
                             and cigar     O"lY

Mixed

Relative risk-_- - _ . _ . _ . _
Percent cases- _ _ _. _ _ _ _ - -
Percent controls _______ -_

1.0 __----___    4.8 ______ -_
15 _________ 41    _ _ _ _ _ _ _ _
32 _______ -_ 18    _ _ _ _ _ _ _ _

2. 3  - - _ - _ _ _ _ _
63 ._----___
58   . _ _ _ _ _ _ _ _

Martinez (62) :
  Cases---~_~___._---_---~-~-- 120
  Controls---- _______ -_-__-__-_ 360

Martinez 1 (63) :

Cases_____-___-_-_-_________ 346
Controls- _ _ _ _ _____ _________ _ 346

Relative risk------- _____
Percent cases----------_
Percent controls _________

Relative risk _____ _ ______
Percent cases- _ _ ______ __
Percent controls ____ _____

1. 0     2.0  __----_-   __- _____
8      9   --------   ____-_-_
14       8   ________ ________

1. 5      2. 2
31       43
34       34

1. 0     2. 0     2.8   ____ -_-_    1. 7      2. 5
21      10     15    ______ -_   34      34
22      9       1    - - _ _ _ _ _ _   36       25

1 Thfs study comblnea data for oral cancer and cancer of the esophagus.


Lung ca.ncer

Abundant evidence has accumulated from epidemiological, experi-
mental, and autopsy studies establishing that cigarette smoking is the
major cause of lung cancer. Several prospective epidemiological
studies have demonstrated higher lung cancer mortality ratios for pipe
and cigar smokers than for nonsmokers, but the risk of developing lung
cancer for pipe and cigar smokers is less than for cigarette smokers.
Table 26 presents a summary of these prospective studies. Dose-
response relationships such as those that helped demonstrate the nature
of the association between cigarette use and lung cancer could not be
as thoroughly studied for pipe and cigar smokers because of the rela-
tively few smokers in these categories. Although the number of deaths
mere few, Doll and Hill (96') reported increased death rates from lung
cancer for pipe and cigar smokers with increasing tobacco CO~SU~P-
tion (table 27). Kahn (50) also demonstrated a dose-response relation-
ship for lung cancer by the amount smoked (table 28).
A few of the retrospective studies contained enough smokers to allow
an examination of dose-response relationships for pipe and cigar smok-
ing and lung cancer (I: 61, 74, 77). An increased risk of developing
lung cancer was demonstrated with the increased use of pipes and
cigars as measured by amount smoked and inhalation. The retrospec-
tive investigation of Abelin and Gsell (1) is of particular interest. The
smoking habits of 118 male patients with cancer of the lung from a
rural area of Switzerland were compared with those reported in a sur-
vey of all male inhabitants of a town in the same region. About 20
percent of the population of this area were regular cigar smokers, the
most popular cigar being the Stiimpen, a small Swiss-made machine-
manufactured cigar cut at both ends with an average weight of 4.5 g.
In this investigation, cigar smokers experienced a risk of developing
lung cancer that was similar to the risk of cigarette smokers. A dose-
response relationship was demonstrated for inhalation and amount
smoked. These data suggest that the heavy smoking of certain cigars
lnay result in a risk of lung cancer that is similar to that experienced
by cigarette smokers.
Several pathologists have reported histologic changes in the
bronchial epithelium in relation to smoking in various forms. Knudt-
Son (57) examined the bronchial mucosa of 150 lungs removed at au-
'&PSy and correlated the histologic changes noted with the history
of smoking, age, occupation, and residence. Specimens obtained from
the six cigar and pipe smokers demonstrated basal cell hyperplasia;
however, there was no squamous or atypical proliferative metaplasia
as is frequently seen in the heavy cigarette smokers.
Sanderud (78) examined histologic sections from the bronchial tree
of 100 male autopsy cases for the presence of squamous epithelial

203


metaplasia. In this study, 39 percent of the population were non-
smokers, 20 percent were pipe. smokers, and 38 percent smoked cig-
aret,tes. A total of 80 percent of the pipe smokers and cigaret,te smokers
demonstrated squamous metaplasia of the bronchial tree, whereas only
54 percent of the nonsmokers had this abnormality.

Auerbach, et al. (6) examined 36,340 histologic sections obtained
from 1,522 white adults for various epithelial lesions including:
presence or absence of ciliated cells, thickness or number of cell rows,
atypical nuclei, and the proportion of cells of various types. The
pathologic findings in the bronchial epithelium of pipe and cigar
smokers are compared to those found in nonsmokers and cigarette
smokers (table 25). Pipe and cigar smokers had abnormalities that
were intermediate between those of nonsmokers and cigarette smokers,
although cigar smokers had pathologic changes that in some categories
approached t.he changes seen in cigaret.te smokers.

TABLE 26.-Mortality ratios for lung cancer deaths in male cigar and
     pipe smokers. A summary of prospective studies

Author, reference

NIXI-
smoker

Hammond and Horn (40) _   1. 00   3. 35   8. 50  - ____ -__  23. 12   19. 71
Doll and Hill ($6, 67') _ - _ _   1.00  ______-_   ------   6. 14   13. 29    7. 43
Best (9) ________________   1. 00    2. 94    4.35  ______ -_  14.91  ________
Hammond (38) ____ _ __ _ _ _   1. 00    1. 85    2. 24    1. 97    9. 20    7. 39
Kahn (60) _ _ _ _ _ _ _ _ _ . _ _ _
       _             1. 00    1. 59    1. 84    1. 67   12.14 __- ___._

TABLE 27 .-Lung cancer death rates jor cigar and pipe smokers by amount
            smoked-Doll and HilJ


            Smoking type               Death rate per 100  Number of deaths

Nonsmoker___-_______----------------------
Cigar and pipe:
  1 to 14 g. per day ______ -- _______________
  15t024g.perdayw---S------ ___________
  >24 g.perday___-___--_..__-__--------
Cigaretteonly_--- ____ -__-_--_---___- _______

0. 07           3


.42           12
.45           6-
.96           3-
.96          143

Source: Doll, R., Hill, A. B. (I).

204


TABLE 28.-Lung cancer mortality ratios for cigar and pipe smokers by
            amount smoked-Kahn

Smoking type

Mortality ratio   Number of deaths

<5 pipefuls per day_ _ _- ________ _. _. _ ._._
5 to 19 pipefuls per day_ _______. _______._
>19 pipefuls per day- _ _ ___ ____. _ __. ____ _
Cigar and pipe:

8 or less cigars, 19 or less pipefuls- - - - - - - - -
>S cigars, >19 pipefuls__- _ _ _. _ _ _. _ _ _. __ _

1. 00          78

1. 14           12
2. 64           11
2. 07            2

.77
2. 20
2. 47

1. 62
2. 19

2
12
3

18
2

Source: Kahn, H. A. (60).

205


i   TABLE %.--Relative risk qf lung cancer-for men, comparing cigar, pipe, and cigarette smokers with ncnwnokers. A sum-
                      mary of retrospective studies

               Relative risk ratlo and percentage of cases and controls by type of smolrlng
Number -------. -___                             ---~----
                       Nonsmoker Cigar only  Pipe only  Total pipe %-P    MLrad
                                           and olger

Levin, et al. (60) :

  Cases _____ --.._--- ____ - _.__ -   236
  Controls ._____. .__- ._________   481

Schrek, et al. (81):

  Cases __________. --._-_- _____    82
  Controls_-- _____ -__-- _______   522

Wynder and Graham (1 II) :
  Cases _____ -- __________ - ____ -   605
  Controls-_-..-- ______ -___--__   780

Doll and Hill (86) :

  Cases ___________ -- __________ 1,357
  Controls _____.__ -__- _______ -_ 1,357

Koulumies (66) :

  Cases- _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _- _ _ _ _   812
  Controls- _ _ _ _ _________ __ _- __   300

Sadowsky, et, al. (77) :
  Cases-__---- ____ -___-___-___   477
   Controls~~--.-~--..~- _____ -..   615

Relative risk ____________
Percent cases.. _ _________
Percent controls _________

Relative risk ______ - _ ____
Percent cases--- -_- _____
Percent controls-F _ _ _ -_ __

Relative risk ______ ______
Percent cases- _ - ________
Percent controls---- - _ _ _ _

Relative risk ____ _ _ _ _ _ _ _ _
Percent cases- _ _ _ _ _ _ __ _ _
Percent controls- _ _ - - _ _ _ _

Relative risk ____ _ _ - - _ _ _ _
Percent cases- _ - L__ _ __ _ _
Percent controls ____ _____

Relative risk ____________
Percent cases.. _ - ________
Percent controls ____ _ __- _

1. 0     0. 7
15      11
22      23


1.0      .6
15       4
22      23


1. 0     5. 1
1       4
15      8


1.0 __-__ -___
5' 5  _--______
    - - - - - -
     -   _  -


1.0  ___- _____
.6  _____ -___
18   ______ -__


1. 0     2. 4
4       2
13       3

0.8 _________
14   - - _ _ _ - - _ -
25   _ _ _ _ _ _ _ _ _

2. 1  ^ _ _ _ - _ _ _ _
66   ---_---_ -
44   _- __-____

7 _____--__
5' __-__--_-
11 -____----

1.7  ____---_-
61   _ __ __ __ _ _
59   _ - - - - - - -
      _

3.6 ___- _____
4   - - - _ _ - - - -
12   __-_ _ ___ _

15.7  ---_-----
91   ______ -_-
65   _- _______

5. 1  - - _ - _ - _ _ _
4   ---_ - --_-
7   - - - - - - - - -

9.6  _________
74   -______ --
69   _______ -_

9.6 _________
2   ---- ---__
6   - - - - - - - _ -

29.3  ---_--- --
77   ------- --
76   _______ -_

1.4 -________    3. 7      5. 6
3   -- --_----    57       31
7   ----__-__    53       19


Relative risk _____ - ______
Percent cases- _ _ _ ____ ___
Percent controls--- _ _ ____

1. 0     2. 5     4.0 _________
4      13       6   _ _ _ _ _ - - - -
21      27      8   _ _ _ _ _ _ _ _ _

8. 5  _ _ - - _ _ _ _ _
77   _ - - - _ _ _ _ _
45   _ _ _ _ _ _ _ _ _

Randig (74) :

Cases---...-.--------------...   415
Controls~~ _- _ - - _ _ _ - - - - - _ _ _ -. _   381

Relative risk--_- _ _ _ _ _ _ _ _
Percent cases- _ _ _ _ _ _ _ _ _-
Percent controls-_- ______

1. 0     5. 3     5.0 _________
1      21      11   ______-__
6     19      11   _-___--__

5.0 __- ______
67   _ _ _ _ _ _ _ _ _
64   _---__ -__

Mills and Porter (66):
  Cases--..-- _______r____ -_-___   444
  Controls_ - - ._ _ _ _ _ - _ _ _ _ _ _ _ _ _ _ _   430

Relative risk ____ _ _ _ _ _ _ _ _
Percent cases- _ _ _ _ _ _ _ _ _ _
Percent controls--- ____ __

1.0  ----____-  __-__-__    0. 0
7   ----__---  _-___--_    37
31   _________  ________    26

5.4 _---_____
55   _ - - - _ _ _ _ _
43   _ - - - _ _ - _ _

Mills and Porter (66) :
  Cases----_~~~-~--~..---___---   484
  Controls_-- ______ - ____ - ______ 1,588

Relative risk---- - - _ _ _ _ _ _
Percent cases- _ ________ _
Percent controls _______ __

1.0  _____ -___  _____ -_-    2.8
8   -------_-  _-___-__    13
28   _______-_  ________    16

4.5 _________
78 _____ -___
57   _ - - - - - - _ _

Schwartz and Denoix (88) :
  Cases_____------_-.---___-_-   430
  Controls-- _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ . _   430

Relative risk ____ __ _ _ _ _ _ _
Percent cases- _ _ _ _ ______
Percent controls-- _ ____ __

1.0 ---_____-    4. 7  _ - _ _ _ _ _ _ _
1   - - - - - _ _ _ -    6   - - _ _ _ - - _ _
11 _________ 14 ____ --___

13. 5 _-_-_____
96   _ _ _ _ _ _ _ _ _
78   _ _ _ _ _ _ _ _ _

Stocks (89) :

Cases_------------.-----..--- 2,101
Controls--- _ _ _ _ _ _ _ _ _ _ _ _ _ _ - _ _ _ 5,960

Relat,ive risk ____ _ _ _ _ _ _ _ _
Percent cases- _ _ _ _ __ ____
Percent controls--_ ____ -_

            3. 1
LO --------- 9   _ - _ _ _ _ _ _ _
2   -----__ --        - - _ - - _ - _ _
9   _ - _ _ _ _ _ _ _    13 ________ -

5.0 -----____
89   _ _ _ _ _ _ _ _ _
78   _ _ _ _ _ _ _ _ _

Lombard and Snegireff (61) :
  Cases--~--~.--_-_------.._-~-   500
  Controls-- ____ ._- ______ __-.__ 1,839

Relative risk ________ __ __
Percent cases- _ ___ __ _ ___
Percent controls- _ _ _ - _ _ _ _

1.0  -----___-  _____-__     1. 7
2   -------_-  _____---     4
10   _________  ______--    15

8. 1  _ _ _ _ _ _ _ _ -
95   _ _ _ _ _ _ _ _ _
75   _ _ _ - - _ _ _ _

Pernu (75) :                     Relative risk ____ _ _-_ _ __ _
  Cases--~-_-~-~_-_~--_-___--- 1,477   Percent cases- _ _ _ _ _ _ _ _ _ _
  Controls ___.____ -__-_-_-- ____   713   Percent controls _________

1.0 _______ --    4.2 _________
7   _ - _ _ _ _ _ _ -     4   - - _ _ _ - - - -
39 _-______- 5 -._- _--__

9. 2     11. 1
77      13
50       7


TABLE 29.--R&& risk of lung cancer for men, comparing cigar, pipe, and cigarette smokers with nowmokers. A sum-
               mary of retrospective st&i.es-Continued

Author. reterence          Number

Relative risk ratio and pm?.%ntage of ~a868 and controls by type of smoking
       Nonsmoker Cl@ only  Pipe only  Total pipe Ck;leytte
                            and cigar

  --
Mixed

Wicken (106) :                    Relative risk ____ ___ _____   `1.0 - _______- _-_- __--    2. 2     4. 3      4. 2
  Cases____..____._____-_--..~--- 803   Percent cases-- _______ -_    4 _________ ____ -___    10      78       7
  Controls--_. _ ___ _. -_ -_ __ _ _ __ _ __ 803  Percentcontrols--------- 14 - ____ -___ -_-___-_ 16      64       6

Abelin and Gsell (1):                Relative risk ____ _ _ - _ _ _ _ _    1. 0    30. 7    21. 8    39. 9    31. 0     24. 7
  Cases----.--_----....---.-------  118   Percent cases- _ _ _ _ _ _ _ _ _ _    2      28       7      58      25       24
  Controls_.- _ _ _ _ _ _ _ - - -                      __ _-    35      19       6      31      17       10
           _ _ _ _ _ _ _ . _  _        524   Percent controls-- ___

Wynder, et al. (216):               Relative risk ____ _ _ __ _ __ -    1.0 _-------- _-_-_-_-    2. 0    12. 4 --_-___-_
  cssas-----__---~-------------- 210   Percent cases- _ _ _ _ _ _ _ _ _ -    3   _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _    5      92   - ______ --
  Controls..- ____ _______ - ______ __ 420   Percent controls _________   21 - ________ _____ -_-    15      47   - _ _ _ _ _ _ - -


TABLE 30.~Changes in bronchial epithelium of male cigar, pipe, and cigarette smokers as compared to nonsmokers

Group

               Percant Bectloas  Percent a plus    Percant
Number ot Bectlons with                                         Pfxcent
                          call rows with             Total
subjects   epltheuum  wit;; ~illal
           P         clua     atypkd ceus
                                  present     sections

1st set (none vs. pipe vs. cigarette-matched
on 1:l basis):

  Nonsmoker- _ . _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
  Pipeonly ____ --__--__-- _________ - ______
  Cigaretteonly--_-_----- ________ - ______
2d set (none vs. pipe vs. cigarette-matched
on frequency basis) :

  Nonsmoker- ____ _ ___ _ ____ -__ ______ ____ _
  Pipe only ____ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _-
  Cigarette only- _ _ ___ _ ______________ ___ _
3d set (none vs. cigar vs. cigarette) :

Nonsmoker- _- __ _____ _ ___ - __ _ _________ _
Cigaronly~._-__-___-__________________
Cigarette only- - _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

20      985      21. 7       11. 2      2. 6    1,031       10. 3
20      924      65. 5      38. 1     37. 0      979       35. 9
20      914      96. 8      88. 6     95. 2      982       72. 1

25    1,246      22. 9
25    1, 164      68. 7
25    1, 126      96. 3

35    1,706      27. 4
35    1,733      90. 8
35    1,526      99. 0

13. 4       7
38. 7   38: 2   1,277       11. 5
           1,247       37. 9
88. 7     89. 5    1,237       75. 5

12. 7       8
   73: 6   1,748
40. 0         1,828
92. 7     97. 8    1,693

15. 3
52. 5
80. 2

Source: Auerbach et al. (6).


Tumorigenic Activity

The tumorigenic activity of tobacco smoke can be modified in both a
quantitative and qualitative sense. Physical or chemical changes in
tobacco that result in a reduction of total particuhte matter upon
combusion of a given quantity of tobacco may result in a reduction
of c.arcinogenic potential. Such factors as tobacco selection, tEat.ment,
blending, cut,, and additives may quantitatively alter tar production.
Wrapper porosity and filtration may also affect tar production.

Quantitative changes in the tumorigenic activity of tobacco tar on
a gram-for-gram basis can be produced by the selection and treatment
of tobacco, the use of additives or tobacco sheets, or adjustments in t,he
cut and packing de,nsity.

Combustion temperature can also produce quantitative changes ia
the particulate matter of tobacco smoke. Although high-temperature
burning produces less part,iculate matter in the smoke, it appears that
tumorigenic components occur in higher concentration when tobacco is
pyrolized at temperatures higher than 700" centigrade (34).

Cigars, pipes, and cigarettes `are similar in that they are smoked
orally and have a common site of introduction to the body. The tissues
of the mouth, larynx, pharynx, and esophagus appear to receive ap-
proximately equal exposure to the smoke of these products. Inhalation
causes smoke to be drawn deeply into the lungs and also allows for
systemic absorption of certain const.ituents of tobacco smoke which
then can be carried further to other organs.

Pipe tobacco and cigars vary from cigarettes in a number of charac-
teristics that can produce bot.h quantitative and qualitative changes in
the t,otal particulate matter produced by their combustion. Experi-
mental evidence suggests that although there is some difference in the
amount. and quality of tar produced by cigars, this cannot account for
the reduced mort.ality observed in cigar smokers compared to cigarette
smoker-s.

Experimental Studies

Several experimental investigations have been conducted to examine
the relative tumorigenic activity of tobacco smokn condensates obtained
from cipare.ttes. cigars, and pipes. Most of these studies were standard-
ized in an attempt to make the results of the cigar and pipe experiments
more directly comparable with the cigarette data and most used t,hr
shared skin of mice for the applicat.ion of tar. Tars from cigars, pipes.
and cigarettes were usually applied on an equal weight basis so that
qualitative differences in the tars could be determined. In several ex-
periments. the nicotine was extracted from the pipe and cigar conden-
sates in an attempt to reduce the acute toxic effects that resulted ia
animals from the high concentrations of nicot,ine frequently found in
these products.

210


Wynder and Wright (117) examined the differences in tumorigenic
nct,ivity of pipe and cigarette condensates. Tars were obt.ained by the
sllloking of a popular brand of king-size cigarettes and the same ciga-
rette tobacco smoked in I', standard-gracle briar bowl pipes. Both the
cigarettes and pipes were pufird three times a minute with a 2-second
luff and a 35ml. volume. Both the cigareltes and pipes attained similar
nlasinium combustion zone temperatures ; however. the use of cigarette
tohac.co in the pipe resulted in a combustion chamber temperature that
:treraged about 150" centigrade higher than temperatures achieved
when pipe tobacco was used. Chemical fractionation was accomplished
and equal concentrations of t,hc neutral fraction were applied in three
I\-eekly applications to the shawd skin of C-IF, and Swiss mice. The
results indicate that neut.ral tar obtained from cigarette tobacco smoked
in pipes is more active than that obtained in the usual manner from
cigarettes. About t,wice as many cancers were obtained in both the CAF,
and the Swiss mice, and t11e latent period was about. 2 months shorter.
Extending these data. Croning~~r. et, al. (-00) r3aiiiined the biologic
activity of tars obtained from cip;lrs. piles. ant1 cigarettes. Each form
of tobacco was smoked as it was manufactured in a manntr to simulate
human smoking or to maintain tobacco combustion. The whole tar was
applied in dilutions of one-to-one and one-to-two with acetone to the
shaved backs of female CAF, and female Swiss mice using three
:lpplications each week for the life-span of the animal. The nicotine was
Wractecl f ram the pipe and cigar condensates to reduce the acut,e
toxicity of the, solutions. The Swiss mice. pipe. cigar. and cigarette tars
produced both benign and malignant t.mmors. The incidence rates of
malignant tumors given as percents were : 44. 41: and 37. respectively.
These results suggested a somc~what higher degree of carcinogenic
clctivity for cigar and pile tars tllilll for c.igar-ette tar.
Similar results were reported by Kcnsler ($9) who applied conden-
Mes obtained from cigars and cigarettes to the shaved skin of mice.
The incidence of papiliomas produced by cigar smoke concentrate was
110 ditf'erent from that of the cigare.tte smoke condensate. Similarly,
there was no differc~nw betwwn cigar and rigarchtte smoke condensates
when carcinoma incidences were compared.
Hornburger, et. al. (4;;) pre.pare(l tars from cigar. pipe. and cigarette
tobaccos that were smoked in the form of cigarettes. In this way. all
tobaccos were smoked in an ident ical manner and uniform combustion
tempcmtuws were acliirved. Because of tllis ~t:lnclal.tlizatioii, cliffer-
(`IWS in tumor vieltl could be attributrd to tobacco blend ilntl not. the
~~iattnrr in w-hi& the tar3 were pwlwrecl. The wl&le tars were diluted
one-to-oncb with acetolw and a1~l~lied to the shawtl skin of C-IF, mice
three times a week for the lifespan of tlw test animal. Skin cancers
Wre produced more quicklv with l'ilw :ml cigar mlokc condensates
than with cigarette smoke cintlcnsates. This suggests that. the smoking

   495-028 0--7:$--l;,                                      211


of pipe and cigar tobaccos in the form of cigarettes does not alter the
condensates to any significant degree.
Davies and Day (.S?) prepared tars from small cigars especially
manufactured from a composite blend of cigar tobacco representing
small cigar brands smoked in the United Kingdom, cigarettes espe-
cially manufactured from the same tobacco used for the cigars de-
scribed above, and plain cigarettes especially manufactured from a
composite blend of flue-cured tobacco representing the major plain
cigaret.te brands smoked in the United Kingdom. The whole tar was
diluted to four concentration levels and applied to the shaved backs
of female albino mice for their lifespan using four dosing regimens.
A statistically significant. increase in mouse skin carcinogenicity was
shown with the cigar smoke condensate compared with the tars
obtained from either flue-cured or cigar t,obacco cigarettes. These
results are consistent with those of the previously reported
investigations.
The effect of curing on carcinogenicit,y was examined by Roe, et al.
(76). Bright tobacco grown in Mexico was either flue-cured or air-
cured and bulk fermented. Both flue-cured and air-cured tobaccos were
made into cigarettes standardized for draw resistance and were smoked
under similar conditions. Condensates from these cigarettes were ap-
plied to mouse skin three times each week in an acetone solution. The
development of skin tumors was higher in mice treated with the flue-
cured condensate than in mice treated wit,h the air-cured condensate
(P<O.Ol). The ditference may have been due to the use of equal
weights of condensate rather than the use of extracts from an equal
number of cigaret.tes. The air-cured cigarettes produced a greater
weight, of condensate than did the flue-cured cigarettes. A chemical
analysis of the two tobaccos and two condensates revealed only small
differences in composition. Evidently air curing of Bright tobacco
in the method used is not associated with a loss of reducing sugars.
A more detailed analysis of these experimental studies is present,ed
in table 31.
These experimental data suggest that cigar and pipe tobacco con-
densates have a carcinogenic potential that is comparable to cigarette
condensates. This is sul)l)orted by human epidemiological data for
those sites exposed equally to the smoke of cigars. pipes, and cigaret,tes.
The partially alkaline smoke derived from pipes and cigars is gen-
erally not inhaled, and as a result there appears to be a lower level
of exposure of the lungs :ni(l other systems to the harmful properties of
pipe and cigar smoke than occurs with cigarette smoking. It is antic-
ipated that modifications in pipe tobacco or cigars which would result
in a product that was more readily inhalable would eventually result
in elevated mortality from cancer of the lung, bronchitis and emphy-
sema, arteriosclerotic cardiovascular diseases, am1 the other condi-
tions which have been clearly associated with cigarette smoking.

212


TABLE~I .-Tumvrigenic activity of cigar, pipe, and cigarette smoke codemates in skin painting experiments on animals

[Key: A=Method. B=Fmquency. C=Dumtion. D=Msterial.l

Author, reference

Aetivlty

Treatment

            Percent
Number
      Paplllomas   Carcinomas

Wynder and
Wright
(117).

Croninger, et
al. (HI).

CAFr and
Swiss mice.

A. Painting shaved skin.
B. 3 times a week.
C. Lifespan (24 months).
D. Neutral fraction tar from
  cigarettes and cigarette
  tobacco smoked in pipes,

Female Swiss
mice.

A. Painting shaved skin.
B. 3 times a week.
C. Lifespan.
D. Whole tar diluted in
    acetone.

CAF, :

Pipe (cigarette tobacco) _ _ _ _ _ _
Cigarette- ____ -_-__--__--___
Swiss:

30     60       20
30     30        3

Pipe (cigarette tobacco) - _ _ _ - _    30     63
Cigarette-_--___-----_.- ____    30     63

50
33

Cigar, nicotine free (1 :I) - _ _ _ - _ _    46     65       41
Pipe, nicotine free (l:l)_--.----    45     71        44
Cigar (1:2) _____ - ___________ -_    78     33       18
Pipe, nicotine free (1:2)------__    89     30       16
Cigarette (l:l))-.- _____ - ___._    86     47       37
Acetonecontrols-_--- _______ --    23      0        0

Kensler (65) _ __ Swiss mice ______ A. Painting shaved skin.
                     B. 3 times a week.
                 C. Lifespan.
                   D. Whole tar diluted in
                             acetone.

Cigar tar (J) 100 mg. per week-..
Cigarette tar (G) 100 mg. per
week.
Cigarette tar (E) 100 mg. per
week.

100     42        41
100     40       28

100     34

34


TABLE 31 .-Tumorigenic actiwity of cigar, pipe, and cigarette smoke condensates in skin painting
            experimenta on animals--Continued
                [Key: A=Method. B=Freguency. C=Durstion. D=Material.]

-

Author. reference      Adllal              Activity                    Treatment

            Percent
Number  ------------_
      Papillomas  Carcinomas

Hornburger, et  CAFl mice__-- - _ A. Painting shaved skin.
al. (46).                B. 2 to 3 times a week.
                C. Lifespan (2 years).
                 D. Whole tar diluted 50 per-
                         cent in acetone

Davies and
Day (ES).

Female albino   A. Painting shaved skin.
mice.       B. Varied.
          C. 116 weeks.
         D. Whole tar in 150 mg.
                acetone.

Roe, et al.     Female Swiss
(76).         mice.

A. Painting shaved skin.
B. 3 times a week.
C. Lifespan.

D. Whole tar diluted in
    acetone.

Cigar tobacco cigarettes 165 mg.
per week.

Pipe tobacco cigarettes 1 64 mg.
per week.

Cigarettes * 62 mg. per week- _ _ _
Acetone controls--_-----_- ____

Cigars, small 83 mm. long 150
per week.

Cigar tobacco cigarettes 150
per week.
Cigarettes 150 per week--_-----

Flue-cured Bright tobacco 180
mg. per week.
Air-cured Bright tobacco 180
mg. per week.
Acetone controls 0.75 cc. per
week.

100     37. 5

100     23


100     I5
100      0

144     44


72     32

144     28       13

400     52


400     68

400      1. 3

19

20

23
0

27

14

30

23

0. 5

1 Cigar. pipe, and cigarette tobacco smoked as cigarettes at similar combustion temperatures.


cARLnovAscoLAR DIsEAsF8

The majority of deat.hs in the United States each year are due to
cardiovascular diseases. Cigarette smoking has been identified as a
major risk factor for the development of coronary heart disease
(CHD) . However, pipe and cigar smokers experience only a small
increase in mortality from coronary heart disease above the rates of
nonsmokers. Cigarette smokers have higher death rates from cerebro-
vascular disease than nonsmokers, whereas pipe and cigar smokers have
cerebrovascular death rates that are only slightly above the rates of
nonsmokers. Table 32 summarizes the major prospective epidemiologi-
ea.1 investigations that examined the association of smoking in various
forms and total cardiovascular diseases, coronary heart disease. and
cerebrovascular disease. Doll and Hill. (28)) Best (9)) and Kahn (50)
examined dose-response relationships for pipe and cigar smokers and
reported a slight increase in mortality from coronary heart disease
with an increase in the number of cigars or pipefuls smoked.

Other prospective epidemiological studies have also examined the
relationship of smoking in various forms to coronary heart disease and
related risk factors. Jenkins, et al. (4.9) in the Western Collaborative
Group Study of coronary heart disease, reported an incidence of coro-
nary heart disease in men aged 50 to 59 who were pipe and cigar smok-
ers that was intermediate between the rates seen in cigarette smokers
and nonsmokers. No increase in incidence of coronary heart disease was
seen among the pipe and cigar smokers in the younger age groups.
Shapiro, et al. (85)) in a study of the health insurance plan (HIP)
population, reported incidence rates for myocardial infarct,ion, angina
pectoris, and possible MI, in pipe and cigar smokers that were similar
to the incidence rates seen in cigarette smokers. These rates were con-
siderably higher than those of nonsmokers. Data from the pooling
project (47) suggested that the incidence of CHD deaths, sudden
death, and the first major coronary event in pipe and cigar smokers
was intermediate between the incidence experienced by cigapette smok-
ers and nonsmokers. In contrast to these. studies, Doyle, et al. (3'0)
reported no increase in CHD deaths, myocardial infarction, or angina
pectoris in pipe and cigar smokers over the rates of nonsmokers in t.he
Framingham study.
The retrospective studies of Mills and Porter (64), Villiger and
Heyden-Stucky (204), Schimmler, et al. (80), and Hood, et al. (46)
contained data suggesting that pipe and cigar smokers experience
mortality rates from coronary heart disease that are essent,ially similar
to t.hose experienced by cigarette smokers. The retrospective study of
Spain and Nathan (86) reported lower rates of coronary heart dis-
ease in all smoking categories than were found in nonsmokers.

Van Buchem (103) and Dawber, et al. (23) examined serum choles-
terol levels in groups of individuals classified according to smoking

215


habits. In these two studies, pipe and cigar smokers had serum choles-
terol levels t.hat were nearly identical with the levels found in
nonsmokers.

Tibblin (91) and Dawber, et al. (23) investigated t.he effect of smok-
ing on blood pressure. The proport,ion of smoker-s decreased in groups
mlth higher blood pressures, although this was not as dramatic for
pipe and cigar smokers as it was for cigarette smokers.

In an experimental study using anesthetized dogs, Kershbaum and
Bellet (54, 55) examined the effects of inhaled and noninhaled ciga-
rette, cigar, and pipe smoke on serum free fatty acid levels and urinary
catecholamine and nicotine excret,ion. In this study, inhalation of to-
bacco smoke from all t,hese sources resulted in similar increases in
serum free fatty acids and in catecholamine and nicotine excretion.

TABLE 32.-Mortality ratios for cardiovascular deaths in male cigar and
pipe smokers. A summary of prospective epidemiological studies

Author, reference       Category

        Type of smoking  ---_
Non-  cigar
smoker  OdY :g pg;d ,:%,ly Mixed

Hammond and   Cardiovascular      1.00  1.26  1.07 ______  1.57  ______
Horn (40).      total.
         Coronary-----------  1.00  1.28  1.03 ______  1.70 _--_._
           Cerebrovascular _____  1. 00  1. 31  1. 23 ______  1. 30 ______
Doll and Hill    Cardiovascular      1.00  -_-__  -----w0.99  1.26   1. 13
(86, 87).       total.
         Coronary ._____ -_-_-  1.00  ---__  ---_-_ .94  1.23   1. 18
           Cerebrovascular-- _-_  1. 00  _..__  . . ____ . 95  1. 13   .97
Best (9)--_---_-  Cardiovascular      1.00  1. 14   95 -_-_-_  1.52  -_-_._
             total.
         Coronary-.._--------  1.00   .99  1.00 ______  1.60  ._._ -_
            Cerebrovascular-----  1. 00  1.28   .85 ._____  .88  ._._ --
Hammond L     Cardiovascular      1.00  ---__  -_-_-_ 1.06  1.90  -----_
(38).          total.
         Coronary_----------  1.00  1.35  1.19 __.___  1.84   1. 58
           Cerebrovascular _.__ -  1.00  -----  ---_-_ 1.09  1.41   1. 40
Kahn (X?)  -  -  - Cardiovascular      1.00  1.05  1. 06 1. 05  1. 75  ----__
             total.
         Coronary.----------  1.00  1.04  1.08 1.05  1.74  ____._
           Cerebrovascular___--  1. 00  1. 08  1. 09 1. 06  1. 52  __._..

1Yortality ratios for ages.56 to 64only are presented.

Chronic bronchitis and pulmonary emphysema account for most of
the morbidity and mortality from chronic respiratory disease in the
I'nited Stattbs. Cigawtt(~ smokers ha\-e higher death rates from these

216


diseases and have more pulmonary symptoms and impaired pul-
monary function than nonsmokers. Cigarette smokers also have more
frequent and more severe respiratory infections than nonsmokers.
The relat,ionship between smoking pipes and cigars and t.hese diseases
is summarized in this chapter. The major prospective epidemiological
studies are summarized in table 33.

In a retrospective study of 1.189 males and matched comrols in
Northern Ireland, Wicken (106) investigated smoking in various
forms and mortality from bronchitis. The relative risk ratios com-
pared to nonsmokers for mortality from chronic bronchitis were 1.98
for all smokers, 1.S for pipe and cigar smokersY 2.25 for cigarette
smokers, and 1.29 for mixed smokers.

From a review of these prospective and retrospective studies, it
appears that pipe and cigar smokers experience mortality rates from
bronchitis and emphysema that are higher than the rates of non-
smokers. Although these morality rates approach those of cigarette
smokers, in most instances they are intermediate bet.ween the rates
of cigarette smokers and nonsmokers.

Pipe and cigar smokers have signific.antly more respiratory symp-
toms and illnesses t.han nonsmokers. Those studies which contain data
011 pipe and cigar smoking as related to respiratory symptoms are
summarized in table 33.

Only a few studies have examined pulmonary function in pipe and
cigar smokers. There appears to be little ditf'erence. in pulmonary func-
tion values for pipe and cigar smokers as compared to nonsmokers
(table 35).
Naeye (67) conducted an autopsy study on 322 Appalachian coal
workers who were classified according to the type of coal mined and
tobacco usage. Emphysema was slight.ly greater in cigarette smokers,
as were anatomic evidences of chronic bronchitis and bronchiolitis.
Those changes found in pipe and cigar smokers were intermediate
between those of cigarette smoking miners and nonsmoking miners.

Changes in pulmonary histology in relation to smoking habits and
age were examined by Auerbach, et al. (8). Fibrosis, alveolar rupture,
thickening of the walls of small arteries, and thickening of the walls
of the pulmonary arterioles were found to be highly related to the
smoking habits of the 1,340 male subjects examined. The 91 pipe and
cigar smokers over the. age of 60 were found to have somewhat more
alveolar rupture than the men of the same age distribution who never
smoked regularly. However, pipe and cigar smokers as a group had
far less rupture than cigarette smokers. The same relations as described
above were found for fibrosis, thickening of the walls of the arterioles
and small arteries, and padlike attachments to the alveolar septums.

Tobacco smoke has been sl~ow~ experiment.ally to 11nvc a ciliostatic
lffect. on the reslnratory elntl~eliunl. The interval between puffs, the

217


amount of volat,ile and particulate compounds in the smoke, and the
exposure volume have been shown to influence the toxic effect of
tobacco smoke. Dalhamn and Rylander (22) exposed the upper trachea
of anesthetized cats to the smoke of cigarettes and cigars, observing
the effect on ciliary activity through an incident-light microscope.
A chemical analysis of the gas and particulate phases revealed that
the cigar smoke. was more alkaline and, in general, contained higher
concentrations of isoprene. ace.tone, acetonitrile, toluene, and total
particulate matter compared to c.igtlrette smoke. The average number
of puffs required to arrest ciliary activity was found to be 73 for the
cigaret.te smoke and 114 for the cigar smoke. The difference is statisti-
cally significant (P <O.Ol). Of the two smokes, the smoke with the
highest concentration of volatile compounds was found to be the least
ciliostatic. This suggests that the degree of ciliotoxicity of a smoke is
not necessarily correlated to the level of one or several of the substances
found in the smoke.

Passey, et' al. (70. 71, 79) studied t,he effect of smoke from flue-cured
cigarette tobacco cigarettes and air-cured cigar tobacco cigaret.tes on
the respiratory system of rats. In two separate but similar experi-
ments, a total of 48 animals were exposed to English cigarette tobacco
smoke, 48 were exposed to air-cured cigar tobacco smoke, and 12 were
exposed to an air-cured Hurley tobacco smoke. The rats in groups were
exposed to the specific smoke in a. smoke-filled cabinet. Animals ex-
posed to t.he smoke from air-cured tobaccos remained healthy through-
out, the experiments. even at high levels of smoke exposure. The three
deat.hs that occurred within this group were from nonrespiratory
causes. In both experiments, the rats exposed to cigarette tobacco smoke
began to die within 1 or 2 months. and in each experiment. most of the
animals died within a week or two of the first deaths. At autopsy the
rats exposed to flue-emed tobacco smoke on gross examination were
fount1 to have greatly enlarged 11mgs. the trachea was often full of
mucus. and there was evidence of pneumonia. On microscopic examina-
tion it was follnd that the trachea and bronchi contained purulent
cellular csudatcs. evidence of metaplastic changes, an absence of cilia,
ant1 goblet cell l~l~yerl~lnsi:~. Typically. the cause of death was a lobar
or bl~oll~llop~lcrlxllonia. T11c allthor concluded that, "the smokes of flne-
cured tobaccos are nlore clangorous to man and to animals t.han those
of air-cured tobaccos."

218


Unfortunately, few details were published concerning the method
used to expose the animals to the different t,ypes of smoke. The fre-
quency and duration of exposure were not specified, and the extent of
act,ual inhalation of smoke by t.he different groups of rats was either
not determined or not reported. It is also difficult to determine t.he
effect of smoke exposure on the frequency and severity of respiratory
infections when animals are exposed to smoke in groups where common
exposure occurs. The rat strain used was not identified. but it. was
noted that animals appeared to suffer from a.n endemic rat bron-
chiectasis. It is not known to what extent epidemics of respiratory
infections occurred among these animals. Because of these difficulties,
no firm conclusion can be drawn concerning the effect of smoking flue-
cured or air-cured tobaccos on the incidence of respiratory infections
in rats.

TABLE 33.-Mortality ratios for chronic obstructive pulmon.ary deaths
in male cigar and pipe smokers. A summary of prospective epidemio-
logical studies

Author, reference       catt?goly             Type of smoking

Hammond and   COPDtotal________ 1.00 1.29 1.77 _.___ 2.85 __.._-
Horn (40).   Emphysema--_----- --__ -___- ___-- ---__ --__--____-.
          Bronchitis~~~~~~~--~ --__ ____- __--- --___ -__--____-__

Doll and Hill   COPD total-_- .___. ____ --___ _____ _____ .__.________
(26, 87).    Emphysema--_-_--- -___ -__-_ _____ --___ --__-_____-_
           Bronchitis---- _.__ -_ 1.00 _-__- _____ 4.00 7.00   6. 67

Best (9) ______ -_ COPD total- _ ____ ._ ____ _____ _____ _____ ________ -___
         Emphysema-..-_----  1.00  3.33   .75  --__-  5.85  -___-_
          Bronchitis-------_--  1. 00  3. 57  2. 11  __-__  11. 42  ______

Hammond (38)-- COPD total- _ _ - _ _ _ _  _ _ _ -  _ _ _ _ _  . _ _ _ _  _ _ _ _ _  _ _ _ _ _ _ _ _ _ _ _ _
         Emphysema-_- _____ 1. 00 - ____ ___-_ 1. 37 1 6. 55 ___.__
          Bronchitis_--_-----_ -__- __.__ _-___ ____- ___---____-_

Kahn (&I- - __- _ COPD total- _ _- _. _ _  1.00    79  2. 36    99  10. 08 _----_
        Emphysema ________  1. 00 1: 24  2. 13 1: 31  14. 17  - _____
          Bronchitis---- ______  1. 00  1. 17  1. 28  1. 17  4. 49  -_----

1 Only mortality ratios for ages 65 to 64 are presented.

495-028 O-73-16

219


TABLE M.-Prevalence of respiratory symptoms and illness by type of
              smoking

-

                                         Percant prevalence
Author, reference  Number and type of       Illness
            population                    NOtI-   Total  Cig*
                                  smoker pipe and rette
                                        c&m   OflY   Mixed

Boske (fO)- _ _ Parents of 59
           families.

Edwards, et   1,737 male
8l. (33).     outpatients.

Ashford, et
8l. (4).

4,014 male
workers in 3
Scottish
collieries.

Bower (11)--- 95 male bank
         employees.

Wynder, et al.
(114).

Densen, et al.
(94).

Cederlof, et
al. (18).

Rimington
(76).

220

315 male pa-
tients in
New York
and 315 male
patients in
California.

5,287 male    Persistent cough- _
postal and    Persistent
7,213 male     sputum
transit      production.
workers in    Dyspnea..- _ _ _ _ _ _ _
New York    Wheeze ______ --___
City.        Chest illness~~-~~~

4,379 twin pairs,  Cough--------_--    4
all U.S.     Prolonged cough-.    2
veterans.     Bronchitis--------    2

41,729 male
volunteers.

Cough . ..___ _____ _   32
Sputum          24
production.
Chest illness------ 5

Chronic bronchitis- 17

Bronchitis--- _ __- _   10   1 35    21    37
Pneumoconiosis---- 11   1 34    14     2

Cough ____ __ ______    0

Sputum           8

production.
Wheeze--- _ _ _ _ _ _ _ _
Chest illness------

8
15

Cough (New
York).
Cough
(California).
Influenza (New
York).
lnfluenza
(California).
Chest illness
(New York).
Chest illness
(California).

Chronic bronchitis-    5

14

22

11

28

9

7

7    11
11    16

16    19
14    21
13    16

32
15


4


`19

0
15


31
54


33


30


21


24


10


6

7
4
3


`9

48 ---___
20  ____._


5  --__-_


31     14

29  -_____
33  ______


33  --____
40  ---_-_


56    51


67    66


24  ____-_


31  --____


12  _-____


11  _-_-._

25  ______
26  _____.

26 -_____
32  -_-__.
18 -__-.-

17 __.---
11  __.---
10  ___---


17  _____-


TABLE 34.-Prevalence of respiratory symptoms and illness by type of
           smoking--Continued

Author, reference  Number and type of       Illness           Percent prevalence

            population                    Non-   Total  C&a-
                                  smoker pipe and rette   Mired
                                         cigar   OdY

Comstock, et 670 male tele-   Persistent cough _ _
81. (19).     phone       Persistent
         employees.     sputum.
                Dyspnea- - _ _ _ - _ _ _
                    Chest illness in
                  past 3 years.

Lefcoe snd   310 male phy-  Chronic respira-
Wonnscott    sicians in     tory disease.
(69).       London,     Chronic bronchitis..
           Ontario.     Obstructive lung
                      disease.
                     Asthma----__----
                     Rhonchi-.- _ _-_ _ - _

10    16    41  __-___
13    20    42  _--___

33    39    44  ____-_
14    18    20  ___--_

9    18    44 -___-_

1    12    34  __-_.-
1    3     4  --__--

7    3    6  -__--_
0    3    9 _-__-_

1 Ngures for pipe only.

TABLE 35.-Pulmonary function dues for cigar and pipe smokers as
         compared to nonsmokers

Author, reierence  Number and type     Function          Type of smoking
          Of population                Non-
                                  smoker To;all gig Cigarette Mixed
                         P    OdY

Ashford, et
81. (4).

4,014 male    FEV,.,,        3. 39   '
                _____ -_         2.59   3. 14   2. 62
workers in
3 Scottish
collieries.

Goldsmith,   3,311 ective   Puffmeter---_ 313. 63  299.26  303. 44  ______
et 81. (57).    or retired   FEV,.o--d---m   2. 99    2. 80   2.91  -___-_
        longshore-   TVC- _ . _ _ _ _ _ _   3. 87    3. 68    3.88  ._____
             men.

Cornstock,    670 msle    FEVl.o _____ -_   3. 12    3. 26   2.82  __--__
et 81. (19).   telephone
        employees.

Lefcoe and    310 msle    FEV,.,, _____ --   3. 39   3. 17   3.11  ______
Wonnacott   physicians   MMFR liters    4. 09    4. 17   3.64  ______
(69).      in London,   per second.
           Ontario.

1 Figures for pipe only.

221


GAGTROINTESTISAL DISORDERS

Cigarette smokers have. an increased prevalence of peptic ulcer
disease and a greater peptic ulcer mortality ratio than is found in
nonsmokers. These relationships are st.ronger for gastric ulcer t.han
for duodenal ulcer. Cigarette smoking appears to reduce the effective-
ness of standard peptic ulcer treatment regimens and slows the rate
of ulcer healing. Cigar and pipe smokers experience higher death
rates from peptic ulcer disease than nonsmokers. These rates are higher
for gastric ulcers than for duodenal uIcers but are somewhat less than
those rates experienced by cigarette smokers. Table 31 presents the
mortality ratios for ulcer disease in cigar and pipe smokers as reported
in the prospective epidemiological studies.

Retrospective or cross-sectional studies by Trowel1 (95), All&one
and Flint (2)) Doll, et al. (.29), and Edwards, et al. (33) contain
data on ulcer disease in pipe smokers as well as cigarette smokers. No
association was found between pipe smoking and ulcer disease in these
investigations.

TABLE 36.-Mortality ratios for peptic ulcer disease in male cigar and
     pipe smokers. Summary of prospective stuo?ies

Author, reference        IlllIeSS

         Type of smoking
-               Total
Non-  cigar   Pipe
smoker  OdY   O&Y  %i W& -
                         Mixed
                   O&Y
               cigar

Hammond and   Duodenalulcer ___. -_  1.00  0.25  1.67  ______  2. 16  __-___
Horn (40).
Doll and Hill   .Gastric ulcer__--_---  1.00  _____   ___-_ 4.00  7.00   5. 30
(66, 27).
Hammond (58)-- Gastric ulcer ______._  1. 00  ____-  -_-__ 2.04  2.95  __-_-.
           Duodenal ulcer ___.__  1.00  - _.__   _____  .92  2.86  ___._ -
Kahn (50) _._._ -  Gastric ulcer ______ -_  1. 00  2. 90  2. 84  2.48  4. 13  ____. -
           Duodenalulcer--_---  1.00  1.58  1.59  1.39  2.98 ____. -

Little Cigars

In the past year, several new brands of little cigars (weighing 3
pounds or less per 1,000) hare appeared on the national market. These
cigarette-sized prodUcts are manufactured, packaged, advertised, and
sold in a manner similar to cigarettes. Little cigars enjoy several legal
advantages over cigaret'tes : They have access to television advertising;
they are taxed by the Federal Government and by most States, at much
lower rates than cigarettes, result,ing in a significant price advantage;

222


and they do not carry the warning label required on cigarette pack-
ages and in cigarette advertising. A market appears to be developing
for these products, as there has recently been a sharp increase in the
shipment of little cigars destined for domestic consumption (table 37).

It is important to estimate the potential public health impact of
these little cigars. An adequate epidemiological evaluation of the ef-
fect of little cigar smoking on health could take 10 or 15 years and is
probably an impractical consideration ; however, a review of the epide-
miological, autopsy, and experimental data concerning the health con-
sequences of cigarette, pipe, and cigar smoking summarized in this and
previous reports is helpful in considering the potential impact on
health of smoking little cigars. An analysis of the chemical c.onstit,-
uents suggests that both cigarettes and cigars contain similar com-
pounds in similar concentrations. Two exceptions are reducing sugars,
which are not found in quantity in the fermented tobaccos commonly
used in cigars, and the pH of the inhaled smoke. The pH of the smoke
from U.S. commercial cigarettes is below 6.2 from the first to the last
puff, whereas the smoke from the last half of a cigar may reach as high
as pH 8 to 9. With increasing pH, nicotine is increasingly present in
the smoke as the free base. Skin painting experiments in mice indicate
that tumor yields with cigar or pipe "tars" are nearly identical wit,h
those obtained with cigarettes "tars". In addition, the epidemiological
data suggest. that depth of inhalation probably accounts for the fact
t.hat cigarettes are so much more harmful than cigars and pipes in con-
tributing to the development of lung cancer, coronary heart disease,
and nonneoplastic respiratory disease. For such diseases as cancer of
the oral cavity, larynx, and esophagus, where smoke from cigars, pipes,
and cigarettes is available to the target organ at comparable levels, the
mortality ratios are very similar for all three forms of tobacco use.
Several factors, including "tar," nicotine, and the pH of the smoke,
probably operate to influence inhalation patterns of smokers. The
relative contribution of individual factors to the inhalability of a
tobacco product has not been determined.

Smoking those brands of little cigars which can be inhaled by a
significant portion of the populat,ion in a manner similar to the pres-
ent use of cigarett.es would probably result in an increased risk of de-
veloping those pulmonary and cardiovascular diseases which have
been associated with cigarette smoking. On the .other hand, smoking
those little cigars which are used like most large ciga.rs whereby the
slnoke is rarely inhaled would probably result in lower rates of those
pulmonary and cardiovascular diseases than would be found among
cigarette smokers.

Only a limited analysis is available comparing the chemical com-
pounds found in little cigars, cigarettes, and large cigars. The FTC
analyzed the tar and nicotine content of all t.he litt.le cigars (34) and
cigar&es (97) currently arailable on the market. Little cigars have

223


generally a higher "tar" and nicotine level than cigarettes, although
considerable overlap results in some little cigar brands having "tar"
and nicotine levels comparable to those of some brands of cigarettes
(figs. 4 and 5). Hoffmann and Wynder (66) recently compared three
brands of little cigars with an unfiltered cigarette, a filtered cigarette,
and a large cigar. They measured a number of smoke constituents, in-
cluding : "tar," nicot,ine, carbon monoxide? carbon dioxide, reducing
sugars, hydrogen cyanide? acetaldehyde, ncrolein, pyridines, phenols,
benz (a) anthracene, and benzo (a) pyrene (table 32). Cigarette A was
the Kentucky reference cigarette, c.igarette n was a popular brand of
filter cigarette. Cigar A was an 85 mm. little cigar, cigar B was an
85 mm. little cigar, cigar C was a 95 mm. small cigar, and ciga.r D was
a 112 mm. popular brand of medium sized cigar.

The smoke pH was analyzed puff by puff (table 39). Cigarette
smoke was found to be acidic (pH less than 7) for %he entire cigarette.
The smoke from little cigars became alkaline only in the last puff or
two, whereas about the last 40 percent of the puffs from the larger
cigar were alkaline. Although t,he pH of the total condensate obtained
from cigarettes is usually acidic and the total condensate obtained
from cigars is usually alkaline, the above data indicate that smoke
pH of tobacco produc.ts changes during the combustion process. Smoke
from large cigars may be acidic during the first portion of the smoke
and not become alkaline unt,il the last half of the cigar is smoked.

Brunnemann and Hoffmann (15) ) using the same techniques de-
scribed above. examined the effect of 60 leaf constituents on smoke pH.
For several varieties of cigarette tobacco. they found a high correlation
between the total aklaloid and nitrogen content and smoke pH. Stalk
position also affected smoke pH. Tobacco leaves near the top of the
plant, which cont.ain high levels of tar and nicotine, yielded a smoke
with a much higher pH than leaves lower on the plant. At present it is
not known to what extent these factors influence the pH of the smoke
of tobaccos commonly used in c.igars or how t.hrsc kinds of pH changes
influence the inhalability of tobacco smoke.

The inha.lation of smoke, however, appears to be the most important
factor determining the impact a cigar will have on overall health.
Those physical and chrmical characteristics of a tobacco product
which most influence inhalation of tobacco smoke have not been
accurately drterminftd. Sc~vertheless, it appears likely that the smoke
of some brands of cigars may be compatible with inhalation by a sig-
nificant. portion of the smoking population, since: (a) Little cigars
have tar and nicotine levels which. in some brands, are similar to the
levels found in cigarettes, and (6) the pH of the smoke of some little
cigar brands is acidic for the major portion of the little cigar and
becomes alkaline only in the last puff or t,wo.

224


It is reasonable to conclude that smoking little cigars may result in
health effects similar to those associated with smoking cigarettes if
little cigars are smoked in amounts and with patterus of inhalation
similar to those used by cigare.tte smokers, for the reasons cited above,
and these additional reasons: (u.) In those little cigars for whic,h pre-
liminary data are available, the concentrations of carbon monoxide,
hydrogen cyanide, acetnldehyde, acrolein, pgridine, phenol, and poly-
cyclic hydrocarbon levels are comparable to those found in cigaret,tes :
(6) cigarette smokers who switch to cigars appear to be more likely
to inhale c.igar smoke than cigar smokers who have always smoked
cigars (24) ; and (c) cigarette smokers who switch to little cigars may
be inclined to use them as they did cigarettes because of the physical
similarit,ies bet.ween the little cigars and cigarettes, including their
size and shape, t.he number in a package, the burning rate, and t.he
time it. takes to smoke them.

Figure 4.-Percent distribution of 130 brands of cigarettes and 25 brands of little cigars by
                        "tar" content.

Little Cinars  I

w. "tar.'     0     0      0   16.0    8.0    32.0   32.0    0     8.0    4.0
Cigarettes   o-4   5-9   lo-14  15-19  20-24  25-29  30-34 35-39   40-44  45-49
Little Cigars  3.1    3.1    10.0   46.2   23.1   10.0    3.9   0.8      0     0
SOURCE: U.S. Department of Health. Education, and Welfare (971 and Federal Trade Commission (34).

225


Figure 5.-Percent distribution of 130 brands of cigarettes and 25 brands of little
     cigars by nicotine content.

40
s
=
e 35
; 30

t 25
3
g 20
;  15

10

CigaretiesB
Little cigars

5

0

SOURCE: U.S. Department of Health, Education. and Welfare (97) and Federal Trade Com-
      mission (34).

226


TABLE 37.-Shipment of smaU and hzrge cigars destined for domestic
        consumption (1970,1971, 1972)

Ye&I              1970            1971            1972

Small cigars

January________--___---    58, 328, 520    85,753,780    123,477,550
February-__--__________    63,431,580    72,092,205    179, 817, 839
March ___________ --__--    85,881,860    46,542,800    198, 165,593
April _______r____ -___-__   101,613,500    59,059,920    125, 335,740
May__--_______________    81,093,180    93, 237,473    159,334, 565
June___-_______.____.--    82,471, 120    94,560, 140    180, 582, 243

Subtotal-----__---   472,819, 760    451, 246, 318    966, 713, 530

July _ _ _ _ . _ _ _ _ _ _ - _ _ _ _ _ _ _
August---- ____ -_-___-__
September ____ ----__.-__
October- _ __ _ __
          _ - _ _ - _ __   _
November ______ -__-__--
December ______ -__-___-

62,143,140    70, 332,500    127,713, 320
68, 220, 365    127, 709, 310    670,936, 869
79,101,045    95,027, 340    422,534, 705
90,752,880    109,567,900    708, 116,830
64, 290, 600    106,666,107    551, 326, 888
63,806,OlO    123,809,553    485,587,014

Subtotal ____ -___-_   428, 314,040    633,112,710   2,966,215,626

Yearly t.otal~~~~~--   901, 133,800  1,084, 359,028   3,932,929, 156


             Large cigars

January___-_-____-_____   581,742,OOl    573,039, 120    534,565,488
February_--_-_-__-_-___   595,249,522    586,810,844    562,414,577
March----_- ______ - ____   629,977, 375    665, 998, 099    654,827, 796
April--- ___________ - ____   652,800,200   655,850,213    554,242,048
May_____--___-________   748,040,796    670,064,933    719,489,529
June-----____--_--_____   644,539,031    692,436,529    578,501,068

   Subtotal ___-_ ____ _  3, 852, 348, 925  3, 844, 199, 738   3,604, 040, 506

July______-______-_____   647, 397,547    619,838, 386    520,873,339
August ________ ____ __ __ -   673,082,971   662,970, 148    682, 331, 630
September..- _ _ _ _ _ _ _ - _ _ _ -   721,561,449    680,476,418    594,843, 957
October- _- _______ _____
              -      797,601,253   679,420,968    693, 150,668
November--- _.___ - ____ -   696,526,464    742,948, 802    650, 746, 540
December- _ _ ___ ____ _-__   596,244, 159   516,879,415    437,429,996

Subtotal _____ -_ _-_  4, 132,413,843  3, 902,534, 137   3,579,356,130

Yearly total- _ _ _ _.  8, 084, 762, 768  7, 746, 733,875   7, 183,396,636

h~ce: U.5. Department of the Treasury (101).

227


TABLE %-Selected compounds in mainstream smoke

Smoke compound

Cigarette A Cigarette B  Little     Little
(nonfilter)                         SIWAll
       (flker)   cigar A    cigar B    cigar c

"Tar", milligram per cigarette- - -
Nicotine, milligram per cigaretk-
Carbon monoxide, volume per-
cent- _____ --- _.____ ---- ____
Carbon dioxide, volume percent-.
Reducing sugars, percent of
tobacco weight _ _ _ _ _ _ _ _ _ _ _ _ - -
Hydrogen cyanide, microgram
per cigarette- _ -. ____ _ __ _ _ _ _ _
Acetaldehyde,  microgram per
cigarette _____ _ _ _ _ _ _ _ _ _ _ _ _ _ - -
Acrolein, microgram per cigar-
ette ______ -_-- ______________
Total pyridines, micrograms per
cigarette---_- _.___________ -_
Phenol, microgram per cigarette--
Benz(a)anthracene, nanogram
per cigarette-- ______________
Benzo(a)pyrene, nanogram per
cigarette _____ __ _. __ _ _ _ _ _ _. _ _

36. 1    20. 3
2. 7     1. 4

4. 6
9. 4

9. 3

536.0

770. 0

105. 0

82. 8
124. 2

74. 0

47. 0

4. 5
9. 6


7. 9


361.0


774. 0


71. 0


27. 3
33. 0


31. 0


20. 0

17. 4     31. 8    40. 6
  .6      1. 8     3. 1


5. 3     11. 1     7. 7
8. 5     13. 2    12. 7


1. 5      2. 9     2. 7


381.0    697. 0  1, 029. 0

630. 0  1, 238. 0  1, 150. 0


41. 0     54. 0    66. 0


58. 0     85. 3    80. 3
35. 1     63. 4    94. 1


34. 0     25. 0    39. 0


18. 0     22. 0    30. 0

Source: Hoffmann, D., Wynder, E. L. (44).

TABLE 39.-The pH of the mainstream smoke oj selected tobacco products

[Numbers in parentheses indicate number of last puff.]

Aversge pH  Cigarette A Cifr;g B    Little      Little      Small     Cigar D
         (nonAlter)           cigar A     cigar B     cigar C

3d puff--..-.  6. 19     6. 15     6. 44     6. 55     6. 53     6. 47
5th puff_--_  6. 14     6. 12     6. 34     6. 46     6. 49      __---_--
7th puff--.._  6.09     6. 01     7. 03     6. 51     6. 56      _ _ _ _ _ _ _ _
9th puff_---  6. 02     5. 83           __  6.98     6. 59     6. 27
13thpuffe_- -____.__ -___-_-_ -_-_____ ________   _ _ _ _ _ _ _ _  6. 39
lSthpuff..- -__._.._ -___-_-_ ________ __-_____   _ _ _ _ _ _ _ _  6. 41
23d puff_--_ -_______ ____-_-_   ________ -_-___--  __- __-_-  6. 81
28thpuffm.w -_______ -_-_---- -_-___-_ ---_-___ __-_-_-_  7. 22
33dpuffe--- -____.._ _.-_---_ -___-___ _--___._   __-_-___  7. 53
38thpuff--- -------_ .__.~.__ --_-_--_ _-_--___ ----_--_ 7.78
Last puff---  5. 96(11)  5. 76(10)  7. 73 (8)  7. 25(10)  7. ll(11)  7. 96(43)

Source: Hoffmann, D., Wynder, E. L. (44).

228


Conclusions

Pipe and cigar smokers in the United States as a group experience
overall mortality rates that are slightly higher than those of nonsmok-
ers, but these rates are substant.ially lower than those of cigarette
smokers. This appears to be due to the fact that the total exposure to
smoke that a pipe or cigar smoker receives from these products is
relat.ively low. The t.ypical cigar smoker smokes fewer than five cigars
a day and the typical pipe smoker smokes less than 20 pipefuls a day.
3Iost pipe and cigar smokers report that they do not inhale the smoke.
Those who do inhale, inhale infrequently and only slight.ly. As a
result, t,he harmful effects of cigar and pipe smoking appear to be
largely limited to increased death rates from cancer at those sites which
are exposed to the smoke of these products. Mortality rates from
cancer of t,he oral cavity. intrinsic and extrinsic larynx?. pharynx, and
esophagus are approximately equal in users of cigars, pipes, and ciga-
rettes. Inhalation is evidently not necessary to expose these sites to
t,obacco smoke. Although these are serious forms of cancer, they account,
for only about, 5 percent. of the cancer mortality among men.

Coronary heart disease, lung cancer, emphysema, chronic bronchitis,
cancer of the pancreas? and cancer of the. urinary bladder are diseases
ivhich are clearly associated with cigarette smoking, but for cigar and
pipe smokers death rates from these diseases are not greatly elevated
above the rates of nonsmokers. These diseases seem to depend on mod-
erate to deep inhalation to bring the smoke. into direct. contact with
the issue at risk or to allow certain constituents, such as carbon mon-
oxide, to be systematically absorbed t.hrough the lungs or to affect the
temporal patterns of absorption of other const.ituents such as nicotine
that can be absorbed either through the oral mucosa or t,hrough t.he
lungs. Evidence from countries where smokers tend to consume more
cigars and inhale t,hem to a greater degree t,han in the United States
indicates that rates of lung cancer become elevated to levels approach-
ing those of cigarette smokers.

Available data on the chemical constituents of cigar, pipe, and
cigarette smoke suggest that there are marked similarities in the com-
position of these products. Pipe and cigar smoke, however, tends to
be more alkaline than cigaretti smoke,, and fermented tobaccos com-
monly used in pipes and cigars contain less reducing sugars than the
rapidly dried varieties commonly used in cigarettes.
Experimental evidence suggests that little difference exists between
the tumorigenic activities of tars obtained from cigar or cigarette

229


tobaccos. Malignant skin tumors appear somewhat more rapidly and
in larger numbers in animals whose skin has been painted with cigar
tars than in those animals painted with cigarette tars.

One must conclude that some risk exists from smoking cigars and
pipes as they are currently used in the United States, but for most
diseases this is small compared to the risk of smoking cigarettes as they
are commonly used. Nevertheless, changes in patterns of usage that
would bring about increased exposure either through increased indi-
vidual use of cigars and pipes or increased inhalation of pipe and cigar
smoke have the potential of producing risks not unlike those now
incurred by cigarette smokers. 3fechanical or chemical modifications
of pipe tobacco and cigars that would result in a smoke more compat-
ible with inhalation could have this effect.

Pipe and Cigar References

(1)

(2)


(3)



(4)

(5)

!G)

(7)



(8)

(9)


(10)



(11)

ABELIN, T., GEFLL, 0. T. Relative risk of pulmonary cancer in cigar and
pipe smokers. Cancer 20( 8) : 128%1296, August 1967.
ALLIBONE, A., FLINT, F. J. Bronchitis, aspirin, smoking, and other factors
in the aetiology of peptic ulcer. Lancet 2: 179-182, July 26, 1958.
ARMITAQE, A. K., T~BNER, D. M. Absorption of nicotine in cigarette and
cigar smoke through the oral mucosa. Nature 226( 5252) : 1231-1232,
June 27, 1!+70.

ASHFORD, J. R., BROWN, S., DIJFFI~~, D. P., SMITH, 0. S., FAY, J. W. J.
The relation between smoking habits and physique, respiratory symp
toms, ventilatory function, and radiological pneumoconiosis amongst
coal workers at three Scottish collieries. British Journal of Preventive
and Social Medicine 15: l&117, 1961.
AUERBACH, O., HAMMOND, E. C., GABFINKEL, L. Histologic changes in the
larynx in relation to smoking habits. Cancer 25 (1) : 92-104, January 1970.
AUERBACH, O., STOUT. A. P., HAMMOND, E. C., GABFINEEL, L. Changes in
bronchial epithelium in relation to sex, age, residence, smoking and
pneumonia. Sew England Journal of Medicine 267(3) : 111-119, July 19,
1962.

AUERUACH. O., STOUT, A. P., HahfbfoND, E. C., GARFINKEL, L. Histologic
changes in esophagus in relation to smoking habits. Archives of Environ-
mental Health 11(l) : 4-15, July 1965.
ACERBACH, 0.. STOUT, A. P.. HAMMOND, E. C., GARFINKEL, L. Smoking
habits and age in relation to pulmonary changes. Rupture of alveolar
septums, fibrosis and thickening of walls of small arteries and arterioles.
Sew England Journal of Medicine 269(20) : 1045-1054, Nov. 14, 1963.
BEST, E. W. R. A Canadian Study of Smoking and Health. Ottawa, Depart-
ment of Sational Health and Welfare, 1966, 137 pp.
BOAKE, W. (`. A study of illness in a group of Cleveland families. XVIII.
Tobacco smoking and respiratory infections. New England Journal of
Medicine 2.59(26) : 124Th249, Dec. 25. 1958.
BOWER, G. Respiratory symptoms and ventilatory function in 172 adults
employed in a bank. American Review of Respiratory Diseases 83:
684-689, 1961.

230


(12) B~ZA~SHAW, E., SCHONLAND, M. Oesophageal and lung cancers in R'atal
    African males in relation to certain socioeconomic factors. An analysis
    of 484 interviews. British Journal of Cancer 23(2) : 275-284, June 1969.
(13) BBODIQM, A. C. Squamous-cell epithelioma of the lip. A study of 537 cases.
    Journal of the American Medical Association 74: 656-664, Nar. 6, 1920.
(14) B~oss, I. D. J., TIDIN~B, J. Switching from cigarettes to small cigars-
    is it likely to reduce the health hazards of smoking? In press: Proceed-
    ings of the American Association for Cancer Research, Narch 1973.
(15) BBUHNEMANN, K. D., HOFFXANN, D. On the pH of tobacco smoke. Paper
    presented at the CORESTA/TGRC meeting, Williamsburg, Va., Oct. 23,
    1972,18 pp.
(16) BUELL, P., Dunn-, J. E., Jr., Baxsrow, L. Cancer of the lung and Los
    Angeles-type air pollution. Prospective study. Cancer 20(12) : 2139-2147,
     December 1967.
(17) CAMPBELL, J. N., LINDBEP, A. J. Polycyclic hydrocarbons in cigar smoke.
    British Journal of Cancer 11: X%195,1957.
(18) CEDERL~F, R., Famsao, L., HSUBEC, Z. Cardiovascular and respiratory
    symptoms in relation to tobacco smoking. A study on American twins.
    Archives of Environmental Health 18(6) : 934-940, June 1969.
(29) COMSTOCIC, G. W., BROWNLOW, W. J., STONE, R. W., SARTWELL, P. E.
    Cigarette smoking and changes in respiratory findings. Archives of
    Environmental Health 21(l) : 50-5'7, July 1970.
(MO) CBONINGER, A. B., GRAHAM, E. A., WYNDER, E. L. Experimental produc-
    tion of carcinoma with tobacco products. V. Carcinoma induction in
    mice with cigar, pipe, and all-tobacco cigarette tar. Cancer Research
    18 : 126%1271, December 1958.
(21) DALHAMN, T., RYLANDEB, R. Ciliotoxicity of cigar and cigarette smoke,
    Archives of Environmental Health 20(2) : 252-253, February 1970.
(22) DAVIEX, R. F., DAT, T. D. A study of the comparative carcinogenicity of
    cigarette and cigar smoke condensate on mouse skin. British Journal
    of Cancer 23 (2) : 363-368, June 1969.
(2s) DAWBER, T. R., KANNEL, W. B., REV(YTSKIE, IV., STOKES, J., KAQAN, A.,
    GOBDON, T. Some factors associated with the development of coronary
    heart disease. Six years' followup experience in the Framingham study.
    American Journal of Public Health and the Nation's Health 4S(lO) :
    13491356. October 1959.
(24) DENSEN, P. M., JONES, E. W., BASS, H. E., Baauxa, J. A survey of respira-
    tory disease among New York City postal and transit workers. 1.
    Prevalence of symptoms. Environmental Research l( 3) : 262-286, No-
     vember 1967.
(25) Do% R., HILL, A. B. A study of the aetiology of carcinoma of the lung.
    British Medical Journal 2 : 1271-1286, Dec. 13,1952.
(26) I)oLL, R., HILL, A. B. Mortality in relation to smoking: Ten years' ob-
    servations of British doctors. (Part 1). British Medical Journal
    1 ( 5395 ) : 1398-1410, May 30,1964.
(27) DOLL, R., HILL, A. B. -Mortality in relation to smoking: Ten years' ob-
    servations of British doctors. (Concluded). British Medical Journal
   l(5396) : 1460-1467, June 6,X%4.
(28) DOLL, R., HILL, A. B. Mortality of British doctors in relation to smoking:
   Observations on coronary thrombosis. In: Haenszel, W. (Editor). Epi-
   demiological Approaches to the Study of Cancer and Other Chronic
   Diseases. Bethesda. Nd., U.S. Public Health Service, National Cancer
   Institute Monograph h'o. 19, January 1966, pp. 205-215.
(26) Dot& R, JOXES, F. A., PYGOTT, F. Effect of smoking on the production
   and maintenance of gastric and duodenal ulcers. Lancet 1: 657-662,
    Mar. 29,1958.                                        231


(SO) D~YI.E, J. T., D.~WBER, T. R., KANNELL, W. B., KINCH, S. H., KAHN, H. A.
   The relationship of cigarette smoking to coronary heart disease. The
   second report of the combined experience of the Albany S.Y., and
   Framingham, Mass., studies. Journal of the American Medical Associa-
    tion lSO(10) : 886-890, Dee. 7,1S64.
($1) DUNN, J. E., Jr., LINDEN, G., BBESLOW, L. Lung cancer mortality expe-
    rience of men in certain occupations in California. American Journal of
    Public Health and the Xation's Health 50(10) : 14751487, October 1960.
(32) EBENIUS, B. Cancer of the lip. A clinical study of 778 cases with particular
   regard to predisposing factors and radium therapy. Acta Radiologica
    (Supplement 48) : l-232,1943.

(33) EDWARDS, F., MCKEOWN, T., WHITFIELD, A. G. W. Association between
    smoking and disease in men over sixty. Lancet 1: lS6-2S0, Jan. 24, 1959.
(34) FEDERAL TRADE COMMISSION. Report of tar and nicotine content of the
    smoke of 25 varieties of small cigars. In: Federal Trade Commission
    Sew l-0703. Jul 3 1972, 2 pp.
        L 8
(55) B'RANKENBURC, W. G. Chemical changes in the harvested tobacm leaf.
    I. Chemical and enzymic conversions during the curing process. Ad-
    vances in Enzymology 6 : 30%387,1S46,
(36) FRASKESBCRG, W'. G. Chemical changes in the harvested tobacco leaf.
    II. Chemical and enzvmic conversions during fermentation and aging.
    Advances in Enzymology 10 : 325-441,1950.
(37) GOLDSXITH, J. R.. HECHTER, H. H., PERKISS, N. M., BORHANI, N. 0.
    Pulmonary function and respiratory findings among longshoremen.
    American Review of Respiratory Diseases 86(6) : 867-874, December
     1962.

(.9R) HAMMOXD, E. C. Smoking in relation to the death rates of one million
    men and women. Z!t: Haenszel, W. (Editor). Epidemiological Ap-
   proaches to the Stu& of Cancer and Other Chronic Diseases. Bethesda,
    Md., U.S. Public Health Service. Sational Cancer Institute Monograph
   No. 19, January lS66, pp. 127-264.

(39) HAJ~MOXII, E. C., GARFISKEL, L. The influence of health on smoking habits.
    Zn: Haenszel. W. (Editor). Epidemiological Approaches to the Study of
    Cancer and Other Chronic Diseases. Bethesda. lid., U.S. Public Health
    Service, R'ational Cancer Institute Monograph No. 19, January 1966,
    pp. 269-285.

(46) Ha11 MOXD, E. (`., HORS, I). Smoking and death rates-Report on 44 months
    of followup of 187,783 men. I. Total mortality. Journal of the American
    Medical Association 166( 10) : 1139-1172. Mar. 8. 1958.
f/Z ) HAM ~oso. E. (`.. HORS, D. Smoking and death rates-Report on 44 months
    of followup of lr;7.i83 men. II. Death rates br cause. Journal of the
    American Medical Association 166(11) : 1294-1308, Mar. 15, 1958.
I $2) HIR.~YAMA. T. Smoking in relation to the death rates of 265,118 men and
    women in Japan. A report of 5 years of followup. Presented at the
    American (`ancer Societv's Fourteenth Science Writers' Seminar, Clear-
    water Beach. Fla.. Afar. '17. lSi2, 1.5 pp.

($3) HOFFMANN, D.. RATHKAYP, G., WYNDEB, E. L. Comparison of the yields
    nf several selected components in the smoke from different tobacco
    products. Journal of the Sational Cancer Institute 31(3) : 627-637,
    September 1063.

(44) HOFFJIAXX, D., WYSDER, E. I,. Smoke of cigarett.es and little cigars. An
    analytical comparison. Science 178;( 1066) : 1197-1199, Dec. 15. lSi2.
(45) HOMB~.RGKR, I?.. TREGER, A.. RAKER, J. R. Mouse-skin painting with smoke
    rondensates from rigarrttrs made of pipe. cigar, and cigarette tobaccos.

232


    Journal of the National Cancer Institute 31(6) : 1445-1459, December
     lQ63.
(46) Hocq B., TJBBLIN, G., WELIN, G., ORXDAHL, G., KOBBAN-BENGTBEN, K.
    Myocardial infarction in early age. III. Coronary risk factors and their
    deficient control. Acta Medlca Scandinavica 135(4) : 241-251, April
     1969.
(47) INTER-SOCIETY COM~~ISSION FOB HEART DIEEASE RESOURCES. Atherosclero-
    sis Study Group and Epidemiology Study Group. Primary prevention of
    the atherosclerotic diseases. Circulation 42 (6) ; A-54-A-95, December
     lQ70.
(48) ISAAC, P. F., RAND, M. J. Cigarette smoking and plasma levels of nico-
    tine. Nature 236(5345) :303-310, April 7,1972.
(49) JENKINB, C. D., ROSENMAN, R. H., ZYZANSKI, S. J. Cigarette smoking.
    Its relationship to coronary heart disease and related risk factors in
    the Western Collaborative Group Study. Circulation 38(6) : 1140-1155,
     December 1968.
(50) KAHN, H. A. The Dorn study of smoking and mortality among U.S.
   veterans : Report on 8yz years of observation. In: Haenszel, W. (Editor).
    Epidemiological Approaches to the Study of Cancer and Other Chronic
    Diseases. Bethesda, Md., US. Public Health Service, National Cancer
    Institute Monograph No. 19, January 1966, pp. 1-125.
(51) KELIXB, A. Z. Cellular types, survival, race, nativity, occupations, habits,
    and associated diseases in the pathogenesis of lip cancers. American
    Journal of Epidemiology Sl(5) : 4fXI-499, May 1970.
(59) KEXLEB, A. 2. Cirrhosis of the liver, alcoholism, and heavy smoking asso-
   ciated with cancer of the mouth and pharynx. Cancer 2Q(6) : 101~lQ22,
    June 1987.
(58) KENSLEB, C. J. The pharmacology of tobacco smoke effects of chronic
   exposure. In: James, G., Rosenthal, T. (Editors). Tobacco and Health,
    Springfield, C. C. Thomas, 1962, pp. 5-20.
(54) KEB~EBAUM, A. A. comparative study of cigarette, cigar, and pipe smoking
   effects on blood lipids, catecholamine excretion, and nicotine content of
    the urine. Acta Cardiologica 23 (4) : 31'7-329,1968.
(55) KERSI-IBAUM, A., BELLET, S. Cigarette, cigar, and pipe smoking. Some
    differences in biochemical effects. Geriatrics 23 (3) : 126-134, March 1968.
    255-260,1953.
(56) KOULUM~~~, M. Smoking and pulmonary carcinoma. Acta Radiologlca 39 :
   255-26o,lQ53.
(57) KNUDTSON, K. P. The pathologic effects of smoking tobacco on the trachea
   and bronchial mucosa. American Journal of Clinical Pathology 33(4) :
    310-317, April lQ60.
(58) KUHN, H. A comparative study of cigarette and cigar smoke. In: Pro-
    ceedlngs of the Fourth International Tobacco Scientitlc Congress. The
   National Tobacco Board of Greece, Athens, Sept. X&26,1966, pp. Q67-Q71.
(59) LEFCOE, N. M., WONNACOTT, T. H. The prevalence of chronic respiratory
   disease in the male physicians of London, Ontario. Canadian Medical
    Association Journal 102 : 381-385, Feb. 28,197O.
(60) LEYIN, M. L., GOLDSTEIX, H., GERHARDT, I'. R. Cancer and tobacco smoking.
   A preliminary report. Journal of the American Medical Association
    143 (4) : 33fL338. alay 27.1950.
(61) LONRARD, H. L., SXEGIREFF, L. S. An epidemiological study of lung cancer.
   Calmer 12(2) : 406413, March-April 1959.
(62) MARTIEEZ, I. Factors associated with cancer of the esophagus, mouth, and
   pharynx in Puerto Rico. Journal of the National Cancer Institute 42(6) :
    106Q-1094, *June 1969.

                                                       233


f68) ~[ARTINEz. I. Retrlbspectire and prospective study of carcinoma of the
    esophagus, mouth. and pharynx in Puerto Rico. Boletin de la Asociacion
    .\ledica de Puerto Rico 62 (6) : 17&l%, June 19iO.
(64) 111~1s C. A., PORTER, .\I. M. Tobacco smoking and automobile-driving stress
    in relation to deaths from cardiac and vascular causes. American Journal
    of the Medical Sciences 234 : 3.F43. *July 1957.
(6.:) MILLS, c'. A., PORTER. 11. 11. Tobacco smoking habits and cancer of the
    mouth and respiratory system. Cancer Research 10 : 539-542, 1950.
(66) M~Ls, C. A., PORTER, M. M. Tobacco smoking, motor exhaust fumes, and
   general air pollution in relation to lung cancer incidence. Cancer Re-
     search 17 : 981-`390, X+57.
(67) NAEYE, R. L. Structural features in Appalachian coal workers, Zn: Key,
    M. M., Kerr, L. E., Bundy, 11. (Editors). Pulmonary Reactions to
    Coal Dust. A Review of U.S. Experience. New York, Academic Press,
    lQ71, pp. 93-110.
(68) OSMAN, S., BARSON, J. Hydrocarbons of cigar smoke. Tobacco 159 (24) :
     30-32, Dec. 11,1964.
(69) OSNAN, S., SCHYELTZ, I., HIGXAN, H. C., STEDMAN, R. L. Volatile phenols
    of cigar smoke. Tobacco 157 (9) : 30-32, Aug. 30,1963.
(70) PASSEY, R. D., BLACKYORE, M. Biological effects of cigar and cigarette
   smoke. British Empire Cancer Campaign for Research, Annual Report
    44 (Part 2) : 6,1966.
(71) PASSEY, R. D., BLACKYOBE. M. The causation of lung cancer. Some experi-
   mental biological effects of cigar and cigarette smoke. (Abstract)
    Thorax 22 (3) : 290, May 1967.
(78) PARLEY R. D., BLACKMORE, M., WARBRICK-SMITH, D., JONEE, R. Smoking
    risks of different tobaccos. British Medical Journal 4(5781) : 19%201,
    Oct. 23, 1971.
(78) PEBNU, J. An epidemiological study on cancer of the digestive organs and
   respiratory system. A study based on 7,078 eases. Annales Medicinae
    Intemae Fenniae 49( Supplement 33) : lQ60,117 pp.
(74) RANDIG, K. Untersuchungen zur xtiologie des Bronchialkarzinoms. (In-
   vestigations on the etiology of bronchial carcinoma.) Offentliche Gesun-
    deheitsdienst 16(Q) : 305-313, December 1954.
(75) RIMINGTON, J. Chronic bronchitis, smoking and social class. A study among
   working people in the towns of Mid and East Cheshire. British Journal
    of Diseases of the Chest 63(4) : 193-205, October 1969.
(76) ROE, F. J. C., CLACK, J. C., BISHOP, D., PETO, R. Comparative circinogenicity
    for mouse-skin of smoke condensates prepared from cigarettes made from
   the same tobacco cured by two processes. British Journal of Cancer
    24 (1) : 107-121, March 1970.
(77) SADOWSKY, D. A., GIL.LIAM, A. G., CORKFIELD, J. The statistical association
   between smoking and carcinoma of the lung. ,Journal of the National
    Cancer Institute 13 : 1237-1258, 1953.
(78) SANDERUD, K. Squamous metaplasia of the respiratory tract epithelium ;
   an autopsy study of 214 cases. II. Relation to tobacco smoking, occupa-
    tion and residence. Acta Pathologica et Microbiologica Scandinavica 43 :
    4741, 1953
(79) SCHIEVELBEIN, H., EBERHARDT, R. Cardiovascular actions of nicotine and
   smoking. Journal of the Satianal Cancer Institute 48(6) : 1735-17Q4,
     June 1972.
(80) SCHIMMLER, W., SEFF, C., SCHIMERT, G. Risikofaktoren und Herzinfarkt.
    Eine retrospektive Studie. (Risk factors and myocardial infarct. A retro-
   spective study.) Miincheuer Medizinische Wochenschrift 110(27) : 1585-
    1594, July 5,1Q63.
234


(81) SCHBEK, R., BAICEB, L. A., BALLAX& G. P., DOLQOFF, S. Tobacco smoking as
   an etiologic factor in disease. 1. Cancer. Cancer Research 16 : 49-53, 1950.
(8.2) SCHWARTZ, D., DENOIX, P.-F., L'enquete Francaise sur l'etiolgie du cancer
   broncho-pulmonaire. Role du tabac. (French investigation on the etiOlOgY
   of bronchopulmonary cancer. Role of tobacco.) Semaine des Hopitaus de
   Paris 33(62/7) : 363%3643, Oct. 30, 195i.
(88) SCHWARTZ, D., DENOIX, P.-F., AN~UEBA, G. Recherche des localisations
   du cancer associees aux facteurs tabac et alcool chew l'homme. (Re
   search on the localisations of cancer associates with tobacco and al-
   coholic factors iu man.) Bulletin de l'hssociation Francaise pour
   1'Etude du Cancer 44 : 336361,1957.

(84) SCHWAI~TZ, D., FLAXANT, R., LELLOUCH. J., DENOIX, P.-F. Results of a
   French surrey on the role of tobacco, particularly inhalation, in different
   cancer sites. Journal of the National Cancer Institute 26(5) : 1035-1108,
    May 1961.

(85) SHAPIBO, S., WEINB~TT, E., F~AXK, C. W., SAGER, R. V. Incidence of COD
   nary heart disease in a population insured for medical care (HIP).
   Myocardial infarction, angina pectoris, and possible myocardial in-
   farction American Journal of Public Health and the Nation's Health
   59( 6, Supplement Part 2), June 1969,101 pp.
(86) SPAIN, D. AI., NATHAN, D. J. Smoking habits and coronary atherosclerotic
   heart disease. Journal of the American Medical Association 177(10) :
   633-688, Sept. 9, 1961.

(87) STASZEWSKI, J. Palenie a rak wargl, jamy ustnej, migdalkoa I krtani.
   (Tobacco smoking and its relation to cancer of the mouth, tonsils and
   larynx.) Kowotwory lO(2) : 121-132,196O.
(88) STELL. P. JI. Smoking and larFngea1 cancer. Lancet l(7751) : 617-618,
    Mar. 18, 1972.

(83) STOCKS, P. Cancer incidence in North Wales and Liverpool region in
   relation to habits and environment. British Empire Cancer Campaign
   35th Annual Report, Supplement to Part II, 1957, 156 pp.
(90) SVOBODA, V. An analysis of some possible epidemiological factors involved
   in carcinoma of the larmx. Seoplasma 15( 6) : 677-684, 1968.
(91) TIBBLIN, G. High blood pressure in men aged %A population study of
   men born in 1913 Acta Medica Scandinavica (Supplementum 470) : l-84,
    1967.

(92) TODD, G. F. (Editor). Statistics of Smoking in the United Kingdom.
   London, Tobacco Research Council, Research Paper I, Fourth Edition,
   1966,103 pp.

(93) TODD, G. F. (Editor). Statistics of Smoking in the United Kingdom.
   London, Tobacco Research Council, Research Paper I, Fifth Edition,
   1969,124 pp.

(94) TODD, G. F. (Editor). Statistics of Smoking in the United Kingdom.
   London, Tobacco Research Council, Research Paper I, Sixth Edition,
   : 972.132 pp.

(95) TROWELL, 0. A. The relation of tobacco smoking to the incidence of chronic
   duodenal ulcer. Lancet 1: 3OF+-809, Apr. 14, 1934.
(96) CXITED STATEE CODE OF FEDERAL REQULATIONS. Title26 [Internal Rerenue
   Service] Part 270-Manufacture of Cigars and Cigarettes. (As adopted
   at 26 F.R. 8173, effective Get. 1, 1961). B(270)3-B(270)5, Oct. 31. 1970.
(37) U.S. DEPARTMENT OF HEALTH.EDCCATION, ANDTVELFABE.T~~ and Nicotine
   Content of Cigarettes. Washington, Federal Trtlde Commission. Mar 1972.
   DHEIV Publication So. (HSJI) 72-7510, 2 pp.

                                                   235
.&95-O% O-73- -Ii


(38) U.S. DEPABThfENT OF HEALTH, EDUCATION, AND WELFABE. National Clear-
    inghouse for Smoking and Health. Survey conducted by National
     Analysts, Inc., Philadelphia, Pa., fall 1964.
(99) U.S. DEPARTMEXT OF HEALTH, EDUCATION, AND WELFARE. National Clear-
    inghouse for Smoking and Health. Survey conducted by National
    Analysts, Inc., Philadelphia, Pa., and Opinion Research Corp., Princeton,
    N.J., spring 1966.
(100) U.S. DEPARTbrENT OF HEALTH, EDUCATION, AND WELFARE. National Clear-
    inghouse for Smoking and Hea1t.h. Survey conducted by the Chilton
     Research Services. Philadelphia, Pa., January 1970.
(101) C.S. DEPARTMENT OF THE TREASURY, BUREAU OF ALCOHOL, TOBACCO AND
    FIrmARMs. Statistical Release: Cigarettes and Cigars, 1970, 1971, 1972.
(102) U.S. DEPARTMENT OF THE TREASURY. Internal Revenue Cumulative Bulle-
    tin. 1969-l. Revenue Ruling 69-198, p. 359.
(103) VAN BUCIIEM, F. S. P. Serum lipids, nutrition and atherosclerotic compli-
    cations in man. Acta Medica Scandinavica 181(4: 403-416, April 1967.
(log) VILLIQEB, C., HEYDEN-STUCKY, S. Das Infarktproill. Unterschiede zwischen
    Infarktpatienten und Kontrollpersonen in des Ostschweiz. (The infarct
    profile. Differences between infarct patients and control persons in East
    Switzerland.) Schweizerische Medizinische Woehenschrift 96(23) :
    748-758, June 11, 1966.
(105) WEIR, J. M., DUNN, J. E., Jr. Smoking and mortality : A prospective study.
    Cancer 25( 1) : 106112, January 1970.
(106) WICKEN, A. J. Environmental and Personal Factors in Lung Cancer and
    Bronchitis Mortality in Northern Ireland, ltXO-62. Research Paper No. 9,
     London, Tobacco Research Council, 1966, 84 pp.
(107) WYNDEB, E. L., BROSS, I. J. A study of etiological factors in cancer of the
    esophagus. Cancer 14(2) : 389-4l3, March-April 1961.
(108) WYNDEI~, E. L., Bnoss, I. J., DAY, E. A study of environmental factors in
    cancer of the larynx. Cancer D(1) : -110, January-February 1956.
(109) WYNDEB, E. L., Baoss, I. J., FELDMAN, R. M. A study of the etiological
    factors in cancer of the mouth. Cancer lO(6) : 1300-1323, November-
     December 1957.
(110) WYNDEB, E L., COBNFLELD, J. Cancer of the lung in physicians. New
    England Journal of Medicine 248(11) : 441444, Mar. 12, 1953.
(111) WYNDER, E. L., GRAHAM, E. A. Tobacco smoking as a possible etiologic
    factor in bronchiogenic carcinoma ; a study of 684 proved cases. Journal
    of the American Medical Association 143 (4) : 328-329, May 27, 1950.
(118) W'YNDEB, E. L., HOFFMANN, D. ?\obacco and Tobacco Smoke. Studies in
    Experimental Carcinogenesis. New York, Academic Press, 1967, 730 pp.
(113) WYNDEB, E. L., HULTBERO, S., JACOBSSON, F., BBOSS, I. J. Environmental
    factors in cancer of the upper alimentary tract. A Swedish study with
    special reference to Plummer-Vinson (Patterson-Kelly) syndrome. Can-
     cer 10 (3) : 47@487, May-June 1957.
(114) WYNDER, E. L., Lmfoa, F. R., MANTEL. N. Epidemiology of persistent
    cough. American Review of Respiratory Diseases 91(5) : 679-700, May
     1965.
(115) WYNDEB, E. L., MABUCHI, K., BEATITE, E. J., Jr. The epidemiology of
    lung cancer. Journal of the American Medical Association 213 (13) :
    2221-2228, Sept. 281970.
(116) WYNDER, E. L., NAVARRETTE, A., AMXTEQUI, G. E., LLAYBES, J. L. Study
    of environmental factors in cancer of the respiratory tract in Cuba.
    Journal of the National Cancer Institute 20(4) : 665673, April 1958.
(117) WYNDER, E. L., WRIGHT, G. A study of tobacco carcinogenesis. I. The pri-
    mary fractions. Cancer lO(2) : 255-271. March-,4pril 1957.



236


CHAPTER 7

Exercise Performance


Contents

Page

Introduction____----------------------------------------   241
Studies of Smokers--------------- ______ ---- ____ -- _______   241
Studies Comparing Smokers to Nonsmokers :
Athletic Performance--- ______ --- ______ -__--_-_-----_-   243
Bicycle Ergometer Performance----- _____ ---_-_-_---_-__   244
  Treadmill Performance_- _______ -_- ____ ----_-----_- ____   245
Performance in Other Tests of Fitness _____ ---- _____ ---__   245
Discussion___________------------------------------------   246
Biomechanisms----- ________________ -- ____ -----___-----_   246
Summary-____-_-_-________-__-------------------------   247
References-- ________________________________ -- ______ --_   248

239


Introduction

Although it has long been held by athletes and coaches that cigarette
smoking is associated with "short~ness of wind" and impaired perform-
ance, until recently there has been little scientific evidence to support
this view. In the past few years, a variety of studies have appeared
dealing with the effect of cigarette smoking on the response of man
t.o exercise. The following is a review of these studies.

Age, sex, training, health, weight, and other factors are known to
influence exercise performance. Because most of the investigations
were carried out in healthy, young male volunt,eers, the groups were
quite comparable with regard to age, sex, and healt,h ; however, weight,
training, and other factors were often inadequately controlled.
Furthermore, problems in study design and statistical analysis limit
the value of several of these studies.

Many forms of exercise were performed in these experiments, in-
cluding : pedaling a bicycle ergometer, running on a treadmill, running
on a track, swimming, step climbing, gripping a hand dynamometer,
and doing several different exercise activities as part of a battery of
tests. Small to maximum amounts of work were carried out in the
various studies revewed.

Studies of Smokers

Most of the studies of habitual cigarette smokers followed a similar
format with respect to smoking: (a) The subjects refrained from
smoking for a few hours prior to t.est.ing, and (6) two test runs were
performed, one without smoking and one in which smoking imme-
diately preceded the exercise or was incorporated with the exercise
protocol.

Several investigators (1, 15, 28) studied the effect of smoking on
maximum grip strength. Willgoose (28) reported a greater mean per-
cent recovery of grip strength after the nonsmoking trial than after
the smoking t.rial. Kay and Karpovich (25) and Anderson and Brown
(1) all followed a protocol similar to that of Willgoose e.xcept, that
they randomized the smoking and nonsmoking t.rials, and substituted

241


a "placebo" cigare,tte for the nonsmoking trial. In neither of these
studies were statistically significant differences observed between the
grip scores for the smoking and nonsmoking trials.
Reeves and Morehouse (84) administered a battery of t&s to 15
colleges students. The tests were: A tapping test, a strength test, a
jumping test, and the short form of the Harvard step test. No statis-
t.ically significant differences in performance were noted under con-
ditions of smoking or nonsmoking.
A total of 32 college students from intermediate swimming classes
abstained from smoking for 15 minutes, 2 hours, and 12 hours in a study
conducted by Pleasants, et al. (23). Following the abstinence, they
swam distances of 100 and 206 yards. Although actual swimming times
were not published, t.he authors reported no statistically significant
differences between the mean swimming times after t,he different
periods of abstinence for either distance.
In 1946, Juurup and Muido (13) carried out several experiments
in which three young cigarette smokers exercised on a Krogh's bi-
cycle ergometer. Smoking was found to increase the pulse rate at
rest as well as during exercise. Although the effect was less con-
sistent than on the heart rate, smoking was also associated with
elevated blood pressure. Smoking had no effect on oxygen consump-
tion. Henry and Fit.zhenry (12)) in 1949, using the bicycle ergometer,
also found that smoking exerted no effect on oxygen consumption.
In t.he same year: Karpovich and Hale (24) st.udied bicycle ergometer
performance in eight young men. In all subjects, the average riding
time was better in nonsmoking tests than in smoking tests; how-
ever, the results were statistically significant for only three of the.
eight subjects.
Kerr&an, et, al. (16) more recently measured direct arterial blood
pressure. heart rate, and cardiac output in 25 habitual smokers at
rest and after exercise. Smoking t.wo cigarettes produced statistically
si*gnificant (P<O.Ol) increases in cardiac index, heart rate, and a&r-
in1 mean pressure, compared to the immediately preceding control
period. Exercise after smoking resulted in an increase in cardiac in-
dex over either t,he resting period or the exercise period which fol-
lowed abstinence ; the resultant cardiac index appeared to be approxi-
mately the sum of the exercise and smoking effects. Exercise tests
preceded by smoking were also associated w-till significantly higher
(P<O.Ol) and more prolonged elevations of blood pressure than those
not preceded by smoking.
In the study by Goldbarg, et al. (II) of nine habitual smokers
performing submaximal exercise on a bicycle ergometer, cardiovas-
cular responses were measured via pulmonary and subclavian artery
cat.heters. ,U rest, after smoking, the mean cardiac index and mean
heart rate increased. 1)urinp successively increasing levels of exercise,
the heart, rate was greater and stroke index lower than values for

242


comparable work before smoking. The net effect of smoking was to
decrease the effiicency of t.he heart during exercise in tlie upright
position by causing a smaller stroke volume. and a higher heart
rate.

Rode and Shephard (26) investigated near maximal treadmill exer-
cise performance in six habitual smokers. A l-day abstinence from
cigarette smoking was associated with a 13- to `i9-percent decrease in
the oxygen cost of breathing. Abstinence was also followed by a S~UW-
ing of the heart rate and a decrease in expiratory minute volume after
exercise.

The study of Krumholz, et al. (28) is different from those cited pre-
viously in that bicycle ergometer exercise performance was measured
in habitual smokers both before and after 3 to 6 weeks of abstinence.
Among the 10 subjects who abstained from smoking for 3 weeks, there
was a statistically significant (P<O.O5) decrease in heart. rate, oxygen
debt,, and ratio of oxygen debt to total increase in oxygen uptake pro-
duced by the 5 minutes of exercise.
Using a "double O-inch progressive step test'? Rode and Shephard
(25) studied several hundred participants of a smoking withdrawal
clinic at the t.ime of entry and at a l-year followup. Among those
who returned for the followup and who gave up smoking, absolute
aerobic power increased insignificant.ly ; however, the relative aerobic
power diminished in both sexes among those who quit smoking because
of the weight gain experienced.

Studies Comparing Smokers to Nonsmokers

Athletic Perfonmmce

In 1968 Cooper, et al. (6') evaluated 419 airmen during their initial
6 weeks on active duty in the USAF. A 12-minute maximum running
test was performed at least. 1 hour after cigarette smoking. The mean
distance covered in 12 minutes by the nonsmokers was significantly
greater (P<O.O5) than that covered by the smokers at the beginning,
the middle, and the end of training. All categories of smokers and non-
smokers improved their performance at the end of training; however,
the maximum change in performance of those smoking 10 to 30 cig-
arettes per day was significantly (P<O.OOl) less than that of non-
smokers.

David (`7) administered a battery of tests to 88 military personnel,
aged 19 to 39 years. h l-mile run was included in the testing. and cip-
arette smoking was associated with a significant decrease in perform-
ance in this event.

243


Some 45 special forces soldiers were investigated at sea level and
13,000 feet above sea level by Fine (8). The subjects were randomly
assigned to a placebo group or an acetazolamide treated group. Cig-
arette smoking was positively correlated to decrements in 600-yard
running performance from sea level to altitude in both groups.

Pleasants (??a) studied 106 students from intermediate university
swimming classes. Swimming times were measured for lOO- and 200-
yard dist.ances before and after training and for 800-yard distances
after training. The mean swimming times of nonsmokers were less
than those of smokers in six of seven listed categories, but these dif-
ferences were not statistically significant.

Bicycle Ergomter Perfornmnce

Chevalier, et al. (5) investigated cardiovascular parameters in 32
young physicians after a standard 5-minute ergometer test. Oxygen
debt accumulation among smokers was significantly (P < 0.01) greater
than among nonsmokers. The heart rate at rest and 3 minut.es after
exercise was significantly (P<O.O2) faster in smokers than in non-
smokers.

Using a 5-minute ergometer test, 18 housestaff physicians, half of
whom smoked, were investigated by Krumholz, et al. (27). They noted
the following: Oxygen debt accumulation after exercise was signifi-
cantly (P < 0.02) grea,ter in smokers than non-smokers, the ratio of the
oxygen debt to total increased oxygen uptake during exercise was sig-
nificantly (P<O.OOl) greater in smokers than in nonsmokers, and
the diffusing capacity at rest and with exercise was significantly
(P<O.O5) decreased in smokers compared to nonsmokers.
Kerrigan, et al. (16) studied cardiovascular parameters in smokers
and nonsmokers at rest, during, and after a B-minute bicycle ergometer
ride. Cardiac index and blood pressure values obtained during exercise
performed immediately after smoking were great,er than those found
in nonsmokers performing the same exercise. Similarly, heart rate and
blood pressure remained elevated for longer periods in those who
exercised immediately after smoking than in nonsmokers performing
the same task.

Aerobic capacity scores were examined in 60 university student vol-
unteers by Peterson and Kelley (90). Subjects worked at submaximal
levels on a bicycle ergometer before, during, and after a training
program. At all of these intervals: nonsmokers had significantly
(P<O.O5) higher mean aerobic capacity scores than smokers. Both
groups increased their aerobic capacity during training but non-
smokers consistently performed better throughout, training.

244


TretzdmiZZ Perforwaunce

In 1960 Blackburn, et al. (4) carried out several measurements of
cardiovascular function after different amounts of treadmill exercise
were performed by 233 professional men, 159 university students, and
414 railroad workers. The differences between the smokers and non-
smokers were of small magnitude. Basal oxygen consumption was
slightly higher in smokers than in nonsmokers. Also. resting pulse
rates were higher in smokers of most groups.

Cooper, et al. (6) studied 4i out. of 410 airmen wit.h treadmill test-
ing. Cardiopulmonary indices measured on the treadmill, including
maximum indices, were comparable in smokers and nonsmokers ex-
cept for a significant. (P<O.Ol) reduction in the maximum minute
volume among the smokers.

A total of 277 prospective Canadian firemen performed the Balke-
Ware test of work capacity in treadmill studies carried out by Glass-
ford and Howell (10). The mean performance scores of nonsmokers
were significamly (P<O.Ol) greater than those of smokers.

The effect of vitamin C supplementation on treadmill exercise per-
formance was investigated in 40 male volunteers by Bailey, et al. (3).
Significant differences in oxygen utilization and ventilatory function
between smokers and nonsmokers were noted in only two of the 24
separate analyses of variance performed.

Maximal oxygen intake during treadmill exercise was examined by
McDonough: et al. (19) in 86 healthy. middle-aged male volunteers.
Cigarette smoking was one of six variables which together provided
a multiple correlation coefficient of 0.73.

Performance in Other Tests of Fitness

When physical fitness tests were administered to 88 military per-
sonnel by David (7), cigarette smoking was found to be associated
wit.h a significant (P<0.061) decrease in performance in the dodge
and jump test, and a significant (P<O.O2) decrease in performance in
the crawling test.

ITsing a step test? a breath holding test, and an ergometer test,
Franks (9) examined 58 middle-aged men. Sonsmokers were able to
hold their breath longer and had greater vital capacity residual after
the step test than the smokers.

In 19il. Kysokinski (2.9) studied 200 young Polish soldiers using
Letunov's test which included 20 knee-bending exercises, a fast run for
20 seconds. and a rnn for 3 minutes. Cigarette smoking was associated
with a significant (P<O.Ol) reduction in the vital rapacit.y and a

245


marked rise in the pulse rate at rest and ,after exercise. Intense exer-
cise also caused a greater rise in the systolic blood pressure in smokers
than in nonsmokers.

Discussion

Most of the studies in habitual cigarette smokers compared exercise
performance in "smoking" and %onsmoking" runs after only a few
hours of abstinence. In some studies, smoking adversely affected per-
formance (11,13,14,16,18,26,28), while in others it did not (I, 1.2,
l&23,24). Some of these apparently discrepant results are due to dif-
ferences in methodology and in amounts and types of work performed.
In all of the more recent studies of habitual smokers in which moderate
to near maximal amounts of work were performed and sophisticated
measurements of oxygen transport and cardiopulmonary function
were made, impairment of function during smoking trials was found
(11,16,18,26).
The data of Krumholz, et al. (18) also raise the question of whether
residual effects of cigarette smoking influence "nonsmoking" trials per-
formed after a few hours of abstinence; they found statistically sig-
nificant decreases in heart. rate and oxygen debt produced by exercise
after 3 weeks of cessation.

The work of Rode and Shephard (25) suggests that physical fitness
improves with cessation, but t.his improvement may be negated if t.he
subject gains a substantial amount of weight. after giving up smoking.

Several investigators compared exercise performance or postexer-
cise cardiopulmonary function of smokers to nonsmokers. Although
only minor differences between smokers and nonsmokers mere found
in a few of these studies (3: 4,22), in most of them (5, 6, 7, 8: 10, 16,
17. 20.29) the performance or function of the nonsmokers was better
than that of the smokers. Both nonsmokers and smokers improved
their performance with t,raining, but nonsmokers maintained their ad-
vantage throughout training (6. ZOO).

Biomechanisms

The cited studies indicate that cigarette smoking exerts its adverse
effect on exercise performance through several mechanisms. Cigarette
smoking appears to impair cardiac performance during exercise by
increasing the heart rate and exerting a variable effect on cardiac

246


output (5,11,13,16,18, $X,29). Cigarette smoking is associated with
an increased oxygen debt after exercise (5,18). Also, one study indi-
cated that the oxygen cost of hyperventilation was greater among
smokers than among nonsmokers (26).

Some of these adverse effects of smoking on oxidative metabolism
are mediated by the elevated carboxyhemoglobin levels found in
smokers. CO exerts these effects through one or more of the following
mechanisms : (a) Reduction of the amount of hemoglobin available for
oxygen transport, (b) shift of the oxygen-hemoglobin dissociation
curve to the left with consequent interference in oxygen release at
the tissue level, (c) induction of arterial hypoxemia, and (d) possible
interference with the homeostatic mechanism by which 2,3,DPG
controls the affinity of hemoglobin for oxygen (27). Because carboxy-
hemoglobin has a half life in the body of at least 3 to 4 hours, its influ-
ence may still be measurable several hours after abstinence from
smoking (27).

A recent investigation of maximal muscular exercise during CO in-
toxication in five male volunteers demonstrated reduced maximal 0,
consumption in spite of a much higher heart rate and a relative hyper-
ventilation (21).

Astrand and Rodahl (2) commented recently on the adverse effect
of cigarette smoking on oxygen transport: "All other factors being
equal, a reduction in t,he oxygen-transporting capacity is associated
with a corresponding reduction in physical performance capacity dur-
ing heavy or maximal work * * *. Because a regular physical t,rain-
ing program only increases the maximal oxygen uptake by some 10 to
20 percent, a 5- to lo-percent reduction in maximal aerobic power due
to smoking may play a significant role in many types of athletic even&
and in very heavy work."

Other studies cited in this review document. the adverse effect of
smoking on pulmonary diffusing capacity (18) and on pulmonary
function with exercise (6,29).

Summary

Clinical studies in healt,hy, young men have shown that cigarette
smoking impairs exercise performance, especially for many types of
athletic events and activities involving maximal work capacity. Some
of these effects are mediated by reduced oxygen transport and reduced
cardiac and pulmonary funct,ion.

247


Exercise Performance References

(1) ANDEBBON, J. M., BROWN, C. W. A. study of the effects of smoking upon grip
   strength and recuperation from local muscular fatigue. Research Qnar-
   terly 22 (1) : 102-108, March 1951.

(2) ASTUND, P.-O., RonAuL, K. Factors affecting performance. In: Textbook
   of Work Physiology. New York, McGraw-Hill Book Co., 1970, 669 pp.
(3) BAILEY, D. A., CABRON, A. V., TEECE, R. G., WEHNER H. J. Vitamin c
   supplementation related to physiological response to exercise in smoking
   and nonsmoking subjects. American Journal of Clinical Nutrition 23(7) :
   905-912, July 1970.

(4) BLACKBURN, H., BBOZEE, J., TAYLOR, H. L. Common circulatory measure-
   ments in smokers and nonsmokers. Circulation 22: 11121124, December
    1960.

(5) CHEVALIER, R. B., ISOWERS, .J. A., BONDURANT, S., Ross, J. C. Circulatory
   and ventilatory effects of exercise in smokers and nonsmokers. Journal
   of Applied Physiology U(2) : 357360, March 1963.
(6) COOPER, K. H., GEY, G. O., BOTTENBERG, R. A. Effects of cigarette smoking
   on endurance performance. Journal of the American Medical Association
   203 (3) : 189-192, Jan. 15,1968.

(7) DAVID, K. H. Age, cigarette smoking, and tests of physical fitness. Journal
   of Applied Psychology 52 (4) : 296-298. August 1968.
(8) FINE, B. J. Personality traits as related to symptomatology and running
   performance at altitude under normal and drug (acetazoleamide) condi-
   tions. Perceptual and Motor Skills 27: 975-990, 196%
(9) FIUNKB, B. D. Smoking and selected cardiovascular-respiratory measures.
   Research Quarterly 41(2) : 140-144, May 1970.
(10) GLASSFORD, R. G., HOWELL, Jf. L. Smoking and physical fitness: A prelim-
   inary report. Canadian Family Physician 15(10) : 69-62, October 1969.
(II) GOLDBARG. A. S., KROXE, R. J.. RESNE~O~, L. Effects of cigarette smoking
   on hemodynamics at rest and during exercise. I. Normal subjects. Chest
   60( 6) : 531-536, December 1971.

(12) HENRY, F. M., FITZIIENRY, .J. R. Oxygen metabolism of moderate exercise,
    with some observations on the effeds of tobacco smoking. Journal of
   Applied Physiology 2 : 464468, February 1950.
(13) *Jc-URVP, A., MUIDO. L. On acute effects of cigarette smoking on oxygen
   consumption, pulse rate, breathing rate and blood pressure in working
   organisms. Acta Physiologica Scaudinavica 11: 48-60, 1946.
(14) KARPOVICH, P. V., HALE, C. J. Tobacco smoking and physical performance.
    Journal of Applied Physiology 3: 616-621, April 1951.
(15) Kar. H. W., KARPO~ICII, I'. V. Effect of smoking upon recuperation from lo-
   cal muscular fatigue. Research Quarterly 20: 250-256, 1949.
(16) KERRIGU-, R.. JMS, A. (`.. DOYLE, J. T. The circulatory response to ciga-
   rette smoking at rest and after exercise. American Journal of the Medi-
    cal Sciences 255: 1X3-119, February 1968.
(17) KBUMHOLZ, R. A., CHEVALIEU, R. B.. Ross, J. C. Cardiopulmonary function
   in young smokers. A comparison of pulmonary function measurements
   and some cardiopulmonary responges to exercise between a group of young
   smokers and a coml)arable groni, of non?;mokers. Annals of Internal Medi-
    cine 60 (4) : 603-610, April 1964.

(18) KRUMHOLZ, R. A., (`IIETALIER, R. B., Ross, .J. C. Changes in cardiopul-
   monary functions related to abstinence from smoking. Studies in young
   cigarette smokers at rest and exercise at 3 and 6 weeks of abstinence.
    Annals of Internal JIedicine 62(2) : 197-207, February 1965.

248


(19) MCDO~O~QH, J. R., KUBUXI, F., BBCCE, R. A. Variations in maximal
   oxygen intake with physical activity in middle-aged men. Circulation
    41(5) : 743-751, May 1970.

(PO) PEXEBSON, F. J., KELLEY, D. L The effect of cigarette smoking upon the
    acquisition of physical fitness during training as measured by aerobic
   capacity. Journal of the American College Health Association 17(3) :
   250-254, February 1969.

(21) PIBNAY, F., DUJAB~IN, J., DEI%OAXXE, R., PITTIT, J. Y. Muscular exercise
    during intoxication by carbon monoxide. Journal of Applied Physiology
    31(4) : 573-575, October 1971.

(22) PLFXSASTS, F., .Jr. Pretraining and post-training swimming endurance of
   smokers and nonsmokers. Research Quarterly 40(4) : 779-782, 1969.
(28) PLEASANTS, F., Jr., GRU~AN, J., RATLIFF. J. W., Jr. Effects of short periods
    of abstinence from cigarette smoking on swimming endurance of chronic
    smokers. Research Quarterly 36(3) : 474479. 1966.
(24) REETES, W. E.. MOREHOUSE, L. E. The acute effect of smoking upon the physi-
   cal performance of habitual smokers. Research Quarterly 21 : 24524S,
    1950.

(25) Ron~, A., SHEPHA~D, R. J. Smoking withdrawal and changes of cardiores-
   piratory fitness. American Review of Respiratory Disease 104( 6) : 933
    935, Deeember 1!)71.

(26) RODE, A., SHEPHABD, R. J. The influence of cigarette smoking upon the oxy-
   gen cost of breathing in near-masimal exercise. Medicine and Science in
    Sports 3 ( 2) : 5155, summer 1971.

(YY) U.S. PWLIC HEALTH SERVICE. The Health Consequences of Smoking. A Re-
   port of the Surgeon General : 1972. U.S. Department of Health, Education,
   and Welfare. Washington, DHEW Publication No. (HSM) 72-7516, 1972,
    15s PP.

(28) WIUGOOSE, C. E. Tobacco smoking, strength, and muscular endurance. Re-
    search Quarterly 18 : 219-225,X+47.

(23) WYSOKINSKI, Z. Effects of tobacco smoking on certain parameters reflecting
   the condition of the circulatory system at rest and during exercise. Polish
    &dical Science and History 14(2) : 713-76, April 1971.

249


    The
Health Consequences
of Smoking

January 1973

INDEX
Pages 251-261

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


INDEX

Abortion, spontaneous
effect of maternal smoking, 123,124
Acenaphthylene
in cigar, pipe, and cigarette smoke, 178
Acetaldehyde

as ciliatoxic agent in cigarette smoke, 51
Aerobic capacity
effect of cessation of smoking, 243      '
effect of exercise and smoking, 243,244
Aii pollution
and bronchitis, in smokers vs. nonsmokers,
36,37
effect on mortality rates from lung cancer,
73

as factor in lung cancer development,
72,73

' in Osaka, Japan, 44
prevalence of respiratory diseases and, 44
and smoking in military and civilian air-
craft, 45

Alcohol consumption
interaction with smoking and other risk
factors in CHD, 10
and smoking, in cancer development, 71
and smoking, in esophageal cancer devel-
opment, 76,200
and smoking, in laryngeal cancer etiology,
  197
and smoking, in oral cancer etiology, 193
hlveolar macrophages
effect of cigarette smoke, 52,53
effect of nitrogen dioxide, 54
Alveolar rupture
in pipe/cigar smokers vs. cigarette smokers
and nonsmokers, 217
Ingina pectoris
carbon monoxide inhalation and, 17,18
incidence in pipe and cigar smokers, 215
' .Inthracene

in cigar, pipe, and cigarette smoke, 178
Cterioles

effect of smoking, 22,23
Lteriosclerosis obliterans
smoking as cause, 19,20
lryl hydrocarbon hydroxylase
effect of benzo(a)pyrene in pregnant rats.
  119

role in metabolism of chemical carcino-
gens, 82,83
.isbestos
effect on pulmonary function in smokers
vs. nonsmokers, 41
effect on radiological findings in smokers
vs. nonsmokers, 41
effect on respiratory symptoms in smokers
vs. nonsmokers, 41

and smoking, effect on mortality rates
from lung cancer, 73
Athletic performance
running, effect of smoking, 243,244
smokers vs. nonsmokers, 243,244
swimming, effect of smoking, 244
Autopsy studies

COPD and smoking, 4548
lung cancer in U.S. veterans, 73,74

Bacterial flora

in smokers vs. nonsmokers with COPD, 54
Benzo(a)pyrene
carcinogenic effect in laboratory animals,
78-80

in cigar, pipe,  and cigarette smoke,
177,178

effect on DNA and RNA, 86,87
effects during pregnancy in laboratory
animals, 117,118
Bicarbonate

in pancreatic secretions, effect of smoking,
159,160

Bicycle Ergometer performance
cardiovascular parameters in smokers vs.
nonsmokers, 242-244
Birth weight
effect of maternal smoking, 103-114,
119-122
effect of maternal smoking before and
during current pregnancy by cigarette
consumption, 107-109
effect of maternal smoking during pre-
vious pregnancies, 112-l 14
effect of maternal smoking, mechanism of
action, 119,120
effect of paternal smoking, 110,111
effect of tobacco smoke, nicotine, or
carbon monoxide in laboratory animals,
  114-118

gestation duration in smokers vs. non-
smokers, 103-106
and maternal smoking, epidemiological
studies, 103-I 14
timing of influence of smoking, 120,121
Bladder cancer
see also Renal cancer
incidence in smokers vs. nonsmokers,
77,78

smoking in etiology of, 77,78
Blood flow

effect of smoking, 19,22,23
Blood lipids

effect of smoking, 11 ,12

251


effect of smoking and relative weight, in
male Parisian civil servants, 11
effect of smoking in middle-aged patients
with angina pectoris, 12
effect of smoking in young Norwegian
military recruits, 11
elevated, as risk factor in CHD, 11
Blood pressure
effect  of exercise and smoking,
242,244-246

effect of pipe and cigar smoking, 216
effect of smoking in middle-aged patients
with angina pectoris, 12
Body height
interaction with smoking as factor in
cerebrovascular disease, 19
Body weight
interaction with smoking as factor in
cerebrovascular disease, 19
and smoking, as factors in CHD incidence,
4-6

and smoking, effect on blood lipids, 11
Bronchial epithelium
histological changes at autopsy and smok-
ing habit, 74
histological changes in cigar, pipe, cigar-
ette smokers vs. nonsmokers, 203, 204,
  209

premalignant changes in smokers, 67
Bronchiole-alveolar cancer
smoking and, 71
Bronchitis

and disability, in smokers vs. nonsmokers,
43

dust exposure as a factor, 44
mortality ratios in male pipe and cigar
smokers, 217,219
prevalence in Duisburg, Germany, by age
and cigarette consumption, 39
prevalence in excoal miners and non-
miners by smoking habit, 42
prevalence in miners and farmers in Hun-
gary, by smoking habit, 42
prevalence in pipe and cigar smokers,
220,221

prevalence in smokers vs. nonsmokers in
Bordeaux, France, 36
prevalence in smokers vs. nonsmokers in
mountainous or low-lying areas, 36,37
prevalence in smokers vs. nonsmokers in
Osaka, Japan, 44
prevalence in smoking vs. nonsmoking
yarn mill workers, 40
in smokers vs. nonsmokers, autopsy stu-
dies, 45,46
smoking vs. coal mining in etiology of, 42
smoking vs. dust inhalation in etiology of,
42

Bronchitis, chronic
see Bronchopulmonary diseases, chronic
  obstructive

252

Bronchopulmonary diseases, chronic ob-
structive
see also Emphysema and bronchitis
autopsy studies, 4548
as cause listed on death certificates vs. at

autopsy, 47

epidemiological studies, 3645
mortality and morbidity studies, 36-39
mortality rates in British citizens by migra-

tion patterns, 36

mortality ratios in male pipe and cigar
smoke&, 216,217,219
summarv of urevious findinas. 35.36
summa& of decent findings,55
Byssinosis
prevalence in  cotton mill employees,
smokers vs. nonsmokers, 55
prevalence in men by index of severity and
smoking habits, 40,41
prevalence in smoking vs. nonsmoking
cotton mill workers, 39
smoking and, 3941

Cancer

see also Specific site, e.g., Lung cancer
mortality rates in alcoholics, 71
recurrent primary, incidence in smokers
vs. nonsmokers, 71,74
summary of previous findings, 67,68
summary of recent findings, 88
Capillaries
effect of smoking, 22
Carbon monoxide
cardiovascular effects, eicperimental stu-
dies, 17-19
effect on birthweight and neonatal mortal-
ity in animals, 133
effect on cholesterol biosynthesis, in vitro,
  18

effect on cholesterol level in aorta in
rabbits, 18
effect on coronary hemodynamics and
ventricular function in dogs, 18
effect on exercise performance in smokers
vs. nonsmokers, 246,247
effect on maximal oxygen consumption,
18

effect on platelet stickiness in rabbits, 18
effect on reflex vasoconstrictor responses,
18,23

effect on vascular resistance and refles
vasoconstriction, 22,23
effects during pregnancy in laboratory
animals, 116,117

Carboxyhemoglobin levels
effect on exercise performance in smokers
vs. nonsmokers, 246,247
following smoking of non-nicotine ciga-
rettes, 17,18


in neonates of smoking mothers, 118,119
Carcinogenesis
cell and tissue culture studies, 84-86
effect of tobacco curing methods, 212
experimental, 78-87
initiating and promoting agents in cigar-
ette smoke, 68
mechanism of action, 78, 80-87
of respiratory tract in laboratory animals,
78-80

role of cigarette smoke condensate, 80-84
Carcinogens
effect on cell transformations, 84-86
effect on respiratory tract in laboratory
animals, 78-80
Cardiac index
effect  of exercise  and  smoking,
  242-244

Cardiovascular diseases
see also Coronary heart disease
mortality ratios in male pipe and cigar
smokers, 215,216
smoking and, 3-23
summary of previous findings, 3
summary of prospective epidemiological
studies for cigar and pipe smokers, 216
summary of recent findings, 23
Catecholamine levels
effect of cigar, pipe, and cigarette smoke
in dogs, 216

Cell and tissue culture studies
tobacco carcinogenesis and, 84-86
Cell cultures

malignant transformations induced by to.
bacco tars on carcinogens, 84-86
Cells, atypical
in ex-smokers, smokers, and nonsmokers
at autopsy, 74

Cerebrovascular disease
interaction of smoking and other risk
factors, 19
mortality ratios in pipe and cigar smokers,
215,216

Cessation of smoking
compared benefits in cigarette vs. pipe/
cigar smokers, 172,173
effect on absolute aerobic power, 243
effect on infant birth weight, 107-109
112-114

effect on pulmonary surfactant levels, 55
as preventive measure in occlusive disease,
21,22
CHD

see Coronary heart disease
Chest illness

prevalence in pipe and cigar smokers,
220,221
Cholesterol
biosynthesis, effect of carbon monoxide
in vitro, 18

Cholesterol levels

effect of carbon monoxide in rabbits, 18
effect of smoking and body weight, 11
effect of smoking and clinical parameters
in British business executives, 11
in pipe and cigar smokers, 215,216
Chronic obstructive bronchopubnonary di-
sease
see Bronchopulmonary disease, chronic
  obstructive
Cigarettes
definition and processing, 175
filtered, effect on respiratory symptoms,
  55
modified, effect on respiratory symptoms
and ventilatory capacity, 37,38
plain vs. filtered, effect on sputum produc-
tion, 37,38
similarities with little cigars, 224,225
Cigarette smoke condensate
effect on RNA. 86
N-nitrosamines-in, 87,88
role in experimental carcinogenesis, 80-84
Cigarettes, non-nicotine
effect on carboxyhemoglobin levels, 17,18
Cigars
definition and processing, 175,176
Cigars, little
chemical composition of, 224,225,228
evaluation of potential public health im-
pact, 222-228
shipment for domestic consumption
1970-1972, 222-224,227
similarity to cigarettes, 224,225
sugar and pH differences with large cigars
and cigarettes, 222-224       - -

tar and nicotine content. 224-226.228

Cigar smokers

relative risk in lung cancer development,
67,68
Cigar smoking
effect on mortality and morbidity com-
pared to cigarette smoking, 171-173
in esophageal  cancer development,
197,200-202

gastrointestinal disorders and, 222
health consequences of, 179
histological effects on bronchial epithe-
hum, 203,204,209
histological effects on esophagus, 200

histological effects on larynx, 197
inhalation patterns and, 184-189
in laryngeal  cancer development,
197-199

in lung cancer development by amount
smoked, 203-206
mortality ratios from cardiovascular di-
seases and, 215,216
mortality ratios from COPD and, 217,219

253


mortality ratios from esophageal cancer
and, 197,200

mortality ratios from laryngeal cancer and,
193,196,197

mortality ratios from lung cancer and
203-205

mortality ratios from oral cancer and
191,193

oral cancer development and, 193-195
overall mortality rates by amount smoked:
180-182

overall mortality rates from cancer and,

189

prevalence in Great Britain, 173,174
urevalence in United States. 173,174
pulmonary histological changes- and, 217
Cihary activity
effect of pipe/cigar smoke vs. cigarette
smoke in cats, 217,218
Clinical laboratory tests
effect of aging and smoking, in healthy
male veterans, 11
Coal dust
effect on pulmonary function in smokers
vs. nonsmokers, 4143
effect on respiratory symptoms in smokers
vs. nonsmokers, 4143
Combustion temperature
effect on tumorigenic activity of pipe and
cigarette tobacco, 210,211
Congenital malformations
maternal smoking and, 136,137
Coronary heart disease
epidemiological studies, 4-l 1     o
experimental studies, 13-19
incidence in European vs. American men,
  9
incidence in farmers vs. nonfarmers by
smoking habit, 7
incidence in Hawaiian men of Japanes
ancestry, 10
incidence in male bank employees ir
Brussels, Belgium, 10
incidence in men in Yugoslavia, 9
incidence in miners in Sardinia, 10
incidence in pipe and cigar smokers,
215,216
incidence in white males by body weight
and smoking habit, 5
incidence in whites vs. blacks in Evans

County, Georgia, 4,5
in India, 11

interaction of smoking with other risk
factors, 4-l 1
mortality rates in Japanese men and wo-
men by cigarette consumption and age a'
initiation of habit, 7,8
mortality rates in smoking men in Finland,
9
mortality ratios in pipe and cigar smokers,
215,216

254

in Nepal, 11

in New Zealand, 11
a smoking, in individuals under 40
years, 10
and smoking, in myocardial ischemic pa-
tients in Italy, 10
COPD
see Bronchopulmonary diseases, chronic
  obstructive
cough
effect of asbestos exposure in smokers vs.
nonsmokers, 41
effect of coal dust exposure in smokers vs.
nonsmokers, 41,42
effect of filtered cigarettes, 55
effect of modified cigarettes, 38
prevalence in pipe and cigar smokers,
220,221
prevalence in smoking vs. nonsmoking
women in Bordeaux, France, 36
Cresols
in cigar, pipe, and cigarette smoke, 177
Curing methods
incidence of respiratory infections in rats
and, 218,219

Cyanide detoxification
in pregnant smokers vs. nonsmokers, 119

7H-Dibenz(c,g)carbazole
carcinogenic effect in laboratory animals,
79
Diet
and smoking, effect on blood lipids, 12
DNA
binding of polycyclic hydrocarbons to,
86,87

Dust exposure
bronchitis and, 44
as occupational hazard, 43,44
smoking and, 44
Dynamic compliance
in smokers vs. nonsmokers under 30.50
Dyspnea
prevalence in cigar and pipe smokers,
220,221

Electrocardiogram
abnormalities, effect of smoking and other
factors, 13
effect of smoking, in middle-aged Dutch
men, 12
effect of smoking, in young military re-
cruits in Poland, 12
Emphysema
see also Brorrchopuhnonary disease,
chronic obstructive


incidence in cigar/pipe smoking coal mi-
ners vs. cigarette smokers and non-
smokers, 217
mortality ratios in male pipe and cigar
smokers, 217,219
prevalence in males by smoking category,
at autopsy, 48
prevalence in pipe/cigar and cigarette smo-
kers vs. nonsmokers, autopsy studies,
45,46
prevalence in smokers vs. nonsmokers, 55
in smokers vs. nonsmokers, autopsy stu-
dies, 4547

Epidemiological studies
bronchopuhnonary diseases and smoking,
3645

coronary heart disease and smoking,
4-13.23
lung cancer and smoking, 68-72
peptic ulcer and smoking, 155-157
Esophageal cancer
alcohol consumption and smoking in de-
velopment of, 200
inhalation patterns and, 197
mortality ratios for cigar, pipe, and ciga-
rette smokers vs. nonsmokers, 197,200
mortality ratios in Japanese male smokers
vs. nonsmokers, 76
relative risk in cigar, pipe, and cigarette
smokers vs.  nonsmokers,
197,200-202
smoking and alcohol consumption in de-
velopment of, 76
summary of retrospective studies, 201,202
Esophagus
histological changes in cigar, pipe, ciga-
rette smokers vs. nonsmokers, 200
Exercise performance
on bicycle ergometer, effect of smoking,
242,243
cardiac index, effect of smoking, 242,243
effect of smoking and smoking abstinence,
241,242,246,247
influencing factors, 241,246,247
summary of findings and mechanism of
action, 246,247
on treadmill, effect of smoking, 243,245
Experimental studies
COPD and smoking, 48-55
coronary heart disease and smoking, 13-19
effect of carbon monoxide on pregnant
animals, 132,133
pregnancy in laboratory animals, effect of
tobacco smoke, nicotine, carbon mono-
xide,  and polycyclic hydrocarbons,
114-118
Ex-smokers
compared mortality rates for cigarette vs.
pipe/cigar smokers, 172,173
histological changes in bronchial epithe-
hum at autopsy, 74

low birth weight infants of, 112-114
mortality rates from lung cancer, 7 l-72
prevalence of respiratory symptoms, 39
pulmonary function, 39
relative risk in lung cancer development,
71-72

survival after treatment for pharyngeal,
laryngeal, or oral cancers, 75

Fatty acid levels
effect of cigar, pipe, and cigarette smoke
in dogs, 216

effect of smoking, 12
Fetal mortality

effect of maternal smoking, 123-135
epidemiological studies in smokers vs. non-
smokers, 126-132
Fibrosis

in pipe/cigar smokers vs. cigarette smokers
and nonsmokers, 217
Fitness tests

various, smokers vs. nonsmokers, 245
Framingham study
interaction of smoking and other risk
factors in CHD, 8

Gastric secretion
effect of nicotine in laboratory animals,
158,159

effect of smoking in ulcer patients,
157,158

LGastrointestinal disorders
prevalence in cigarette and pipe/cigar smo-
kers, 222
Gestation
and low birth weight infants, effect of
maternal smoking, 103-106
Gestational age
effect on perinatal mortality rates in smo-
king vs. nonsmoking mothers, 126-132

Glucos< intolerance -
as a risk factor in CHD, 8

Grip strength
effect of smoking, 241,242

Heart rate
effect  of exercise  and  smoking,
242-246

Histological studies
lung cancer in U.S. veterans, 73
Histopathological studies
in laboratory animals, 49,50
in smokers vs. nonsmokers, 48,49
Honolulu Heart Study
interaction of smoking and other risk
factors in CHD, 8,9

255


Ilypercholesterolemia
incidence in male British business execu.
tives, by smoking habit and clinical
parameters. 1 I

as risk factor in CHD, 8,9,11
Hypertension

interaction with smoking as risk factor in
cerebrovascular disease, 9
as risk factor in CHD, 8,9
Hypoxia

carbon monoxide induced, 18.23

Infant

small-fordate, effect of maternal smoking,
  106-l 14
Infant mortality
of black vs. white smoking mothers,
  129-132

causes of death by maternal smoking
habit, 133
effect of genetic differences and smoking,
132

effect of maternal smoking, 123-135
effect of previous obstetrical experience
and smoking, 132
effect of socioeconomic background and
smoking, 131,132

epidemiological studies in smokers vs. non-
smokers, 126-132
factors other than smoking, 131,132
risk of low-birth-weight infants of smoking
vs. nonsmoking mothers, 126-132
Influenza

prevalence in pipe and cigar smokers,
220,22 1

Inhalation patterns
effect  of previous  smoking habits,
  186-189
frequency-per-puff in cigar and cigarette
smokers, 186,187
of pipe, cigar,  and cigarette smokers,
  184-189
possible determining factors, 183,184
Intermittent claudication
smoking and, 21
International Cooperative Study
interaction of smoking and other risk
factors in CHD, 9

Lactate metabolism
effect of smoking, in patients with angina
pectoris, 13
Lactation
effect of maternal smoking, 138-141
effect of maternal smoking, summary of
findings, 141

epidemiological studies, 138
experimental studies, 138,139

256

Laryngeal cancer

inhalation patterns and, 193
mortality ratios for pipe, cigar, and ciga-
rette  smokers vs.
193,196,197      nonsmokers,

mortality ratios in Japanese male smokers
vs. nonsmokers, 76,77
recurrent, incidence in smokers vs. ex.
smokers, 71,74-77
relative risk for cigar, pipe, and cigarette
smokers vs.  nonsmokers,
76,77,197-199

summary of retrospective studies, 198,199
Larynx
histological changes in cigar, pipe, cigar-
ette smokers vs. nonsmokers, 197
Leukoplakia
prevalence in tobacco chewing coal mi-
ners, 75

reverse smoking and, 76
Lip cancer

cigar smoking in etiology of, 190,191
cigarette smoking in etiology of, 190,19I
pipe smoking in etiology of, 190,191
relative risk in pipe, cigar, and cigarette
smokers vs. nonsmokers, 190,191
summary of retrospective studies, 192
Little cigars
see Cigars, little
Lung cancer
air pollution as a factor, 72
epidemiological studies, 68-72
race as a factor, smokers vs. nonsmokers,
70

incidence in smokers vs. nonsmokers in
Jersey, Channel Isles, 70
incidence in smokers vs. nonsmokers in La
Plata, Argentina, 70
incidence in smokers vs. nonsmokers in
Philadelphia, 70

inhalation patterns and, 203
mortality rates in asbestos workers, smo-
kers vs. nonsmokers, 73
mortality rates in British physicians vs.
general population in England and Wales,
70

mortality ratios for cigar, pipe, and cigar-
ette  smokers  vs.  nonsmokers.-
203-205

mortality ratios in Japanese by amount
smoked and age at initiation of habit, 69
occupational exposures and smoking, 67
prevalence in smokers vs. nonsmokers in
Czechoslovakia, 70

prospective study in Japanese adults,-
68,69
relative risk in cigar, pipe, and cigarette
smokers vs.  nonsmokers,
203,206-208

relative risk in ex-smokers vs. continuing
smokers, 72


relative risk in pipe/cigar smokers, 67,68
smoking as cause, 67
summary of retrospective studies, 206-208

Maternal-fetal exchange
polycyclic hydrocarbons and, 119
Maternal smoking
see Smoking, maternal
3-Methylcholanthrene
effects during pregnancy in laboratory
animals, 117
Morbidity
from chronic bronchopulmonary diseases,
36-39
Mortality
compared rates for cigarette vs. pipe/cigar
ex-smokers. 172,173
from chronic bronchopulmonary diseases,
36-39

from COPD, in cigar/pipe smokers vs.
cigarette  smokers  and  nonsmokers,
216,217
overall rates for cigar smokers vs. pipe
smokers, 179,180
overall rates for pipe/cigar smokers and
dose-response relationships, 180-189
overall rates for pipe/cigar smokers vs.
nonsmokers, 179,180
overall rates from cancer in pipe and cigar
smokers, 189
ratio in pipe and cigar smokers by age and
inhalation, 184,187
Mortality rates
CHD in Japanese men and women by
cigarette consumption and age at initia-
tion of habit, 7,8
Myocardial infarct
incidence in European vs. American men,
9
incidence in men in Yugoslavia, 9
incidence in miners in Sardinia, 10
incidence in pipe and cigar smokers, 215
prevalence in smoking vs. nonsmoking
men in Czechoslovakia, 10
and smoking, in patients in Leningrad
hospitals, 10

Nicotine

in cigar, pipe, and cigarette smoke, 177
clinical effects on offsurine. of smoking

mothers, 140,141 - -
in duodenal ulcer induction in cats,
158,159

effect on cardiovascular system in dogs, 17
effect on gastric secretion in cats, 158,159
effect on gastric secretion in rats, 159
effect on heart blood flow in dogs, 17

effect on lactation in laboratory animals,
138,139

effect on lactation in smokers vs. non-
smokers, 139,140
effect on lipid biosynthesis in aorta in
dogs, 17
effect on microcirculation in atrium in
cats, 17

effect on pancreatic secretions in animals,
161,162

effect on pipe/cigar smoke inhalation,
183,184

effect on rat and mouse fetus, site of
action, 121
effects during pregnancy in laboratory
animds,115,116
experimental studies, 16,17
in little cigars compared to cigarettes and
cigars, 223-226,228
in milk of laboratory animals, 138,139
in milk of smoking mothers, J39
as potentiator of duodenal ulcers in ani-
mals, 161-163
Nicotine levels
in blood, new assay method, 15,23
Nicotine secretion
effect of cigar, pipe, and cigarette smoke
in dogs, 216

Nitrogen dioxide
effect on alveolar wall cells in guinea pigs,
50
effect on bacterial retention in hamsters,
  54

effect on rat lung, 49,50
Nitrosamines

effect on lactating hamsters, 139
N-Nitrosamines

determination in cigarette and tobacco
smoke condensate, 87,88

Obesity

as a risk factor for CHD, 9
Occlusive disease
smoking and, 21
Occupation

and smoking, as factor in CHD incidence,
5,7

Occupational diseases

asbestosis, 4 1
bvssinosis. 3941
coal workers pneumoconiosis, 42
Occupational exposure
pancreatic cancer and, 77
and smoking, bladder cancer and, 78
Occupational hazards
asbestos exposure, 41.73
coal dust exposure. 4143
cotton, flax, and hemp dust exposure,
  3941

257


dust exposure, 43,44
100% pure oxygen exposure, 43
radiation exposure in uranium miners, 72
smoking and, 3944
smoking as additive risk for COPD, 55
Oral cancer

alcohol consumption and smoking in etio-
logy of, 193
inhalation patterns and, 191
mortality rates in Japanese male smokers
vs. nonsmokers, 74
mortality ratios for pipe, cigar, and cigar-
ette  smokers vs.  nonsmokers,
191-193

recurrent, incidence in smokers vs. ex-
smokers, 71,74,75
relative risk of development in pipe, cigar,
and cigarette smokers vs. nonsmokers,
191.194.195
reverse smoking and, 76
smoking in etiology of, 74-76
summary of retrospective studies, 194,195
Oxygen debt
effect of smoking, 246,247
exercise performance and, 246,247

Pancreatic cancer
occupational exposure and, 77
smoking and, 77
Pancreatic secretions
bicarbonate content, effect of smoking,
  159,160
effect of nicotine in animals, 161,162
effect of smoking, 159,160
Passive smoking
effect on cardiovascular function in dogs,
  14
Peptic ulcer
see Ulcer, peptic
Perinatal mortality
effect of maternal smoking, summary of
findings, 134,135
Peripheral arteriosclerosis
smoking and, 21
Peripheral vascular disease
smoking and, 19-23
PH
pipe/cigar smoke inhalation and, 183
of smoke in cigarettes, cigars, and Little
cigars, 223,224,228
Phagocytosis
effect of cigarette smoke in laboratory
animals, 5354
Pharyngeal cancer
recurrent, incidence in smokers vs. ex-
smokers, 74,75
Pharyngeal fungi
smokers vs. nonsmokers in South Africa,
  54

258

Phenols

in cigar, pipe, and cigarette smoke, 177
Phenylmethyloxadiazole (PMO)
protection-against adverse effects of cigar-
ette smoke in animals, 49,53
Physical activity
as a factor in coronary heart disease, 4,5
Pipe smokers
relative risk in lung cancer development,
67,68
Pipe smoking
effect on mortality and morbidity com-
pared to cigarette smoking, 171-173
in esophageal  cancer development,
197,200-202

gastrointestinal disorders and, 222
health consequences of, 179
histological effects on bronchial epithe-
bum, 203,204,209
histological effects on esophagus, 200
histological effects on larynx, 197
inhalation patterns and. 184-189
in laryngeal  cancer development,
197-199

in lung cancer development by amount
smoked, 203-206
mortality ratios from cardiovascular di-
seases and, 215,216
mortality ratios from COPD and, 217,219
mortality ratios from laryngeal cancer and,
193,196,197,200
mortality ratios from lung cancer and,
203-205

mortality ratios from oral cancer and,
191,193
oral cancer development and, 193-195
overall mortality rates by amount smoked,
180-182

overall mortality rates from cancer and,
189

prevalence in Great Britain, 173,174
prevalence in United States. 173.174
pulmonary histological changes' and, 217
Pipe tobacco
definition and processing, 176
Plethysmogram
abnormalities, in smokers vs. nonsmokers,
  22

Pneumoconiosis
in coal miners, smokers vs. nonsmokers,
42

Pneumothorax, spontaneous
smoking and, 37

Polycyclic hydrocarbons
binding to DNA and RNA, 86,87
effects during pregnancy in laboratory
animals, 117,118
maternal-fetal exchange and, 119
Post-operative complications
in duodenal ulcer removal, smokers vs.
nonsmokers, 157


smoking, obesity, anesthesia and, 39
Preeclampsia
maternal smoking and, 142
in smoking vs. nonsmoking women, 142
Pregnancy
effect of maternal smoking, 103-142
effect of maternal smoking, mechanism of
action, 119,120
effect of tobacco smoke, nicotine, and
carbon monoxide in laboratory animals,
  114-118

and previous smoking habits, effect on
infant birth weight, 112-l 14
timing of influence of smoking on birth
weight, 120,121
Prematurity
effect of smoking, 112
Pulmonary arterioles
histological effects of pipe/cigar smoking
vs. cigarette smoking, 217
Pulmonary clearance
effect of heavy smoking, 52,53
effect of smoking, 55
mechanical vs. bactericidal clearance in
guinea pigs, 53
mechanism, in smokers vs. nonsmokers,
52.53
in monozygotic vs. dizygotic twins, 51
particle deposition in smokers vs. non-
smokers, 53

Pulmonary diffusing capacity
in smokers vs. nonsmokers in Berlin, New
Hampshire, 50,51
Pulmonary emphysema
see Emphysema

Pulmonary function
in asymptomatic young men in Romania,
39

in coal miners, smokers vs. nonsmokers.
42,43
in coal miners vs. nonminers, 42
effect of asbestos exposure and smoking,
41

effect of coal dust exposure and smoking,
4143

effect of lung hyperinflation in coal mi-
ners, 42,43
effect on exercise performance in smokers
vs. nonsmokers, 246,247
in ex-smokers, 39
in jet fighter pilots, smokers vs. non-
smokers, 43
in pipe/cigar smokers vs. nonsmokers,
217,221

pulmonary hypertension and, 43
in smokers vs. nonsmokers, 55
in smokers vs. nonsmokers in Berlin, New

Hampshire, 50,51
in smokers vs. nonsmokers, under 30 years

smoking and, 38,39
Pulmonary histology
of pipe/cigar smokers vs. cigarette smokers
and nonsmokers, 217
Pulmonary macrophages
effect of smoking, 55
Pulmonary surfactant levels
effect of smoking, 55
Pulmonary tissue
histopathological differences in smokers
vs. nonsmokers, 48,49
Pyrene
m cigar, pipe, and cigarette smoke, 178

Race

as a factor in coronary heart disease,
4,5,23
as a factor in perinatal mortality in smok-
ing vs. nonsmoking mothers, 129-132
as a factor in stillbirth rates, 124,125
Radiation exposure
and smoking, as cause of respiratory can-
cers, 72

Radioactive particles
in tobacco leaf, tobacco smoke, and smo-
kers' lungs, 72
Renal cancer

mortality ratio in Japanese men and wo-
men, smokers vs. nonsmokers, 77
smoking in etiology of, 77,78
Respiratory symptoms
see ulso Cough, Sputum production
effect of asbestos exposure in smokers vs.
nonsmokers, 41
prevalence in Duisburg, Germany by age
and cigarette consumption, 39
prevalence in ex-smokers, 39
prevalence in pipe and cigar smokers,
217,220,221
prevalence in smokers vs. nonsmokers, 55
prevalence in smokers vs. nonsmokers in
Bordeaux, France, 36
in smokers vs. nonsmokers by amount
smoked, 37

Reverse smoking
leukoplakia and, 76
oral cancers and, 76
RNA
binding of polycyclic hydrocarbons to,
86,87
Running
effect of smoking, 243,244

Sex ratio

effect of maternal smoking, 135,136
Single-breath tests

of age, 50                 smokers vs. nonsmokers, 5 1

259


Smoke, cigar

chemical constituents in, 177-179
cihotoxicity, 218
effect of curing methods, 218,219
effect of uH on inhalation of, 183
tumorigenic activity in laboratory animals,
  210-214
Smoke, cigarette
chemical constituents in, compared to
pipe/cigar smoke, 177,178
effect of curing methods. 218,219
effect on bact&al retention in hamsters,
  54
effect on bronchial epithelium in dogs, 49
effect on phagocytosis in laboratory ani-
mals, 53,54
effect on pulmonary clearance, 5 l-53
effect on rat and mouse fetus, site of
action, 121
effect on ventricular fibrillation threshold
in dogs, 13,14
experimental studies in dogs, 13,14
reduction of adverse effects in animals by
phenylmethyloxadiazole (PMO), 49,53
and sulphur dioxide, effect on glands in
laboratory animals, 49
Smoke, little cigar
pH of, compared to cigarette and cigar
smoke, 224,228
Smoke, pipe
chemical constituents in, 177,178
ciliotoxicity of, 218
effect of pH on inhalation of, 183
tumorigenic activity in laboratory animals,
  210-214

Smoke, tobacco

effect on air pollution in aircraft, 45
effect on nonsmokers, in aircraft, 45
effect on stillbirth rate in laboratory ani-
mals, 125
effects during pregnancy in laboratory
animals, 114,115
pH of, effect of leaf constituents, 224
tumorigenic activity, 210-214
Smoking
effect on blood lipids, 11,12
effect on cardiac lactate metabolism, 13
effect on leg blood mean-flow capacity, 22
effect on plasma nicotine levels, 15-17
effect on precapillary sphincters, 22
health hazards of, similarities of cigarettes
with little cigars, 224,225
interaction with other risk factors in CHD,
4-l 1

as most important cause of COPD, 35,36
prevalence in U.S. and Great Britain,
173,174

Smoking abstinence
effect on  exercise performance,
241,242,246,247

Smoking, maternal
as cause of birth of small-for-dates infants,
  106-111

congenital malformations and, 136,137
effect on birth weight, 103-114,119-122
effect on birth weight, summary of fmd.
ings, 122
effect on gestation duration, 103-106
effect on lactation, 138-141
effect on neonatal carboxyhemoglobu,
levels, 118,119
effect on sex ratio, 135,136
effects during pregnancy, 103-142
effects during pregnancy, mechanism of
action, 119,120
indirect association with small-for-dates
infants, 110-l 14
preeclampsia and, 142
selective action on fetus of certain Women
vs. others, 131
spontaneous abortions and, 123,124
stillbirths and, 124,125
timing of influence on birth weight,
120,121

Smoking, paternal
effect on infant birth weight, 110,111
Sputum production
effect of asbestos exposure in smokers vs.
nonsmokers, 41

effect of filtered cigarettes, 55

effect of modified cigarettes, 37,38
effect of plain vs. filtered cigarettes. 37.38
in males by amount smoked and type'of
cigarette, 37,38
prevalence in pipe and cigar smokers,
220,221

Stillbirths

effect of maternal smoking, 124,125
rates in blacks vs. whites, 124,125
in smokers vs. nonsmokers, 124,125
Sudden death

incidence in pipe and cigar smokers, 215
Sulphur dioxide
and cigarette smoke, effect on glands in
laboratory animals, 49
Swimming

effect of smoking, 242,244

Tar content

effect on respiratory symptoms and venti-
latory capacity, 38
Tars

in little cigars, compared to cigarettes and
cigars, 223-226,228
Thrombosis

smoking and, 19
Tobacco

flue-cured vs. air-cured, effect on respira-
tory system in animals, 217,218

260


Tobacco chewing
leukoplakia and, 75
Tobacco leaf extracts
effect on cell cultures,

85.86

Tracheal cancer
smoking and, 7 1
Treadmilt performance
cardiovascular parameters in smokers vs.
nonsmokers, 242-245
effect of vitamin C, 245
oxygen intake in smokers vs. nonsmokers,
  245

Triglyceride levels
CHD and, 8

Tumorigenic activity
of cigar, pipe, and cigarette smoke conden-
sate in skin painting experiments in
animals, 210-214

of tobacco smoke. 210-214

Ulcer, duodenal

mortality ratios in male cigar and pipe
smokers, 222
nicotine induced, in cats, 158,159
post-operative complications in smokers
vs. nonsmokers, 157
potentiating action of nicotine, in animals,
161-163

prevalence in smokers, mechanism of act-
ion, 160
Ulcer, peptic
clinical studies, 155-157
epidemiological studies, 155-157
gastric secretion in smokers vs. nonsmok-
ers, 157,158

increased mortality in Japanese smokers
vs. nonsmokers, 155,156
mortality ratios in Japanese adults by age
at initiation of smoking habit, 155,156
mortality ratios in male cigar and pipe
smokers, 222

predisposing factors, 157
recurrence in smokers vs. nonsmokers, 157
and smoking, summary of previous find-
ings, 155

Urinary bladder cancer
see Bladder cancer

Vascular disease, peripheral
smoking and, 19-23
Vascular reconstruction
effect of smoking, 22.23
Ventilatory function
effect of exercise and smoking, 244,245
Ventricular fibrillation
effect of cigarette smoke in dogs, 13,14
Ventricular hypertrophy
as a risk fat tor in CHD, 8
Vitamin B, z

in pregnant smokers vs. nonsmokers, 119
Vitamin C

effect on treadmill performance in smo-
kers vs. nonsmokers, 245
in milk of smoking mothers, 14 1
in pregnant smokers vs. nonsmokers, 119

Water hardness

and smoking as risk factors in CHD, 9,lO

261